Biology subjects

Lau, B.

Publications and source records attributed to Lau, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Aneuploidy profiling among different types of brain metastases reveals a colon cancer-specific chromosomal signature

Brain metastasis is a significant cause of patient morbidity and mortality. There is increasing evidence that genomic instability features such as aneuploidy are associated with metastases to the brain and other organs. We analyzed the genomic instability of brain metastases among different cancer types. This included brain metastases from non-small cell lung, breast, melanoma and colorectal cancer. Our study identified a significantly higher degree of genomic instability in colorectal brain metastases compared to the other types of brain metastases. Nex, we examined the brain metastases for the types of aneuploidy events, namely chromosomal arm imbalances that involved gains or losses. Colorectal cancer brain metastases had specific chromosomal arm imbalance profiles that included gains of 13q and 20q which were significantly more frequent compared to the other cancer types. We examined other colorectal cancer metastatic sites in the lung, liver, lymph nodes and the primary colon. Examining colorectal cancer metastases more closely, aneuploidy gains across either arms for chromosomes 7 and 16 were also higher among brain metastases compared to liver, lung and lymph node metastases. Overall, this study shows that colorectal cancer brain metastasis has specific aneuploidy profiles different than other cancer types as well as being different among other metastatic organ sites.

cancer biology↗

bioRxiv2026

Intratelencephalic neurons in the medial prefrontal cortex mediate the acquisition of goal-directed actions.

The medial prefrontal cortex (mPFC) and its connections with the posterior dorsomedial striatum are implicated in goal-directed learning, but the specific mPFC cell types involved have not been clearly established. The current study investigated mPFC intratelencephalic (IT) and pyramidal tract (PT) neuron involvement in goal-directed learning. In Cre-driver mouse lines, we mapped bilaterally projecting IT neurons and unilaterally projecting PT neurons from mPFC to dorsal striatum and showed that chemogenetic inhibition of IT, but not PT neurons, attenuated goal-directed learning. We then demonstrated training induced elevations in pERK signaling in IT neurons, which were transient in superficial mPFC layers, and more persistent in deeper layers. This was associated with plasticity in deep layer IT neurons, reflected in a shift towards excitatory over inhibitory synaptic inputs. Together, these data suggest that goal-directed learning influences synaptic input and downstream plasticity markers in mPFC IT neurons, and this functionally contributes to goal-directed learning.

neuroscience↗

bioRxiv2026

Tumor extracellular vesicle RNA profiling predicts treatment response in pediatric diffuse midline glioma

Detection of reliable markers of therapy response and drug resistance remains a major unmet need in brain cancer, as serial tumor biopsy is often not feasible. This challenge is particularly acute in diffuse midline glioma (DMG), a fatal pediatric brain tumor for which new targeted therapies are entering clinical use, yet tools for real-time molecular analysis of tumor evolution during therapy remain lacking. Here, we demonstrate that plasma tumor-derived extracellular vesicle (EV) profiling provides a minimally invasive and complementary approach for diagnosis and longitudinal molecular monitoring in H3K27M-mutant DMG. Across patient-derived tumor models and clinical plasma samples, EV mRNA levels correlated strongly with parental tumor transcriptomes. EV H3K27M mRNA enabled discrimination of DMG from non-DMG controls, and exploratory EV response-associated mRNAs were linked to radiographic response and progression-free survival in patients receiving ONC201. To enable tumor-selective EV enrichment and multiplexed molecular profiling within a clinically practical workflow, we developed a new integrated platform supporting same-day EV analysis from small plasma volumes. This work represents the first proof-of-concept demonstration of the diagnostic and treatment response relevance of tumor-derived EV RNA in pediatric DMG and establishes a generalizable framework for minimally invasive longitudinal molecular monitoring in diseases where tissue access is inherently limited.

cancer biology↗

bioRxiv2026

Visual Cortical Response Variability in Infants at High Familial Likelihood for Autism

Visual processing undergoes rapid development in the first year of life, supporting the emergence of higher-order cognitive, language, and motor functions. Visual evoked potentials (VEPs) provide a non-invasive measure of visual system maturation that may shed light on heterogeneous developmental trajectories among infants at high familial likelihood for autism. Infants with an older sibling with autism spectrum disorder (N = 177 at 6 months; N = 132 at 12 months) participated in the Infant Brain Imaging Study-Early Prediction (IBIS-EP) study. Pattern-reversal VEPs were recorded at 6 and 12 months, and developmental skills were assessed at 24 months using the Bayley Scales of Infant and Toddler Development (Bayley-4). VEP components (P1 and N1) were characterized by their amplitude and latency, as well as trial-to-trial variability in these measures. Associations with 24-month cognitive, language, and motor scores were examined using general linear models controlling for age, site, sex, and trial count. Robust VEPs were observed at both time points, with age-appropriate morphology and expected developmental changes, including decreases in P1 latency and amplitude from 6 to 12 months. Greater trial-to-trial variability in P1 latency at both time points was associated with higher cognitive and language scores at 24 months. In contrast, conventional measures of mean P1 latency and amplitude were not associated with developmental outcomes. These findings suggest that temporal variability in early visual responses may index adaptive sensory-circuit flexibility during a period of rapid experience-dependent development. VEP response-timing variability may therefore provide an early mechanistic marker of sensory-circuit organization relevant to later developmental trajectories. Research HighlightsO_LIGreater trial-to-trial variability in visual cortical response timing was associated with higher cognitive and language scores in infants at high familial likelihood for autism. C_LIO_LIConventional average VEP measures were unrelated to outcomes, suggesting temporal variability may more sensitively capture relevant neural-circuit differences in this population. C_LIO_LIGreater variability in early visual responses may reflect adaptive sensory-circuit flexibility during a critical period of neurodevelopment. C_LIO_LIVEP response-timing measures provide an early mechanistic window into sensory-circuit organization and its relation to later developmental trajectories. C_LI

neuroscience↗

bioRxiv2026

Body-segment coordination as a new predictor of freezing of gait in people with Parkinson disease

Freezing of gait (FOG) in Parkinsons disease (PD) involves impaired integration of posture and locomotion with altered body-segment coordination. We measured coordination using gait kinematics during walking in 16 PD patients with FOG, preoperatively with and without dopaminergic medication (OFF/ON-DOPA), and postoperatively with and without subthalamic deep brain stimulation (OFF/ON-DBS). Body-segment coordination was modeled from acceleration-based intersegmental correlations across trunk, pelvis, and limbs. We tested whether coordination metrics predict individual postoperative FOG severity using LASSO regression with nested cross-validation, including preoperative demographics, clinical scores, gait and coordination metrics. Preoperatively, DOPA decreased trunk-pelvis-upper-limb coordination but increased crossed upper-lower-limbs coupling; while STN-DBS selectively increased inter-upper-limb coordination, with DOPA- and STN-DBS-induced changes being correlated. Whole-body coordination predicted individual postoperative FOG severity, with the most important couplings being the trunk-pelvis and pelvis-lower-limb. Body-segment coordination captures clinically relevant gait metrics in PD, highlighting coordination as a potential biomarker for patient stratification and treatment response.

neuroscience↗

bioRxiv2026

Distinct roles of the human cuneiform and pedunculopontine nuclei in gait initiation and freezing of gait

Freezing of gait in Parkinsons disease (PD) is a major cause of disability, often resistant to dopaminergic therapy and deep brain stimulation (DBS). Its underlying mechanisms remain unclear, mainly because the roles of the human mesencephalic locomotor region (MLR) nuclei are not well understood. Here, we combined rare local field potentials (LFP) recordings from the cuneiform (CuN) and pedunculopontine nuclei (PPN) with biomechanical markers of gait initiation (GI) in four PD patients. We identified functional differences: increases in CuN alpha-band activity precede anticipatory postural adjustments (APA) and correlate with the rhythm of upcoming steps, whereas decreases in PPN beta-band activity occur during APA just before the lead foot lifts off. Imminent freezing is characterized by a breakdown of this organization, marked by mistimed alpha-band surges across the MLR and abnormal PPN beta-band modulation. CuN stimulation selectively improved the stepping rhythm, while PPN stimulation worsened pace or forward vigor. Furthermore, exaggerated mesencephalic alpha-band power was associated with poor clinical responses. These results clarify the individual roles of MLR nuclei in human locomotion and identify pathological alpha dynamics as a biomarker for advancing adaptive neurostimulation.

neuroscience↗

bioRxiv2025

Motor cortical beta power reflects adaptation to task constraints

The amplitude of beta-band activity ({beta} power; 13-30 Hz) over motor cortical regions is used to assess and decode movement in clinical settings and brain-computer interfaces, as {beta} power is often assumed to predict the strength of the brains motor output, or "vigor". However, recent conflicting evidence challenges this assumption and underscores the need to clarify the relationship between {beta} power and movement. In this study, sixty participants were trained to self-regulate {beta} power using electroencephalography-based neurofeedback before performing different motor tasks. Results showed that {beta} power modulations can impact different motor variables, or the same variables in opposite directions, depending on task constraints. Importantly, downregulation of {beta} power was associated with better task performance regardless of whether performance implied increasing or decreasing motor vigor. These findings demonstrate that {beta} power should be interpreted as a measure of motor flexibility, which underlies adaptation to environmental constraints, rather than vigor.

neuroscience↗

bioRxiv2025

Subthalamic Signature of Freezing of Gait in Parkinson Disease

Freezing of gait (FOG) is a significant disability in Parkinsons disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) only partially alleviates it, with approximately one-third of patients experiencing worsening FOG within a year after surgery. The precise role of STN dysfunction in gait disabilities and FOG remains not fully elucidated. To investigate this, we recorded gait and STN local field potential (LFP) activity in 38 PD patients, both Off and On dopamine medication. Our analysis focused on the relationship between gait performance and STN neuronal activity, particularly examining differences in LFP activity across the posterior-sensorimotor and central-associative regions of the STN. When Off dopamine medication, 12 patients experienced FOG during recordings, with a total of 263 FOG episodes documented. Even in trials without FOG episodes, these patients exhibited altered gait initiation strategies, prioritizing stepping rhythm to manage balance and initiate walking. In contrast, non-FOG patients maintained a higher walking pace. STN activity patterns revealed key differences. In FOG patients, weaker STN alpha/low beta band activity in the STN was associated with walking pace, while stronger decreased low beta band activity correlated with rhythm and balance control. This low beta band association extended from the posterior-sensorimotor to the central-associative STN. In contrast, non-FOG patients showed a more restricted relationship between low beta band activity and gait performance, confined to the posterior STN. As stepping rhythm deteriorated further in FOG patients, FOG episodes occurred. FOG episodes were preceeded by a significant positive relationship between high beta power and rhythm restricted to the posterior STN, with a reverse negative relationship with pace, and a disruption in low beta desynchronization across both posterior and central STN regions. Dopamine medication significantly improved gait patterns, and partially restored STN neuronal activity, reducing differences between FOG and non-FOG patients. These findings differentiate two FOG states, i.e. predisposition and occurrence, each associated with distinct gait initiation strategies and STN activity patterns. They suggest distinct pathophysiological roles of low and high beta band STN activity within specific STN regions in regulating gait and FOG. These findings provide key insights for refining targeted DBS therapies.

neuroscience↗

bioRxiv2024

Effectiveness of FLASH vs conventional dose rate radiotherapy in a model of orthotopic, murine breast cancer

PurposeRadiotherapy is an effective breast cancer treatment that enhances local tumor control and prolongs overall survival yet is associated with undesirable side effects which can impair quality of life. Ultra-high dose rate radiotherapy (FLASH) has been shown to induce less normal tissue toxicity while producing comparable tumor growth delay in a variety of preclinical tumor models when compared with conventional dose rate radiotherapy (CONV). However, growth delay is not a surrogate for tumor eradication, which is a critical endpoint of cancer therapy, and studies using FLASH in breast cancer are limited. We sought to evaluate whether FLASH produced comparable tumor control to CONV in a breast cancer model with tumor eradication as the primary endpoint. Methods and Materials106 cells from the radiation sensitive mammary tumor cell line Py117 were used to create non-metastatic, syngeneic, orthotopic tumors in the left 4th mammary fat pad of C57BL/6J mice (n=67). Tumors were established for two distinct sequential irradiation studies (Rounds 1 and 2), utilizing either large (7.5 mm into the body) or small (5 mm) treatment tumor margins, respectively. For Round 1, mice were divided into groups with either small (20-40 mm3) or large (250-800 mm3) tumors, whereas only small tumors were included in Round 2. Tumors were irradiated with FLASH (93, 192 and 200 Gy/s) or CONV (0.08 Gy/s) using 16.6 MeV FLASH and 15.7 MeV CONV electron beams. Mice in the small tumor cohort were treated with single fractions of 20, 25, or 30 Gy. The larger tumors were treated with a single fraction of 30 Gy. Tumor eradication was determined by palpation and with histology as needed to clarify physical findings. ResultsSingle fractions of FLASH and CONV demonstrated comparable treatment responses within matched cohorts of small and large tumors. A portion of small tumors treated with single fractions of 20 or 25 Gy were eradicated though most regrew within 2 to 3 weeks. Eradication of small tumors was best seen treated with 30 Gy and a large treatment tumor margin. These mice had no tumor regrowth at 30 days with either FLASH or CONV: however, euthanasia criteria were met at the 30-day time point due to concerns over skin toxicity for both FLASH and CONV groups. Small tumors treated with 30 Gy and a smaller treatment tumor margin had less skin toxicity with 75% of mice remaining tumor free at 48 days. 30 Gy FLASH and CONV applied to larger tumors demonstrated growth delay equally with a partial reduction in size but without tumor eradication. ConclusionsFLASH and CONV produced comparable tumor control in this model of orthotopic, murine breast tumors. Single fractions of 30 Gy with both FLASH and CONV applied to small tumors achieved the highest rates of tumor eradication in particular when delivered with a wider treatment margin. Skin toxicity seen at this dose and in this location could be ameliorated with the use of multiple fractions or different tangents in future studies. Efforts at eradicating larger tumors would require testing higher single fraction doses, multiple fractions, and/or hypofractionated treatment regimens. The equivalent effectiveness between FLASH and CONV in this study of murine breast tumors supports ongoing evaluation of FLASH for use in treating human breast cancer. To this end future efforts at tumor eradication with single fraction FLASH doses with comprehensive evaluation of the toxicity of organs at risk as compared to CONV will be necessary. Additionally, studies of dose-response in a range of tumor volumes with additional breast cancer cell lines and tumors, including human xenografts, along with refined target margins, will guide future studies into the use of FLASH in the adjuvant therapy of primary human breast cancer.

cancer biology↗

bioRxiv2024

Rapid Sterilization of Clinical Apheresis Blood Products using Ultra-High Dose Rate Radiation

BACKGROUND AND OBJECTIVESApheresis platelets products and plasma are essential for medical interventions, but both still have inherent risks associated with contamination and viral transmission. Platelet products are vulnerable to bacterial contamination due to storage conditions, while plasma requires extensive screening to minimize virus transmission risks. Here we investigate rapid irradiation to sterilizing doses for bacteria and viruses as an innovative pathogen reduction technology. MATERIALS AND METHODSWe configured a clinical linear accelerator to deliver ultra-high dose rate (6 kGy/min) irradiation to platelet and plasma blood components. Platelet aliquots spiked with 105 CFU of E.coli were irradiated with 0.1-20 kGy, followed by E.coli growth and platelet count assays. COVID Convalescent Plasma (CCP) aliquots were irradiated at a virus-sterilizing dose of 25 kGy and subsequently, RBD- specific antibody binding was assessed. RESULTS1 kGy irradiation of bacteria-spiked platelets reduced E.coli growth by 2.7- log without significant change of platelet count, and 5 kGy or higher produced complete growth suppression. The estimated sterilization (6-log bacterial reduction) dose was 2.3 kGy, corresponding to 31% platelet count reduction. A 25 kGy virus sterilizing dose to CCP produced a 9.2% average drop of RBD-specific IgG binding. CONCLUSIONThis study shows proof-of-concept of a novel rapid blood sterilization technique using a clinical linear accelerator. Promising platelet counts and CCP antibody binding were maintained at bacteria and virus sterilizing doses, respectively. This represents a potential point-of-care blood product sterilization solution. If additional studies corroborate these findings, this may be a practical method for ensuring blood products safety. HIGHLIGHTSO_LI1 kGy irradiation of bacteria-spiked platelets reduced E.coli growth by 2.7-log without significant change of platelet count, and 5 kGy or higher produced complete growth suppression. C_LIO_LIThe estimated sterilization (6-log bacterial reduction) dose was 2.3 kGy, corresponding to 31% platelet count reduction. C_LIO_LIA 25 kGy virus sterilizing dose to CCP produced a 9.2% average drop of RBD- specific IgG binding. C_LI

microbiology↗

bioRxiv2024

H/ACA snoRNP guides ribosomal RNA subdomain folding in a satellite particle before joining the core 90S pre-ribosome

During synthesis, modification and maturation of the ribosomal RNA, correct subdomain folding without additional guidance poses a major challenge. An essential H/ACA snoRNP, snR30, was observed to be outsourced from the core of the 90S, the earliest known pre-ribosome, to form a "satellite particle". This particle interacts with the so-called 18S rRNA platform subdomain, guiding its independent folding through localized structural interactions. Once this subdomain achieves its proper conformation, it is integrated into the core pre-ribosome, contributing to the overall maturation of the 18S rRNA. By temporarily segregating the folding process within a specialized satellite particle, the correct assembly of individual components is facilitated, thereby reducing the risk of errors during the complex process of ribosome assembly. In a broader sense, molecular outsourcing in cellular processes, where transient subcomplexes handle specific tasks before rejoining the main assembly line, can enhance efficiency and accuracy of complex molecular processes like ribosome biogenesis.

biochemistry↗

bioRxiv2024

GABA production induced by imipridones is a targetable and imageable metabolic alteration in diffuse midline gliomas

Diffuse midline gliomas (DMGs) are lethal primary brain tumors in children. The imipridones ONC201 and ONC206 induce mitochondrial dysfunction and have emerged as promising therapies for DMG patients. However, efficacy as monotherapy is limited, identifying a need for strategies that enhance response. Another hurdle is the lack of biomarkers that report on drug-target engagement at an early timepoint after treatment onset. Here, using 1H-magnetic resonance spectroscopy, which is a non-invasive method of quantifying metabolite pool sizes, we show that accumulation of {psi}-aminobutyric acid (GABA) is an early metabolic biomarker that can be detected within a week of ONC206 treatment, when anatomical alterations are absent, in mice bearing orthotopic xenografts. Mechanistically, imipridones activate the mitochondrial protease ClpP and upregulate the stress-responsive transcription factor ATF4. ATF4, in turn, upregulates glutamate decarboxylase, which synthesizes GABA, and downregulates ABAT, which degrades GABA, leading to GABA accumulation in DMG cells and tumors. Functionally, GABA secreted by imipridone-treated cells acts in an autocrine manner via the GABAB receptor to induce expression of superoxide dismutase (SOD1), which mitigates imipridone-induced oxidative stress and, thereby, curbs apoptosis. Importantly, blocking autocrine GABA signaling using the clinical stage GABAB receptor antagonist SGS-742 exacerbates oxidative stress and synergistically induces apoptosis in combination with imipridones in DMG cells and orthotopic tumor xenografts. Collectively, we identify GABA as a unique metabolic adaptation to imipridones that can be leveraged for non-invasive assessment of drug-target engagement and therapy. Clinical translation of our studies has the potential to enable precision metabolic therapy and imaging for DMG patients. One Sentence SummaryImipridones induce GABA accumulation in diffuse midline gliomas, an effect that can be leveraged for therapy and non-invasive imaging.

cancer biology↗

bioRxiv2024

Agency accounts for the effect of FB transparency onmotor imagery neurofeedback performance

ObjectiveNeurofeedback (NF) is a cognitive training procedure based on real-time feedback (FB) of a participants brain activity that they must learn to self-regulate. A classical visual FB delivered in a NF task is a filling gauge reflecting a measure of brain activity. This abstract visual FB is not transparently linked--from the subjects perspective--to the task performed (e.g., motor imagery). This may decrease the sense of agency, that is, the participants reported control over FB. Here, we assessed the influence of FB transparency on NF performance and the role of agency in this relationship. ApproachParticipants performed a NF task using motor imagery to regulate brain activity measured using electroencephalography. In separate blocks, participants experienced three different conditions designed to vary transparency: FB was presented as either 1) a swinging pendulum, 2) a clenching virtual hand, 3) a clenching virtual hand combined with a motor illusion induced by tendon vibration. We measured self-reported agency and user experience after each NF block. Main resultsWe found that FB transparency influences NF performance. Transparent visual FB provided by the virtual hand resulted in significantly better NF performance than the abstract FB of the pendulum. Surprisingly, adding a motor illusion to the virtual hand significantly decreased performance relative to the virtual hand alone. When introduced in incremental linear mixed effect models, self-reported agency was significantly associated with NF performance and it captured the variance related to the effect of FB transparency on NF performance. SignificanceOur results highlight the relevance of transparent FB in relation to the sense of agency. This is likely an important consideration in designing FB to improve NF performance and learning outcomes.

neuroscience↗

bioRxiv2024

Inhibitory control of gait initiation in humans: an electroencephalography study

Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event-related potential [ERP] and time-frequency data) during a modified Go/NoGo gait initiation task in 23 healthy adults. The task comprised Go-certain, Go-uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go-uncertainty resulted in delayed reaction time (RT), without any difference for the other parameters of gait initiation. Proactive inhibition, i.e. Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito-parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative--Go-uncertain versus Go-certain and NoGo versus Go-uncertain--stimuli. These findings demonstrate that the uncertainty context induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time-frequency activities. This study shows protracted influence of inhibitory control in gait initiation.

neuroscience↗

bioRxiv2023

ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways

Human cytomegalovirus (HCMV) is a major human pathogen whose life-long persistence is enabled by its remarkable capacity to systematically subvert host immune defences. In exploring the finding that HCMV infection upregulates tumor necrosis factor receptor 2 (TNFR2), a ligand for the pro-inflammatory anti-viral cytokine TNFa, we discovered the underlying mechanism was due to targeting of the protease, A Disintegrin And Metalloproteinase 17 (ADAM17). ADAM17 is the prototype sheddase, a family of proteases that cleaves other membrane-bound proteins to release biologically active ectodomains into the supernatant. HCMV impaired ADAM17 surface expression through the action of two virally-encoded proteins in its UL/b region, UL148 and UL148D. Proteomic plasma membrane profiling of cells infected with a HCMV double deletion mutant for UL148 and UL148D with restored ADAM17 expression, combined with ADAM17 functional blockade, showed that HCMV stabilized the surface expression of 114 proteins (p<0.05) in an ADAM17-dependent fashion. These included known substrates of ADAM17 with established immunological functions such as TNFR2 and Jagged1, but also numerous novel host and viral targets, such as Nectin1, UL8 and UL144. Regulation of TNF-induced cytokine responses and NK inhibition during HCMV infection were dependent on this impairment of ADAM17. We therefore identify a viral immunoregulatory mechanism in which targeting a single sheddase enables broad regulation of multiple critical surface receptors, revealing a paradigm for viral-encoded immunomodulation. Significance statementHuman cytomegalovirus (HCMV) is an important pathogen, being the commonest infectious cause of brain damage to babies and the primary reason for hospital readmissions in transplant recipients. Even though HCMV induces the strongest immune responses by any human pathogen, it evades host defences and persists for life. This study describes a novel immunoregulatory strategy through which HCMV modulates multiple immune pathways simultaneously, by targeting a single host protein. HCMV UL148 and UL148D impair the maturation of the sheddase, A Disintegrin And Metalloproteinase 17, profoundly altering surface expression of numerous immunoregulatory proteins. This is the first description of viral genes targeting this pathway. Our findings may be relevant for future viral therapies and understanding the impact of HCMV in developmental biology.

microbiology↗

bioRxiv2023

Single cell and spatial alternative splicing analysis with long read sequencing

Long-read sequencing has become a powerful tool for alternative splicing analysis. However, technical and computational challenges have limited our ability to explore alternative splicing at single cell and spatial resolution. The higher sequencing error of long reads, especially high indel rates, have limited the accuracy of cell barcode and unique molecular identifier (UMI) recovery. Read truncation and mapping errors, the latter exacerbated by the higher sequencing error rates, can cause the false detection of spurious new isoforms. Downstream, there is yet no rigorous statistical framework to quantify splicing variation within and between cells/spots. In light of these challenges, we developed Longcell, a statistical framework and computational pipeline for accurate isoform quantification for single cell and spatial spot barcoded long read sequencing data. Longcell performs computationally efficient cell/spot barcode extraction, UMI recovery, and UMI-based truncation- and mapping-error correction. Through a statistical model that accounts for varying read coverage across cells/spots, Longcell rigorously quantifies the level of inter-cell/spot versus intra-cell/ spot diversity in exon-usage and detects changes in splicing distributions between cell populations. Applying Longcell to single cell long-read data from multiple contexts, we found that intra-cell splicing heterogeneity, where multiple isoforms co-exist within the same cell, is ubiquitous for highly expressed genes. On matched single cell and Visium long read sequencing for a tissue of colorectal cancer metastasis to the liver, Longcell found concordant signals between the two data modalities. Finally, on a perturbation experiment for 9 splicing factors, Longcell identified regulatory targets that are validated by targeted sequencing.

bioinformatics↗

bioRxiv2023

Deep brain stimulation and dopamine medication enhance free choice preference in Parkinson's disease

BackgroundHumans prefer making choices freely, even when they dont maximize future outcomes, suggesting free-choice is intrinsically rewarding. However, whether reward-related brain networks influence choice preference remains unclear. In Parkinsons disease (PD), value-based decision impairments are well-documented, but mechanisms underlying intrinsically motivated behavior are poorly understood. This study investigates how the dopaminergic and basal ganglia systems encode intrinsic reward in PD. MethodsWe designed a decision-making task dissociating free-choices intrinsic value from extrinsic reward. Twenty PD patients with subthalamic deep brain stimulation (STN-DBS) and twentyfive on dopamine (DA) therapy performed the task ON and OFF their treatments. Their performances were compared to twenty age-matched healthy controls. To explore neural mechanisms, we analyzed DBS active contacts, modeled the volume of tissue activated, and examined cortico-subthalamic connectivity using high-resolution diffusion MRI. ResultsPD patients OFF STN-DBS exhibited reduced free-choice preference, which increased when STN-DBS was ON, particularly in risky choices. This effect correlated with the recruitment of the right medial prefrontal cortex (mPFC). DA therapy did not modulate free-choice preference acutely, but higher chronic DA levels correlated with increased free-choice preference. ConclusionsOur findings suggest STN-DBS enhances free-choice preference via the right mPFC-STN network, while chronic DA therapy amplifies free-choice sensitivity. This implies that freechoice preference is influenced by mPFC modulation, increasing impulsivity toward risky choices, and dopamines role in enhancing sensitivity to both extrinsic and intrinsic rewards.

neuroscience↗

bioRxiv2022

Application of a Latent Trait Modeling Method for Missing Data Across Datasets: Guidance on Appropriate Factor Structure

Latent trait space can be leveraged to harmonize small data into big data when the constituent datasets measure the same underlying (latent) domains using a set of partially overlapping measurement instruments in each domain. The latent trait space then acts as a common metric space for each dataset, thus ensuring the same scale for the latent traits across datasets, despite the use of non-identical sets of measurement instruments within datasets. This approach, as originally published, only applied to a narrow set of circumstances, namely, that each measurement instrument occurred in more than one dataset. Here, we extend the latent trait approach to drop this requirement by using matrix completion methods. Using a simulation study, we evaluate the reliability of this extension and offer guidance on circumstances when the latent trait approach to missing data is robust and practical on real datasets.

bioinformatics↗