Biology subjects

Khoo, H. M.

Publications and source records attributed to Khoo, H. M..

10 recordsLinked to original sources

bioRxiv2026

Ripples precede insight in the right human hippocampus

Insight is a sudden transition from uncertainty to awareness of a solution, often preceded by non-conscious processing. Despite the ubiquity of insights in human cognition, the neural mechanisms underlying this pre-conscious restructuring phase remain largely unknown. Recent theoretical frameworks suggest that the hippocampus, through its capacity for rapid associative retrieval and flexible recombination of stored representations, may facilitate the non-conscious exploration that precedes insight. Hippocampal ripples associated with memory replay and consolidation, represent a promising candidate mechanism for this process. We recorded intracranial local field potentials from depth electrodes in the hippocampus of ten patients with drug-resistant epilepsy while they performed non-verbal reasoning tasks. Participants indicated the moment of solution awareness via button press, enabling precise temporal alignment of neural activity to subjective insight. We observed a significant increase in ripple rate during a pre-response window. Critically, this effect was lateralized to the right hippocampus. These findings provide the first direct human electrophysiological evidence linking right-lateralized hippocampal ripples to the non-conscious phase of insight. We propose that right hippocampal ripples support rapid retrieval and flexible recombination of representations, potentially triggering cortical processes that culminate in conscious solution awareness.

neuroscience↗

bioRxiv2025

Inhibition of MLLT1 limits growth of MLL-AF4 leukaemias without killing healthy haematopoietic stem cells

A major challenge in cancer therapeutics has been the identification of targets that are selectively toxic to cancer cells while displaying limited effects on healthy counterparts. Toxicities related to blood production from haematopoietic stem and progenitor cells (HSPCs) can be particularly problematic and result in patient morbidity and mortality. Within haematological malignancies, therapy response rates and patient survival vary widely between cancer subtypes, with leukaemias driven by the MLL-AF4 fusion protein associated with poor prognosis. MLLT1 has been recently identified as a key potential target in acute myeloid leukaemia. Here we evaluated a panel of leukaemia cell lines and healthy HSPCs for their sensitivity to the MLLT1 inhibitor SGC-iMLLT. We found that SGC-iMLLT strongly inhibited MLL-AF4-driven leukaemia growth in vitro and in vivo. By contrast, SGC-iMLLT did not alter in vitro colony forming potential of human HSPCs or affect long-term in vivo function of mouse HSPCs. These results suggest that SGC-iMLLT may have a promising therapeutic window in the treatment of MLL-AF4-driven leukaemias, and that further clinical development is warranted.

cancer biology↗

bioRxiv2024

Image retrieval based on closed-loop visual-semantic neural decoding

Neural decoding via the latent space of deep neural network models can infer perceived and imagined images from neural activities, even when the image is novel for the subject and decoder. Brain-computer interfaces (BCIs) using the latent space enable a subject to retrieve intended image from a large dataset on the basis of their neural activities but have not yet been realized. Here, we used neural decoding in a closed-loop condition to retrieve images of the instructed categories from 2.3 million images on the basis of the latent vector inferred from electrocorticographic signals of visual cortices. Using a latent space of contrastive language-image pretraining (CLIP) model, two subjects retrieved images with significant accuracy exceeding 80% for two instructions. In contrast, the image retrieval failed using the latent space of another model, AlexNet. In another task to imagine an image while viewing a different image, the imagery made the inferred latent vector significantly closer to the vector of the imagined category in the CLIP latent space but significantly further away in the AlexNet latent space, although the same electrocorticographic signals from nine subjects were decoded. Humans can retrieve the intended information via a closed-loop BCI with an appropriate latent space.

neuroscience↗

bioRxiv2024

Hypoxia-Inducible Factor-1 activated by PIM1 assembles a non-canonical transcription complex and resultant regulon that drives progression of JAK2V617F myeloproliferative neoplasms

Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival under limited oxygen (hypoxia) and frequently activated within malignancy. Malignant context affects the role of HIFs within oncogenesis; however, the mechanisms regulating HIF context-specificities are not well characterised. Applying the JAK2V617F (JVF) model of myeloproliferative neoplasms (MPNs), in which HIF-1 is active in normoxia (20% O2), we sought to determine whether the modality of HIF-1 activation directs its function. We identify that HIF-1 is stabilised in JVF cells downstream of STAT1/5 signalling and upregulation of PIM1: PIM1 mediates phosphorylation of HIF-1 (Thr498/Ser500) in JVF cells that inhibits proteasomal degradation. PIM1 inhibition eradicates HIF-1 from JVF cells. Applying a single-input dual-omics output chromatin interactome methodology (DOCIA), we define JVF-specific transcription cofactors and genomic redistribution of HIF-1, and a JVF-HIF-1 regulon in primary haematopoietic stem/progenitor cells. In a cohort of 172 JVF-MPN patients, we observe significant association of the JVF-HIF-1 regulon (but strikingly, not canonical HIF-1 genes) with disease severity, progression, and patient survival. Finally, we identify a core set of JVF-HIF-1 targets significantly associated with spontaneous transformation of MPNs to AML. Our findings identify that HIF-1 activation by the JVF-PIM1 axis substantially alters its function, and that this reprogramming drives MPN disease progression, restoring the potential for targeted therapies that delineate HIF-1 activity co-opted by malignancy from essential roles within physiological oxygen homeostasis. Key PointsO_LIHIF-1 activation via PIM1 in JAK2V617F-MPNs drives non-canonical transcription complex formation/function. C_LIO_LIThe JAK2V617F-HIF-1 regulon drives MPN disease progression, transformation to AML and worse patient outcomes. C_LI

cancer biology↗

bioRxiv2023

Hippocampal sharp-wave ripples correlate with naturally occurring self-generated thoughts in humans

Core features of human cognition, for example, the experience of mind wandering, highlight the importance of the capacity to focus on information separate from the here and now. However, the brain mechanisms that underpin these self-generated states remain unclear. An emerging hypothesis is that self-generated states depend on the process of memory replay, which, in animals, is linked to sharp-wave ripples (SWRs) originating in the hippocampus. SWRs are transient high-frequency oscillations that exhibit circadian fluctuations and, in the laboratory, are important for memory and planning. Local field potentials were recorded from the hippocampus of 11 patients with epilepsy for up to 15 days, and experience sampling was used to describe their association with ongoing thought patterns. SWRs were correlated with patterns of vivid, intrusive ongoing thoughts unrelated to the task being performed, establishing their contribution to the ongoing thoughts that humans experience in daily life.

neuroscience↗

bioRxiv2022

Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging

The biological mechanisms that sustain the vast blood production required for healthy life remain incompletely understood. To search for novel regulators of hematopoiesis, we performed genome-wide in vivo hematopoietic stem cell (HSC)-based CRISPR knockout screens for regulators of hematopoiesis. We discovered SAGA complex members, including Tada2b and Taf5l, as key regulators of hematopoiesis. Loss of Tada2b or Taf5l strongly inhibited hematopoiesis in vivo, led to a buildup of immature hematopoietic cells in the bone marrow, and was associated with upregulation of interferon pathway genes. Loss of these factors also enhanced the cell outgrowth and the interferon pathway in an in vivo human myelodysplastic syndrome model, suggesting that loss of SAGA complex activity could contribute to hematological disease progression. In summary, this study has identified the SAGA complex as an important regulator of hematopoiesis.

genetics↗

bioRxiv2021

Frequency band coupling with high-frequency activities during seizures shifts from θ band in tonic phase to δ band in clonic phase

ObjectiveTo clarify variations in the relationship between high-frequency activities (HFAs) and low-frequency bands from the tonic to the clonic phase in focal to bilateral tonic-clonic seizures (FBTCS), using phase-amplitude coupling. MethodsThis retrospective study enrolled six patients with drug-resistant focal epilepsy who underwent intracranial electrode placement for presurgical invasive electroencephalography at Osaka University Hospital (July 2018-July 2019). We used intracranial electrodes to record seizures in focal epilepsy (11 FBTCS). The magnitude of synchronization index (SIm) and receiver-operating characteristic (ROC) analysis were used to analyze the coupling between HFA amplitude (80-250 Hz) and lower frequencies phase. ResultsThe {theta} (4-8 Hz)-HFA SIm peaked in the tonic phase, whereas the {delta} (2-4 Hz)-HFA SIm peaked in the clonic phase. ROC analysis indicated that the {delta}-HFA SIm discriminated well the clonic from the tonic phase. ConclusionsThe main low-frequency band modulating the HFA shifted from the {theta} band in the tonic phase to the {delta} band in the clonic phase. SignificanceIn FBTCS, low-frequency band coupling with HFA amplitude varies temporally. Especially, the {delta} band is specific to the clonic phase. These results suggest dynamically neurophysiological changes in the thalamus or basal ganglia throughout FBTCS. HighlightsO_LIThe {theta} band (4-8 Hz) was mainly coupled with high-frequency activity (HFA) in the tonic phase of focal to bilateral tonic-clonic seizures (FBTCS). C_LIO_LIThe {delta} band (2-4 Hz) was mainly coupled with HFA in the clonic phase of FBTCS. C_LIO_LIThe magnitude of the synchronization index related to {delta}-HFA phase-amplitude coupling discriminated well the clonic from the tonic phase. C_LI

physiology↗

bioRxiv2020

Swallowing-related neural oscillation: An intracranial EEG study

Swallowing is a unique movement due to the indispensable orchestration of voluntary and involuntary movement. The transition from voluntary to involuntary swallowing is executed on the order of milliseconds. We hypothesized that its neural mechanism is revealed by high frequency cortical activities. Eight epileptic participants fitted with intracranial electrodes over the orofacial cortex were asked to swallow a water bolus, and cortical oscillatory changes, including high {gamma} band (75-150 Hz) and {beta} band (13-30 Hz) were investigated at the time of mouth-opening, water-injection, and swallowing. High {gamma} power increases associated with mouth-opening were observed in the ventrolateral prefrontal cortex with water-injection in the lateral central sulcus and with swallowing in the region along the Sylvian fissure. Mouth-opening induced a {beta} power decrease, which continued until the completion of swallowing. The high {gamma} burst activity was focal and specific to swallowing, however, the {beta} activities were extensive and not specific to swallowing. At the boundary time between voluntary and involuntary swallowing, swallowing-related high {gamma} power achieved the peak, and subsequently, the power decreased. We demonstrated three distinct activities related to mouth-opening, water-injection, and swallowing induced at different timings, using high {gamma} activities. The peak of high {gamma} power related to swallowing suggests that during voluntary swallowing phases, the cortex is the main driving force for swallowing rather than the brain stem.

neuroscience↗

bioRxiv2020

Visualization of Phase-Amplitude Coupling Using Rhythmic High-Frequency Activity

ObjectiveHigh-frequency activities (HFAs) and phase-amplitude coupling (PAC) are gaining attention as key neurophysiological biomarkers for studying human epilepsy. We aimed to clarify and visualize how HFAs are modulated by the phase of low-frequency bands during seizures. MethodsWe used intracranial electrodes to record seizures of symptomatic focal epilepsy (15 seizures in seven patients). Ripples (80-250 Hz), as representative of HFAs, were evaluated along with PAC. The synchronization index (SI), representing PAC, was used to analyze the coupling between the amplitude of ripples and the phase of lower frequencies. We created a video in which the intracranial electrode contacts were represented by circles that were scaled linearly to the power changes of ripple. ResultsThe main low frequency band modulating ictal-ripple activities was the {theta} band (4-8 Hz), and after completion of ictal-ripple burst, {delta} (1-4 Hz)-ripple PAC occurred. The video showed that fluctuation of the diameter of these circles indicated the rhythmic changes during significant high values of {theta}-ripple PAC. ConclusionsWe inferred that ripple activities occurring during seizure evolution were modulated by {theta} rhythm. In addition, we concluded that rhythmic circles fluctuation presented in the video represents the PAC phenomenon. Our video is thus a useful tool for understanding how ripple activity is modulated by the low-frequency phase in relation with PAC.

neuroscience↗

bioRxiv2020

Motor and Sensory Cortical Processing of Neural Oscillatory Activities revealed by Human Swallowing using Intracranial Electrodes

Swallowing, a unique movement, is attributed to the indispensable orchestration of motor-output and sensory-input. We hypothesized that swallowing can illustrate differences between motor and sensory neural processing. Eight epileptic participants fitted with intracranial electrodes over the orofacial cortex were asked to swallow a water bolus. Mouth-opening and swallowing were treated as motor tasks, while water-injection as sensory tasks. Phase-amplitude coupling between lower frequency and high {gamma} (HG) band (75-150 Hz) was investigated. An (10-16 Hz) -HG coupling appeared before motor-related HG power increase (burst), and a {theta} (5-9 Hz) -HG coupling appeared during sensory-related HG burst. The motor- and sensory-related HG amplitude were modulated at the trough of oscillations and peak of {theta} oscillations, respectively. These contrasting results acquired from the orofacial cortex can help to fully elucidate the sensory-motor function in the brain.

neuroscience↗