Biology subjects

Lin, J. J.

Publications and source records attributed to Lin, J. J..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception

Chemical platforms that facilitate both the identification and elucidation of new areas for therapeutic development are necessary but lacking. Activity-based protein profiling (ABPP) leverages active site-directed chemical probes as target discovery tools that resolve activity from expression and immediately marry the targets identified with lead compounds for drug design. However, this approach has traditionally focused on predictable and intrinsic enzyme functionality. Here, we applied our activity-based proteomics discovery platform to map non-encoded and post-translationally acquired enzyme functionalities (e.g. cofactors) in vivo using chemical probes that exploit the nucleophilic hydrazine pharmacophores found in a classic antidepressant drug (e.g. phenelzine, Nardil (R)). We show the probes are in vivo active and can map proteome-wide tissue-specific target engagement of the drug. In addition to engaging targets (flavoenzymes monoamine oxidase A/B) that are associated with the known therapeutic mechanism as well as several other members of the flavoenzyme family, the probes captured the previously discovered N-terminal glyoxylyl (Glox) group of Secernin-3 (SCRN3) in vivo through a divergent mechanism, indicating this functional feature has biochemical activity in the brain. SCRN3 protein is ubiquitously expressed in the brain, yet gene expression is regulated by inflammatory stimuli. In an inflammatory pain mouse model, behavioral assessment of nociception showed Scrn3 male knockout mice selectively exhibited impaired thermal nociceptive sensitivity. Our study provides a guided workflow to entangle molecular (off)targets and pharmacological mechanisms for therapeutic development.

neuroscience↗

bioRxiv2023

Comparing rapid rule-learning strategies in humans and monkeys

Inter-species comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of macaque monkey and human strategies on an analogue of the Wisconsin Card Sort Test, a widely studied and applied multi-attribute measure of cognitive function, wherein performance requires the inference of a changing rule given ambiguous feedback. We found that well-trained monkeys rapidly infer rules but are three times slower than humans. Model fits to their choices revealed hidden states akin to feature-based attention in both species, and decision processes that resembled a Win-stay lose-shift strategy with key differences. Monkeys and humans test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidates. An attention-set based learning stage categorization revealed that perseveration, random exploration and poor sensitivity to negative feedback explain the under-performance in monkeys.

animal behavior and cognition↗

bioRxiv2022

Asymmetric coding of reward prediction errors in human insula and dorsomedial prefrontal cortex

The signed value and unsigned salience of reward prediction errors (RPEs) are critical to understanding reinforcement learning (RL) and cognitive control. Dorsomedial prefrontal cortex (dMPFC) and insula (INS) are key regions for integrating reward and surprise information, but conflicting evidence for both signed and unsigned activity has led to competing proposals for the nature of RPE representations in these brain areas. Recently, the distributional RL theory (dRL) has been used to explain RPE coding diversity in the rodent midbrain by proposing that dopaminergic neurons have differential sensitivity to positive and negative RPEs. Here, we use intracranially recorded high frequency activity (HFA) to show that this asymmetric scaling strategy captures RPE coding diversity in human dMPFC and INS. We found neural populations responding to valence-specific positive and negative RPEs, as well as unsigned RPE salience, which are spatially interleaved within each region. Furthermore, directional connectivity estimates suggest a leading role of INS in communicating positive and unsigned RPEs to dMPFC. These findings support asymmetric scaling across distinct but intermingled neural populations as a core principle in RPE coding, expand the scope of dRL, and reconcile longstanding theoretical debates on the role of dMPFC and INS in RL and cognitive control.

neuroscience↗

bioRxiv2022

Auditory prediction hierarchy in the human hippocampus and amygdala

Our brains can extract structure from the environment and form predictions given past sensory experience. Predictive circuits have been identified in wide-spread cortical regions. However, the contribution of subcortical areas, such as the hippocampus and amygdala in the formation of predictions remains under-explored. Here, we hypothesized that the hippocampus would be sensitive to predictability in sound sequences, while the amygdala would be sensitive to unexpected violations of auditory rules. We presented epileptic patients undergoing presurgical monitoring with standard and deviant sounds, in a predictable or unpredictable context. Onsets of auditory responses and unpredictable deviance effects were detected at earlier latencies in the temporal cortex compared to the amygdala and hippocampus. Deviance effects in 1-20 Hz local field potentials were detected in the lateral temporal cortex, irrespective of predictability. The amygdala showed stronger deviance responses in the unpredictable context. Additionally, low frequency deviance responses in the hippocampus (1-8 Hz) were observed in the predictable but not in the unpredictable context. Our results reveal a distributed cortical-subcortical network underlying the generation of auditory predictions, comprising temporal cortex and the hippocampus and amygdala, and suggest that the neural basis of sensory predictions and prediction error signals needs to be extended to subcortical regions.

neuroscience↗

bioRxiv2022

Decision and response monitoring during working memory are sequentially represented in the human insula

Emerging research supports a role of the insula in human cognition. Here, we used intracranial EEG to investigate the spatiotemporal dynamics in the insula during a verbal working memory (vWM) task. We found robust effects for theta, beta, and high frequency activity (HFA) during probe presentation requiring a decision. Theta and beta band activity showed differential involvement across left and right insulae while sequential HFA modulations were observed along the anteroposterior axis. HFA in anterior insula tracked decision making and subsequent HFA was observed in posterior insula after the behavioral response. Our results provide electrophysiological evidence of engagement of different insula subregions in both decision-making and response monitoring during vWM and expand our knowledge of the role of the insula in complex human behavior.

neuroscience↗

bioRxiv2022

An evolutionary conserved division-of-laborbetween hippocampal and neocortical sharp-wave ripplesorganizes information transfer during sleep

The hippocampal sharp-wave ripple (SW-R) is the key substrate of the hippocampal-neocortical dialogue underlying memory formation. Recently, it became evident that SW-R are not unique to archicortex, but constitute a wide-spread neocortical phenomenon. To date, little is known about morphological and functional similarities between archi- and neocortical SW-R. Leveraging intracranial recordings from the human hippocampus and prefrontal cortex during sleep, our results reveal region-specific functional specializations, albeit a near-uniform morphology. While hippocampal SW-R trigger directional hippocampal-to-neocortical information flow, neocortical SW-R reduce information flow to minimize interference. At the population level, hippocampal SW-R confined population dynamics to a low-dimensional subspace, while neocortical SW-R diversified the population response; functionally uncoupling the hippocampal-neocortical network. Critically, our replication in rodents demonstrated the same division-of-labor between archi-and neocortical SW-R. These results uncover an evolutionary preserved mechanism where coordinated interplay between hippocampal and neocortical SW-R temporally segregates hippocampal information transfer from neocortical processing.

neuroscience↗

bioRxiv2022

LKB1 loss rewires JNK-induced apoptotic protein dynamics through NUAKs and sensitizes KRAS-mutant NSCLC to combined KRASG12C + MCL-1 blockade

The efficacy of molecularly targeted anti-cancer therapies may be limited by the presence of co-occurring mutations within a tumor1-3. Conversely, these alterations may confer collateral vulnerabilities that can be leveraged for the development of novel therapeutic approaches. KRAS-mutant lung cancers are distinguished by recurrent inactivating mutations in the tumor suppressor STK11/LKB14 that facilitate tumorigenesis by modulating energy balance5, 6, enhancing metastatic potential7,8 and enabling immune evasion9,10. However, whether LKB1 plays a role in modulating cellular responses to therapeutic stress is largely unknown. Here we show that LKB1 suppresses JNK-dependent stress signaling in KRAS-mutant lung cancer cells upon acute loss of oncogenic signaling. In LKB1-deficient KRAS-mutant cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover a previously unknown role for LKB1 in regulating stress signaling and the mitochondrial apoptotic response of cancer cells independent of its tumor suppressor activity mediated by AMPK11-13 and SIK14,15 kinases. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancer cells that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.

cancer biology↗

bioRxiv2022

Multi-areal neural dynamics encode human decision making

Value-based decision-making involves multiple cortical and subcortical brain areas, but the distributed nature of neurophysiological activity underlying economic choices in the human brain remains largely unexplored. Here, we use intracranial recordings from neurosurgical patients to show that risky choices are reflected in high frequency activity distributed across multiple prefrontal and subcortical brain regions, whereas reward-related computations are less widely represented and more modular. State space modeling reveals sub-second neural dynamics underlying choices during deliberation and allows high-accuracy trial-by-trial decoding of subjects choices robustly across patients despite differences in anatomical coverage. These results shed light into the neural basis of choice across brain areas and open the door to new intracranial approaches for brain state decoding.

neuroscience↗

bioRxiv2022

To share or not to share? iEEG evidence for state-dependent inequity encoding in the human OFC

Social decision-making requires the integration of reward valuation and social cognition systems, both dependent on the orbitofrontal cortex (OFC). How these two OFC functions interact is largely unknown. We recorded intracranial activity from the OFC of ten patients making choices in the context of different types of inequity (disadvantageous vs. advantageous). We found that high-frequency activity (70-150 HZ) encoded the amount of self-reward, consistent with previous reports. We also observed novel evidence for encoding in human OFC of the social counterparts reward as well as the type of inequity being experienced. Additionally, we find social context modulates reward encoding: depending on inequity type, reward encoding was switched on and off rapidly within electrodes, across trials. These results provide direct evidence for explicit encoding of self- and other- rewards in the human OFC, and for rapid and reversible changes in encoding schemes driven by socially relevant contexts.

neuroscience↗

bioRxiv2022

Multiple memory systems for efficient temporal order memory

We report the distinct contribution of multiple memory systems to retrieval of the temporal order of events. The neural dynamics related to retrieval of movie scenes revealed that recalling the temporal order of close events elevates hippocampal theta power, like that observed for recalling close spatial relationships. In contrast, recalling far events elevates beta power in the orbitofrontal cortex, reflecting recall based on the overall movie structure.

neuroscience↗

bioRxiv2022

Human REM sleep controls neural excitability in support of memory formation

Sleep oscillations provide a key substrate to facilitate memory processing, the underlying mechanism of which may involve the overnight homeostatic regulation of plasticity at a synaptic and whole-network level. However, there remains a lack of human data demonstrating if and how sleep enhances memory consolidation and associated neural homeostasis. We combined intracranial recordings and scalp electroencephalography (EEG) in humans to reveal a new role for rapid eye movement (REM) sleep in promoting the homeostatic recalibration of optimal excitation/inhibition-balance. Moreover, the extent of this REM-sleep homeostatic recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal-- neocortical excitability favoring remembering rather than forgetting. The findings describe a novel, fundamental role of human REM sleep in maintaining neural homeostasis, thereby enhancing long-term memory.

neuroscience↗

bioRxiv2021

Discrete LAT condensates encode antigen information from single pMHC:TCR binding events

LAT assembly into a two-dimensional protein condensate is a prominent feature of antigen discrimination by T cells. Here, we use single-molecule imaging techniques to resolve the spatial position and temporal duration of each pMHC:TCR molecular binding event while simultaneously monitoring LAT condensation at the membrane. An individual binding event is sufficient to trigger a LAT condensate, which is self-limiting, and neither its size nor lifetime is correlated with the duration of the originating pMHC:TCR binding event. Only the probability of the LAT condensate forming is related to the pMHC:TCR binding dwell time. LAT condenses abruptly, but after an extended delay from the originating binding event. A LAT mutation that facilitates phosphorylation at the PLC-{gamma}1 recruitment site shortens the delay time to LAT condensation and alters T cell antigen specificity. These results identify a role for the LAT protein condensation phase transition in setting antigen discrimination thresholds in T cells.

biophysics↗

bioRxiv2021

Awake ripples enhance emotional memory encoding in the human brain

Intracranial recordings from the human amygdala and the hippocampus during an emotional memory encoding and discrimination task reveal increased awake sharp-wave/ripples (aSWR) after encoding of emotional compared to neutral stimuli. Further, post-encoding aSWR-locked memory reinstatement in the amygdala and the hippocampus was predictive of later memory discrimination. These findings provide electrophysiological evidence that post-encoding aSWRs enhance memory for emotional events.

neuroscience↗

bioRxiv2021

Structural and functional analysis of lorlatinib analogs reveals roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mutations was achieved primarily through two different mechanisms of improved targeting of either G1202R- or I1171N/S/T-mutant kinases. Based on these results, we propose a classification of heterogenous ALK compound mutations designed to focus the development of distinct therapeutic strategies for precision targeting of compound resistance mutations following sequential TKIs.

cancer biology↗

bioRxiv2021

Left Hemisphere Dominance for Bilateral Kinematic Encoding in the Human Brain

Neurophysiological studies in humans and non-human primates have revealed movement representations in both the contralateral and ipsilateral hemisphere. Inspired by clinical observations, we ask if this bilateral representation differs for the left and right hemispheres. Electrocorticography (ECoG) was recorded in human participants during an instructed-delay reaching task, with movements produced with either the contralateral or ipsilateral arm. Using a cross-validated kinematic encoding model, we found stronger bilateral encoding in the left hemisphere, an effect that was present during preparation and was amplified during execution. Consistent with this asymmetry, we also observed better across-arm generalization in the left hemisphere, indicating similar neural representations for right and left arm movements. Notably, these left hemisphere electrodes were centered over premotor and parietal regions. The more extensive bilateral encoding in the left hemisphere adds a new perspective to the pervasive neuropsychological finding that the left hemisphere plays a dominant role in praxis.

neuroscience↗

bioRxiv2021

APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

cancer biology↗

bioRxiv2020

Patient-specific optimization of automated detection improves seizure onset zone localization based on high frequency oscillations

ObjectiveHigh frequency oscillations (HFOs) are a biomarker of the seizure onset zone (SOZ) and can be visually or automatically detected. In theory, one can optimize an automated algorithms parameters to maximize SOZ localization accuracy; however, there is no consensus on whether or how this should be done. Therefore, we optimized an automated detector using visually identified HFOs and evaluated the impact on SOZ localization accuracy. MethodsWe detected HFOs in intracranial EEG from 20 patients with refractory epilepsy from two centers using (1) unoptimized automated detection, (2) visual identification, and (3) automated detection optimized to match visually detected HFOs. ResultsSOZ localization accuracy based on HFO rate was not significantly different between the three methods. Across patients, visually optimized detector settings varied, and no single set of settings produced universally accurate SOZ localization. Exploratory analysis suggests that, for many patients, detection settings exist that would improve SOZ localization. ConclusionsSOZ localization accuracy was similar for all three methods, was not improved by visually optimizing detector settings, and may benefit from patient-specific parameter optimization. SignificanceVisual HFO marking is laborious, and optimizing automated detection using visual markings does not improve localization accuracy. New patient-specific detector optimization methods are needed.

neuroscience↗

bioRxiv2020

Amplitude of high frequency oscillations as a biomarker of the seizure onset zone

ObjectiveStudies of high frequency oscillations (HFOs) in epilepsy have primarily tested the HFO rate as a biomarker of the seizure onset zone (SOZ), but the rate varies over time and is not robust for all individual subjects. As an alternative, we tested the performance of HFO amplitude as a potential SOZ biomarker using two automated detection algorithms. MethodHFOs were detected in intracranial electroencephalogram (iEEG) from 11 patients using a machine learning algorithm and a standard amplitude-based algorithm. For each detector, SOZ and non-SOZ channels were classified using the rate and amplitude of high frequency events, and performance was compared using receiver operating characteristic curves. ResultsThe amplitude of detected events was significantly higher in SOZ. Across subjects, amplitude more accurately classified SOZ/non-SOZ than rate (higher values of area under the ROC curve and sensitivity, and lower false positive rates). Moreover, amplitude was more consistent across segments of data, indicated by lower coefficient of variation. ConclusionAs an SOZ biomarker, HFO amplitude offers advantages over HFO rate: it exhibits higher classification accuracy, more consistency over time, and robustness to parameter changes. SignificanceThis biomarker has the potential to increase the generalizability of HFOs and facilitate clinical implementation as a tool for SOZ localization.

neuroscience↗