Biology subjects

Chen, P.-C.

Publications and source records attributed to Chen, P.-C..

17 recordsLinked to original sources

bioRxiv2026

Hippocampal ripples evoke a stereotyped cortical response followed by spindle-mediated network synchronization.

Hippocampal sharp-wave ripples (SWRs) are thought to play a key role in systems memory consolidation by broadcasting reactivated memory content to distributed cortical networks while we sleep. Elucidating how this hippocampal-cortical dialogue unfolds at the brain-wide level is therefore essential to understanding how sleep transforms new experiences into lasting memories. Here we combined simultaneous hippocampal intracranial EEG and 21-channel scalp EEG during overnight sleep to characterize the large-scale cortical impact of hippocampal ripple events. We found that individual hippocampal ripples elicited a decodable, phase-locked cortical response at the scalp level. This cortical response was followed by increases in cortico-cortical synchronization and network density in the spindle-band. Mediation analyses revealed a sequential pathway in which ripple magnitude predicted large-scale cortical connectivity through this intermediate cortical response and subsequent spindle activity. These findings demonstrate that hippocampal ripples trigger a two-step cascade, i.e., an early stereotyped cortical response followed by spindle-mediated network synchronization, consistent with the view that SWRs co-activate distributed cortical nodes and potentiate the cortical-cortical connections that support memory consolidation. By demonstrating that ripple-related cortical responses are decodable noninvasively, our results moreover suggest a new strategy for inferring hippocampal ripple activity from scalp electrophysiology. Significance StatementHippocampal sharp-wave ripples are brief bursts of coordinated neural activity believed to support memory consolidation by coordinating communication between the hippocampus and the cortex during sleep. Although animal studies show that ripples influence widespread cortical activity, their large-scale cortical effects in humans have previously only been measurable through invasive brain recordings. By combining hippocampal intracranial recordings with scalp EEG, we show that hippocampal ripples evoke a cortical response decodable noninvasively, followed by widespread spindle-mediated synchronization across cortical networks. These findings reveal a temporally structured cascade linking hippocampal activity to large-scale cortical coordination during sleep and suggest that ripple-driven brain-wide responses can be monitored using non-invasive EEG recordings.

neuroscience↗

bioRxiv2026

Single Plaque Proteomics Reveals the Composition and Dynamics of the Amyloid Microenvironment in Alzheimer's Disease

Alzheimers disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events.

neuroscience↗

bioRxiv2026

Cell type-resolved proteomics reveals intra- and intercellular signalingin Alzheimers disease

Alzheimers disease (AD) arises from pathological interactions among diverse brain cell types, but cell-specific proteomic changes remain underexplored. Here, we present deep proteomic profiling of sorted or proximity-labeled brain cells from AD mouse models (5xFAD and AppNL-G-F) at multiple ages, quantifying 13,411 proteins in microglia (three subtypes), astrocytes, oligodendrocyte precursor cells, and neurons. We identified 3,028 differentially abundant proteins across these cell types, the majority of which were not detected in bulk proteomic datasets, and constructed cell type-specific networks to define functional modules and hub proteins. Comparison with transcriptomic data revealed that [~]30% of proteomic changes are RNA-independent. Further analyses uncovered cross-cell type signaling proteins conserved in human AD brains, such as pleiotrophin (Ptn), which is transcriptionally enriched in astrocytes but accumulates in microglia. Importantly, recombinant PTN directly activates induced microglia-like (iMG) human cells. Thus, these findings provide a comprehensive cell type-resolved proteomic atlas of AD models, highlighting novel intra- and intercellular signaling events. HighlightsO_LIA high-resolution cell type-resolved proteomic atlas of Alzheimers disease mouse models C_LIO_LI[~]3,000 cell type-specific protein alterations identified beyond bulk tissue analyses C_LIO_LIProteomic profiling of microglial subtypes reveals subtype-specific changes in Alzheimers disease C_LIO_LIAstrocyte-microglia signaling is highlighted and validated through PTN-mediated interactions C_LI

neuroscience↗

bioRxiv2025

Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation

Proteomic profiling of Alzheimers disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with A{beta} since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates A{beta} assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both A{beta}40 and A{beta}42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of Mdk gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble proteome in these mouse models indicates significant accumulation of A{beta} and A{beta}-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimers disease.

biochemistry↗

bioRxiv2024

Human-mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome

Murine models of Alzheimers disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. We comprehensively profiled age-dependent brain proteome and phosphoproteome (n > 10,000 for both) across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata, and prioritized novel components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Determining the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including A{beta}-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identify potential new targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.

biochemistry↗

bioRxiv2024

Hippocampal ripples during offline periods predict human motor sequence learning

High-frequency bursts in the hippocampus, known as ripples (80-120 Hz in humans), have been shown to support episodic memory processes. However, converging recent evidence in rodent models as well as human neuroimaging suggests that the hippocampus may be involved in a wider range of memory domains, including motor sequence learning (MSL). Nevertheless, no direct link between hippocampal ripples and MSL has yet been established. Here, we recorded intracranial electroencephalography from the hippocampus in 20 epilepsy patients during a MSL task in which participants showed steady improvement across nine 30-second training blocks interspersed with 30-second rest ( offline) periods. We first demonstrate that ripple rates strongly increase during rest periods relative to training blocks. Importantly, ripple rates during rest periods tracked learning behaviour, both across blocks and across participants. These results suggest that hippocampal ripples during offline periods play a functional role in motor sequence learning and that the hippocampus may be involved in offline learning beyond episodic memory.

neuroscience↗

bioRxiv2024

Heart Rate Variability During REM Sleep is Associated with Reduced Negative Memory Bias

Emotional memories change over time, but the mechanisms supporting this change are not well understood. Sleep has been identified as one mechanism that supports memory consolidation, with sleep selectively benefitting negative emotional consolidation at the expense of neutral memories, with specific oscillatory events linked to this process. In contrast, the consolidation of neutral and positive memories, compared to negative memories, has been associated with increased vagally-mediated vagal heart rate variability (HRV) during wakefulness. However, how HRV during sleep contributes to emotional memory consolidation remains unexplored. We investigated how sleep oscillations and vagal contributions during sleep contribute to the consolidation of neutral and negative memories. Using a double-blind, placebo-controlled, within-subject, cross-over design, we examined the impact of pharmacological vagal suppression using zolpidem on overnight emotional memory consolidation. Thirty-two participants encoded neutral and negative pictures in the morning, followed by picture recognition tests before and after a night of sleep. Zolpidem or placebo was administered in the evening before overnight sleep, and participants were monitored with electroencephalography and electrocardiography. In the placebo condition, greater overnight improvement for neutral pictures was associated with higher vagal HRV in both Non-Rapid Eye Movement Slow Wave Sleep (NREM SWS) and REM. Additionally, the emotional memory tradeoff (i.e., difference between consolidation of neutral versus negative memories) was associated with higher vagal HRV during REM, but in this case, neutral memories were remembered better than negative memories, indicating a potential role for REM vagal HRV in promoting a positive memory bias overnight. Zolpidem, on the other hand, reduced vagal HRV during SWS, increased NREM sigma power, and eliminated the positive memory bias. Lastly, we used a stepwise linear mixed effects regression to determine how NREM sigma power and vagal HRV during REM independently explained the variance in the emotional memory tradeoff effect. We found that the addition of vagal HRV in combination with sleep significantly improved the models fit. Overall, our results suggest that sleep brain oscillations and vagal signals synergistically interact in the overnight consolidation of emotional memories, with REM vagal HRV critically contributing to the positive memory bias.

neuroscience↗

bioRxiv2024

Slow Oscillations Modulate Functional Brain Changes Supporting Working Memory

Working memory (WM), the temporary mental storage and manipulation of information, is a skill that can improve with training. Sleep, and specifically slow oscillations (SOs), has been linked with WM improvement, yet it is unknown how processing during SOs modulates WM function across sleep. The current study examines how WM-related neural processing changes with sleep, and how these changes are related to activity during SOs. To do so, participants performed a WM task during fMRI before and after sleep, and the first 2.5 hrs of sleep was monitored by simultaneous EEG-fMRI. Reliable overnight changes in WM-related activity patterns were found, with reduced recruitment of the dorsal precuneus after compared to before sleep. Moreover, greater neural activation during SOs was associated with reduced overnight recruitment during WM across multiple levels of analysis. Our findings highlight the important role of SOs, elucidating how SOs may support changes in WM function across sleep.

neuroscience↗

bioRxiv2021

Ovulation sources coagulation protease cascade and hepatocyte growth factor to support physiological growth and malignant transformation

The fallopian tube fimbrial epithelium (FTE), which is exposed to the follicular fluid (FF) contents of ovulation, is regarded as the main origin of ovarian high-grade serous carcinoma (HGSC). Previously, we found that growth factors in FF, such as IGF2, are responsible for the malignant transformation of FTE. However, ovulation is a monthly transient event, whereas carcinogenesis requires continuous, long-term exposure. Here, we found the transformation activity of FF sustained for more than 30 days after drainage into the peritoneal fluid (PF). Hepatocyte growth factor (HGF), activated through the ovulation injury-tissue factor-thrombin-HGFA-HGF cleavage cascade confers a sustained transformation activity to FTE, HGSC. Physiologically, the high reserve of the coagulation-HGF cascade sources a sustained level of HGF in PF, then to the blood circulation. This HGF axis promotes the growth of the corpus luteum and repair of tissue injury after ovulation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/448625v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@13d26d3org.highwire.dtl.DTLVardef@1c00c35org.highwire.dtl.DTLVardef@1619373org.highwire.dtl.DTLVardef@117a24d_HPS_FORMAT_FIGEXP M_FIG C_FIG The fluid content of the ovulating ovarian follicle (follicular fluid [FF]) exerts a long-lasting transformation effect that is sustained after mixing with peritoneal fluid (PF). The coagulation protease cascade and hepatocyte growth factor (HGF) are responsible for the sustained activity. The high abundance of cascade proteins and pro-form HGF activator and HGF in FF/PF supports the constant supply of active-form HGF lasting for a whole month, covering the entire ovulation cycle. This sustained HGF activity promotes the proliferative repair of the ovarian surface and fallopian tube fimbrial epithelia as well as the growth of the corpus luteum. The same activity also inadvertently promotes the malignant transformation of the fimbrial epithelium, high-grade serous carcinoma, and epithelial ovarian cancer. In addition to the peritoneal cavity, ovulation sources HGF to blood circulation, which may serve an endocrine role. HIGHLIGHTO_LIOvulatory follicular fluid (FF) exerts a long-lasting transformation activity covering throughout the ovulation cycle. C_LIO_LIThe ovulation injury-coagulation proteases-hepatocyte growth factor (HGF) cascade is responsible for the sustained activity. C_LIO_LIOvulation sources HGF into the peritoneal cavity, then into the blood circulation. C_LIO_LIThis coagulation-HGF cascade promotes the transformation of fallopian tube epithelial cells and ovarian cancer cells. C_LIO_LIPhysiologically, it promotes the growth of the corpus luteum and injured epithelium after ovulation. C_LI

cancer biology↗

bioRxiv2021

The sleeping brain switches between working memory and long-term memory processing.

We provide evidence that human sleep is a competitive arena where cognitive domains vie for limited resources. Using pharmacology and effective connectivity analysis, we demonstrate that long-term memory and working memory are served by distinct offline neural mechanisms that are mutually antagonistic. Specifically, we administered zolpidem to increase central sigma activity and demonstrated targeted suppression of autonomic vagal activity. With effective connectivity, we determined the central activity has greater causal influence over autonomic activity, and the magnitude of this influence during sleep produced a behavioral trade-off between offline long-term and working memory processing. These findings show the first evidence of a sleep switch mechanism that toggles between central sigma-dependent long-term memory and autonomic vagal-dependent working memory processing. Significant StatementSleep facilitates both long-term episodic memory consolidation and short-term working memory functioning. However, the mechanism by which the sleeping brain performs both complex feats, and which sleep features are associated with these processes remain unclear. Using a pharmacological approach, we demonstrate that long-term and working memory are served by distinct offline neural mechanisms, and that these mechanisms are mutually antagonistic. We propose a Sleep Switch model in which the brain toggles between the two memory processes via a complex interaction at the synaptic, systems, and mechanistic level, with implications for research on cognitive disturbances observed in neurodegenerative disorders such as Alzheimers and Parkinsons disease, both of which involve the decline of sleep.

neuroscience↗

bioRxiv2020

Age-related differences in Autonomic/Central Coupling during a Daytime Nap

Age-dependent functional changes are mirrored by declines in both the central the autonomic nervous systems and have been related to pathological aging. Prior studies in our group have identified a temporal coupling of Autonomic and Central Events (ACEs) during sleep using electrocardiogram to measure heart rate and electroencephalography to measure brain rhythms, with heart rate bursts (HRBs) temporally coincided with increased slow-wave-activity (SWA, 0.5-1Hz) and sigma activity (12-15Hz), followed by parasympathetic surge (RRHF) during non-rapid eye movement (NREM) sleep. ACEs predicted working memory (WM) improvement in young adults. Given that there are paralleling age-related declines in both the ANS and CNS, the current study investigated differences in ACE activity during daytime sleep in older and younger adults and their functional impact on working memory. Compared to youngers, older adults showed lower amplitude of ACEs during NREM sleep, but no age-related difference during Wake. Furthermore, while younger adults demonstrated a parasympathetic surge after HRBs, older adults showed a different pattern, with a earlier rise and maintenance of the RRHF. Finally, we examined whether ACE predicted WM in older adults. We found that older adults with good WM show stronger coupling, whereas low WM performers had less robust ACE activity. Taken together, our results demonstrated that autonomic-central coupling declines with age, with possible links to deterioration in WM function. Given that age-related deterioration in autonomic and central nervous system activity is implicated in pathological decline, the current findings may facilitate novel insights to the cognitive neuroscience of aging.

neuroscience↗

bioRxiv2020

Age-related losses in cardiac autonomic activity during a daytime nap

In healthy, young individuals, a reduction in cardiovascular output and a shift from sympathetic to parasympathetic (vagal) dominance is observed from wake into stages of nocturnal and daytime sleep. This cardiac autonomic profile, measured by heart rate variability (HRV), has been associated with significant benefits for cardiovascular health. Aging is associated with decreased nighttime sleep quality and lower parasympathetic activity during both sleep and resting. However, it is not known whether age-related dampening of HRV extends to daytime sleep, diminishing the cardiovascular benefits of naps in the elderly. Here, we investigated this question by comparing the autonomic activity profile between young and older healthy adults during a daytime nap and a similar period of wakefulness (quiet wake; QW). For each condition, from the electrocardiogram (ECG), we obtained beat-to-beat HRV intervals (RR), root mean square of successive differences between adjacent heart-beat-intervals (RMSSD), high frequency (HF), low frequency (LF) power and total power (TP), HF normalized units (HFnu), and the LF/HF ratio. As previously reported, young subjects showed a parasympathetic dominance during NREM, compared with REM, pre-nap rest, and WASO. On the other hand, older, compared to younger, adults showed significantly lower vagally-mediated HRV (measured by RMSSD, HF, HFnu) during NREM. Interestingly, however, no age-related differences were detected during pre-nap rest or QW. Altogether, our findings suggest a sleep-specific reduction in parasympathetic modulation that is unique to NREM sleep in older adults.Impact Statement Sleep is naturally modulated by the autonomic nervous system (ANS), with greater dominance of parasympathetic over sympathetic activity during non-rapid-eye-movement (NREM) sleep. As such, sleep has been termed a “cardiovascular holiday” and has been associated with positive health outcomes. Aging, however, is linked to decreases in cardiac autonomic activity and sympathovagal imbalance. While the impact of aging on ANS activity during nocturnal sleep has received some attention, the cardiac profiles during a daytime nap, to our knowledge, have not yet been studied under the context of aging. Herein, young adults demonstrated increased parasympathetic activity during deep sleep. Older adults, however, showed less parasympathetic modulation during NREM sleep, suggesting loss of the cardiovascular holiday. Importantly, no age-related declines in parasympathetic activity were detected during wake, suggesting a sleep-specific reduction in parasympathetic modulation that is unique to NREM sleep in older adults.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2020

Autonomic/Central Coupling Boosts Working Memory in Healthy Young Adults

Working memory (WM) is an executive function that can improve with training. However, the precise mechanism for this improvement is not known. Studies have shown greater WM gains after a period of sleep than a similar period of wake (Kuriyama et al. 2008a; Zinke, Noack, and Born 2018), with WM improvement correlated with slow wave activity (SWA; 0.5-1Hz) during slow wave sleep (SWS) (Sattari et al. 2019; Pugin et al. 2015; Ferrarelli et al. 2019). A different body of literature has suggested an important role for autonomic activity during wake for WM (Hansen et al. 2004; Mosley, Laborde, and Kavanagh 2018). A recent study from our group reported that the temporal coupling of autonomic and central events (ACEs) during sleep was associated with memory consolidation (Naji et al. 2019). We found that heart rate bursts (HR bursts) during non-rapid eye movement (NREM) sleep are accompanied by increases in SWA and sigma (12-15Hz) power, as well as increases in the high-frequency (HF) component of the RR interval, reflecting vagal rebound. In addition, ACEs predict long-term, episodic memory improvement. Building on these previous results, we examined whether ACEs may also contribute to gains in WM. We tested 104 young adults in an operation span task (OSPAN) in the morning and evening, with either a nap (with electroencephalography (EEG) and electrocardiography (ECG)) or wake between testing sessions. We identified HR bursts in the ECG and replicated the increases in SWA and sigma prior to peak of the HR burst, as well as vagal rebound after the peak. Furthermore, we showed sleep-dependent WM improvement, which was predicted by ACE activity. Using regression analyses, we discovered that significantly more variance in WM improvement could be explained with ACE variables than with overall sleep activity not time-locked with ECG. These results provide the first evidence that coordinated autonomic and central events play a significant role in sleep-related WM improvement and implicate the potential of autonomic interventions during sleep for cognitive enhancement.

neuroscience↗

bioRxiv2020

Autonomic activity during a daytime nap facilitates working memory improvement

Recent investigations have implicated the parasympathetic branch of the autonomic nervous system (ANS) in higher-order executive functions. These actions are purported to occur through ANSs modulation of the prefrontal cortex, with parasympathetic activity during wake associated with working memory ability (WM). Compared with wake, sleep is a period with substantially greater parasympathetic tone. Recent work has reported that sleep may also contribute to improvement in WM. Here, we examined the role of cardiac parasympathetic activity during sleep on WM improvement in healthy young adults. Participants were tested in an operation span task (OSpan) in the morning and evening, and during the inter-test period subjects either experienced a nap or wake. We measured high frequency heart rate variability (HF HRV) as an index of cardiac, parasympathetic activity during both wake and sleep. Participants showed the expected boost in parasympathetic activity during nap, compared with wake, as well as greater WM improvement after a nap compared with an equivalent period awake. Furthermore, parasympathetic activity during sleep, but not wake, was significantly correlated with WM improvement. Together these results indicate that the natural boost in parasympathetic activity during sleep has substantial benefits to gains in prefrontal executive function in young adults. We present a conceptual model illustrating the interaction between sleep, autonomic activity, and prefrontal brain function, and highlight open research questions that will facilitate understanding of the factors that contribute to executive abilities in young adults, as well as in cognitive aging. Significance StatementRecently, the neurovisceral integration model has implicated activity on the parasympathetic branch of the autonomic nervous system (ANS) during wake in executive functioning. Parasympathetic activity peaks during deep sleep, and sleep has been shown to facilitate executive functioning. Yet, the role of parasympathetic activity during sleep for executive functioning is not known. Herein, participants demonstrated increased parasympathetic activity during deep sleep, sleep-dependent WM improvement, and associations between performance gains and parasympathetic activity in sleep, not wake. Our conceptual model illustrates the interaction between sleep, autonomic activity, and prefrontal brain function that may contribute to executive abilities in young adults and to cognitive aging.

neuroscience↗

bioRxiv2020

Transmembrane Stem Cell Factor Protein Therapeutics EnhanceRevascularization in Ischemia without Mast Cell Activation

Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF (tmSCF) has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using tmSCF embedded in proteoliposomes or lipid nanodiscs. Mouse models of anaphylaxis and ischemia revealed the tmSCF-based therapies did not activate mast cells and improved the revascularization in the ischemic hind limb. Proteoliposomal tmSCF preferentially acted on endothelial cells to induce angiogenesis while tmSCF nanodiscs had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid nanocarrier used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found that tmSCF-based therapies can provide therapeutic benefits without off target effects.

bioengineering↗

bioRxiv2019

Integrative model to coordinate the oligomerization and aggregation mechanisms of CCL5

The CC-type chemokine ligand 5 (CCL5) is involved in the pathogenesis of many inflammatory conditions. The oligomerization and aggregation of CCL5 are considered to be responsible for its inflammatory properties. The CC-type dimer acts as the basic unit to constitute the oligomer. However, the structural basis of CCL5 oligomerization remains controversial. In this study, NMR and biophysical analyses proposed evidence that no single dimer-dimer interaction dominates in the oligomerization process of CCL5. CCL5 could oligomerize alternatively through two different interactions, E66-K25 and E66-R44/K45. In addition, a newly determined trimer structure reported an interfacial interaction through the N-terminal 12FAY14 sequence. The interaction contributes to aggregation and precipitation. In accordance with the observations, an integrative model explains the CCL5 oligomerization and aggregation process. CCL5 assembly consists of two types of dimer-dimer interactions and one aggregation mechanism. For full-length CCL5, the molecular accumulation triggers oligomerization through the E66-K25 interaction, and the 12FAY14 interaction acts as a secondary effect to derive aggregation. The E66-R44/K45 interaction dominates in CCL5 N-terminal truncations. The interaction would lead to filament-like formation in solution.

biochemistry↗

bioRxiv2016

Metabolome Identification by Systematic Stable Isotope Labeling Experiments and False Discovery Analysis with a Target-Decoy Strategy

We introduce a formula-based strategy and algorithm (JUMPm) for global metabolite identification and false discovery analysis in untargeted mass spectrometry-based metabolomics. JUMPm determines the chemical formulas of metabolites from unlabeled and stable-isotope labeled metabolome data, and derives the most likely metabolite identity by searching structure databases. JUMPm also estimates the false discovery rate (FDR) with a target-decoy strategy based on the octet rule of chemistry. With systematic stable isotope labeling of yeast, we identified 2,085 chemical formulas (10% FDR), 892 of which were assigned with metabolite structures. We evaluated JUMPm with a library of synthetic standards, and found that 96% of the formulas were correctly identified. We extended the method to mammalian cells with direct isotope labeling and by heavy yeast spike-in. This strategy and algorithm provide a powerful a practical solution for global identification of metabolites with a critical measure of confidence.

biochemistry↗