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Long, S.

Publications and source records attributed to Long, S..

At least 19 recordsLinked to original sources

Digital molecular kinetics enabled by large-scale nanopore arrays for multidimensional biophysical profiling

While widely used, traditional technologies like surface plasmon resonance (SPR) are limited by narrow temporal windows (transient capture and baseline drift), dynamic heterogeneity, and poor physiological temperature performance. Meanwhile, early nanopore approaches are often constrained by limited throughput and heavy reliance on customized modification schemes. Here, we present a digital molecular kinetics (DMK) platform based on large-scale nanopore arrays. By introducing a universal coupling and probe reporting system, DMK achieves broad versatility across diverse molecular pairs, including proteins, peptides, small molecules, DNA, and polymerase complexes. In addition to accurately recovering classical SPR association and dissociation rate constants, by harnessing massive single-molecule event analysis, DMK breaks traditional performance boundaries: it facilitates robust thermodynamic-kinetic profiling across a wide temperature range, resolves distinct conformations in heterogeneous samples, enables ultra-low dissociation rate quantification via maximum likelihood estimation, and reveals energy wells via voltage gradients for binding analysis against environmental perturbations. Furthermore, DMK enables the capture of rapid binding events missed by SPR, offering a new perspective on molecular interaction complexity. This platform offers an effective alternative and upgrade to SPR, opening a digital paradigm for complex molecular analysis and drug discovery.

biophysics↗

A Temporal Reliability and Sustainability Score Framework for Ranking Heart Rate Variability Metrics During Pharmacological Autonomic Blockade in Rats

Background: While Heart Rate Variability (HRV) is a cornerstone of non-invasive autonomic assessment, the sensitivity and sustainability of specific HRV parameters remain debated. This study introduces a "sustainability score" to systematically validate which metrics best reflect autonomic nervous system (ANS) modulation following pharmacological blockade. Methods: Ten male Sprague-Dawley rats were implanted with ECG electrodes. After recovery, rats underwent randomized atropine (1 mg/kg, intraperitoneal) and propranolol (10 mg/kg, intraperitoneal) sessions separated by at least 3 days. Baseline ECG was recorded for 30 min before each session, followed by 90-min post-drug ECG recording. HRV parameters were analyzed in sequential 15-min and 30-min segments. Reliability was assessed using average p-values across post-drug segments and a sustainability score, defined as the number of segments significantly different from baseline. Results: After atropine, HF Power showed the strongest rapid parasympathetic-related response in 15-min segments, with the lowest average p-value (0.1476) and highest sustainability score (4), followed by RSA (p=0.16148; score=4). HFn was less reliable in 15-min segments (p=0.23147; score=2) but became the most reliable parasympathetic-related metric in 30-min segments (p=0.0001; score=3). After propranolol, SI was the most reliable sympathetic-related metric in both 15-min (p=0.18225; score=2) and 30-min segments (p=0.0393; score=2), while SD2/SD1 showed the strongest 30-min sympathovagal-balance response (p=0.0200; score=3). Conclusion: HF Power is recommended for rapid parasympathetic-related assessment in short windows, HFn for longer-window parasympathetic assessment, SI for sympathetic-assessment, and SD2/SD1 for 30-min sympathovagal-balance analysis. Sustainability scoring provides a structured framework for selecting ECG-derived autonomic markers.

pharmacology and toxicology↗

Denoising the central autonomic network: characterizing processes jointly associated with arousal and non-neuronal physiological artefacts in dynamic fMRI analyses

Using a multimodal dataset including fMRI, EEG-fMRI and concurrent physiological recordings, we investigated the effect of denoising systemic low frequency oscillations (sLFOs) on the characterization of dynamic signatures of central autonomic regulation and their relation to ongoing physiological states. We demonstrated that the time-frequency profiles of couplings between BOLD time series and cardiac and respiratory processes were statistically comparable between regions of the brain associated with autonomic function and non-autonomic motor regions, suggesting that these couplings largely do not reflect neuronal activation related to autonomic activity. We further showed that model-based (via physiological response functions) and data-driven (via CompCor nuisance regressors extracted from cerebrospinal fluid) methods of sLFO denoising had a statistically similar effect on these frequency profiles. We novelly applied co-activation pattern analysis to assess state dynamics of autonomic-associated regions of the brain, finding that such brain states interrelate decreases in vigilance and increases in heart rate, respiratory flow, and head motion, thus providing evidence for global arousal processes affecting BOLD signal in autonomic-associated regions. Lastly, we modelled sliding-window dynamic functional connectivity within the central autonomic network (CAN) as modulated by heart rate variability, showing significant differences in model outcomes linked to each denoising pipeline. With these findings, we provide a comprehensive discussion of the implications for the application of denoising techniques to the CAN and comment on the origins of dynamic components of the BOLD signal linked to autonomic regulation, highlighting the global role played by arousal.

neuroscience↗

Spatiotemporal Propagation of Sensorimotor Beta Bursts Across Adulthood

Beta activity (13-30 Hz) is a prominent feature of motor control, widely distributed across the cerebral cortex. However, how beta bursts (transient high-amplitude events) propagate along cortical organizational axes, such as the posterior-anterior gradient that coordinates cortical structure and function from sensory to association regions, remains poorly understood. Using magnetoencephalography (MEG) data from the Cambridge Centre for Ageing and Neuroscience (CamCAN) dataset, beta burst propagation was characterized using burst onset timing and optical flow analysis during motor tasks and rest in 573 participants (ages 18-88). Beta bursts propagated systematically along the posterior-anterior cortical axis during motor tasks, with propagation direction reversing between movement phases and exhibiting hemispheric asymmetry. In contrast, the resting state exhibited no consistent spatial organization of beta burst propagation. Propagation patterns in motor tasks significantly correlated with cortical distributions of GABAA, cholinergic, and mu-opioid receptors in a hemisphere-specific and phase-dependent manner. Propagation energy was highest in sensorimotor regions and decreased towards more peripheral areas of the cortex. Older adults exhibited significant temporal expansion of beta activity (earlier pre-movement, later post-movement), suggesting a mediation effect of age on reaction time. These results suggest that the propagation of beta bursts is influenced by cortical architecture and may provide a mechanistic explanation for the age-related slowing of motor function.

neuroscience↗

Early immune responses anticipate HIV rebound and precede viral control

Sustained viral suppression following antiretroviral treatment (ART) cessation is a major goal of HIV cure research1. Rare individuals mount immune responses able to control viral rebound without intervention2,3, however, the earliest moments in which these responses form remain poorly defined. We performed an intensively sampled, prospective analytical treatment interruption (ATI) to study the initial immune response to rebound and to understand its role in defining subsequent virus control. Profiling of peripheral blood mononuclear cells and plasma revealed consistent immune activation prior to systemic rebound, including upregulation of antiviral transcriptional pathways, expansion of CD16++ non-classical monocytes, and increases of inflammatory and antiviral soluble plasma proteins. Individuals with prior viral control (controllers) diverged from non-controllers with a slower slope of rebound, a longer period of immune activity prior to rebound, and engagement of a multifaceted immune program with less systemic inflammation. An intermediate immune signature emerged in a separate ATI cohort of individuals who experienced delayed rebound after receiving broadly neutralizing antibodies4, suggesting that immunotherapy can induce a potentially protective pre-rebound immune response. Together, these data resolve the earliest systemic host immune responses to HIV rebound and demonstrate broad immune differences associated with HIV control phenotypes.

immunology↗

Convergent cortical temporal axis: common cortical oscillatory modes

Brain dynamics provide the most direct substrate for neural function and representation. Extensive prior work has demonstrated that the human brain is organized into hierarchical structures across molecular, cellular, microstructural, and macroscale network levels. However, whether these hierarchies can be directly linked through shared patterns of neural dynamics remains unresolved, and clear evidence from data-driven analyses is still lacking. A central open question is whether brain dynamics vary along a single continuous dimension, or whether they are instead composed of a limited number of reproducible coordination modes that could provide a unifying basis for cross-scale integration. Here, using source-resolved resting-state magnetoencephalography (MEG), we adopt a fully data-driven approach that imposes no a priori assumptions about cortical hierarchy or gradient structure. By characterizing full-spectrum power relationships across cortical regions, we identify a set of stable and reproducible spectral coordination modes. These modes capture how multiple frequency components jointly co-vary across space, defining distinct dynamical configurations rather than conventional band-limited oscillations or continuous gradients. The identified spectral coordination modes exhibit pronounced spatial differentiation across the cortex, distinguishing regions dominated by narrowband rhythmic activity from those characterized by broadband or multi-frequency coordination. Importantly, these modes do not correspond to predefined hierarchical axes, nor can they be reduced to existing MEG gradients or functional connectivity organizations. Instead, they emerge directly from the data, revealing a finite set of shared organizational patterns underlying cortical dynamics. Multimodal analyses further demonstrate that individual spectral coordination modes show selective associations with neurotransmitter system distributions, laminar microarchitecture, and cell-type-specific gene expression, suggesting that these dynamical patterns may serve as linking mechanisms between micro- and macroscale brain organization. Computational modeling supports this interpretation, showing that differences in local circuit parameters are sufficient to generate distinct spectral coordination states without invoking a single global dynamical hierarchy. Across the adult lifespan, these coordination modes exhibit frequency- and region-specific reorganization, indicating multiple parallel trajectories of dynamical aging. In Parkinsons disease, alterations are observed in specific spectral coordination modes, particularly within higher-order cortical regions, suggesting that the disorder preferentially disrupts distinct dynamical configurations rather than inducing a global breakdown of cortical dynamics. Together, these findings indicate that large-scale brain dynamics are not organized along a single pre-existing hierarchical axis, but instead are structured by a limited number of data-driven spectral coordination modes. This framework provides a new dynamical perspective for linking brain organization across modalities and scales, and offers a principled avenue for understanding systematic changes associated with aging and neurological disease.

neuroscience↗

Mitotic bookmarking by Prox1 preserves mammalian neuronal lineage identity memory via promoting timely H3K27me3 restoration

Mitosis poses a daunting challenge to transgenerational inheritance of cell identity memory. How neuronal lineage identity is faithfully transmitted across mitosis remains largely unexplored. Here we report that, in mouse hippocampus, the transcription factor Prox1 acts as a mitotic bookmark for safeguarding neuronal lineage identity across cell divisions. Prox1 exhibits mitotic retention in dentate gyrus (DG) neural stem cells and defines DG lineage identity by suppressing the alternative cornu ammonis (CA) identity. Mitotic bookmarking by Prox1 at key bivalent CA identity genes promotes timely and precise restoration of Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 deposition to avoid ectopic expression of CA identity genes and lineage identity crisis. Remarkably, specific mitotic retention-deficient Prox1 conditional knock-in mice produce severe DG developmental defects. Thus, mitotic bookmarking imprints neuronal lineage identity in mouse hippocampus, which is likely to represent a fundamental principle underlying the preservation of lineage identity memory in mammalian brain development.

developmental biology↗

The Cortical Temporal Axis: MEG-Based Cross-Frequency Gradients with Biological Anchors

Neural oscillations have long been used to characterize the temporal dynamics of individual brain regions, yet a parsimonious, system-level representation that integrates multi-rhythmic activity has been lacking. Using source-localized resting-state magnetoencephalography (MEG) data, we computed regional power spectra and assessed spectral similarity, then applied diffusion map embedding to construct cross-frequency neurophysiological gradients that place whole-brain oscillations within a unified, low-dimensional coordinate system. We found the first three gradients accounted for over 40% of the variance, remained stable across individuals, and aligned with established functional, structural, and geometric cortical axes. Computational modeling showed that these gradients reflect local excitation-inhibition balance, while multimodal analyses revealed strong associations with neurotransmitter receptor distributions, cytoarchitecture, and cell-type-specific gene expression. Lifespan analyses further demonstrated systematic gradient reorganization, with distinct cognitive mappings onto functions such as language, memory, and multisensory integration. Clinically, Parkinsons disease patients displayed disrupted gradients, particularly in regions linked to language and social cognition. Finally, these gradient patterns exhibited high test-retest reliability. These findings establish MEG-derived neurophysiological gradients as robust, low-dimensional representations of cortical organization, offering a biologically grounded framework for studying brain aging and disease.

neuroscience↗

Enhancing salt tolerance in a hybrid poplar (Populus nigra x maximowiczii) through exogenous putrescine application: Growth, physiological, and biochemical responses

IntroductionPutrescine, a polyamine involved in plant growth and stress responses, has shown potential in mitigating abiotic stress effects. However, little is known about the exogenous addition of putrescine regarding salt tolerance in trees. MethodsThis study was conducted to investigate whether exogenous putrescine application via foliar spray enhances growth in a hybrid poplar (Populus nigra x maximowiczii, clone NM6) under a short duration of salt stress. Salt stress was induced by irrigating roots with 100 mM and 200 mM NaCl, followed by foliar spraying of putrescine on several days. Measurement of growth including plant height and stem diameter for each plant were recorded in the greenhouse every 15 days throughout the experiment. Gas exchange, total chlorophyll, carotenoids, soluble sugars and proteins, amino acids, polyamines, and relative water content were analyzed in foliage collected 3, 6, 7, 13, 20, 35 days after treatment. ResultsPutrescine spray on the salt-treated plants caused a significant increase in plant growth. Putrescine application caused a significant increase in fructose, glucose, and galactose in all plants, but putrescine spray had a variable impact on the sucrose content of 100 mM NaCl-treated plants. Based on metabolic responses, plants treated with 100 mM NaCl fared better when sprayed with putrescine than those treated with 200 mM NaCl. DiscussionExogenous application of putrescine mitigated growth inhibition effects of salinity. These finding highlight the potential of putrescine as a practical approach to increase salt tolerance in young poplar trees, with implications for forestry and land reclamation in saline environment.

plant biology↗

Adolescents with major depression featured by sensory-association subtyping show divergent information dynamics and streams

Adolescent major depressive disorder (MDD) exhibits complex and heterogeneous alterations of brain functional organization. To understand the neurobiological basis of adolescent MDD, we adopted resting-state functional MRI data and used various matrix decomposition approaches to obtain the organization gradients, temporal dynamics, and information streams. With clustering sensory-association gradient features in our exploratory sample (NMDD = 250 and NControls = 203), we identified two MDD subtypes. Subtype 1 was characterized by sensory contraction and subtype 2 was associated with association expansion. In addition, two subtypes showed divergent bottom-up and top-down information flows in sensory and association areas using temporal dynamics analysis. These subtypes exhibit distinct age-related changes and reorganization trajectories along sensory-association and auditory-visual axes, highlighting that cortical information flow patterns systematically vary and relate differently to sensory integration, cognitive complexity, and aging. These network distinctions are linked to clinical severity and molecular mechanisms. Subtype 1 is predominantly associated with early neurodevelopmental abnormalities and emotional regulation deficits, while Subtype 2 is more related to synaptic dysfunction and reduced neuronal excitability. These results could be largely replicated in another independent sample (NMDD = 73 and NControls = 28). We therefore construct a sensory-association dual functional framework to characterize MDD heterogeneity in adolescent MDD. Itl integrates cortical hierarchy, developmental trajectories, and genetic influences, offering novel insights into MDD pathophysiology and providing a theoretical foundation for precision psychiatry, facilitating personalized diagnosis and intervention strategies.

neuroscience↗

Multi-task benchmarking of single-cell multimodal omics integration methods

Single-cell multimodal omics technologies have empowered the profiling of complex biological systems at a resolution and scale that were previously unattainable. These biotechnologies have propelled the fast-paced innovation and development of data integration methods, leading to a critical need for their systematic categorisation, evaluation, and benchmark. Navigating and selecting the most pertinent integration approach poses a significant challenge, contingent upon the tasks relevant to the study goals and the combination of modalities and batches present in the data at hand. Understanding how well each method performs multiple tasks, including dimension reduction, batch correction, cell type classification and clustering, imputation, feature selection, and spatial registration, and at which combinations will help guide this decision. This study develops a much-needed guideline on choosing the most appropriate method for single-cell multimodal omics data analysis through a systematic categorisation and comprehensive benchmarking of current methods. The Stage 1 protocol for this Registered Report was accepted in principle on 30th July 2024. The protocol, as accepted by the journal, can be found at https://springernature.figshare.com/articles/journal_contribution/Multi-task_benchmarking_of_single-cell_multimodal_omics_integration_methods/26789902.

bioinformatics↗

MOL-AE: Auto-Encoder Based Molecular Representation Learning With 3D Cloze Test Objective

3D molecular representation learning has gained tremendous interest and achieved promising performance in various downstream tasks. A series of recent approaches follow a prevalent framework: an encoder-only model coupled with a coordinate denoising objective. However, through a series of analytical experiments, we prove that the encoderonly model with coordinate denoising objective exhibits inconsistency between pre-training and downstream objectives, as well as issues with disrupted atomic identifiers. To address these two issues, we propose MO_SCPLOWOLC_SCPLOW-AE for molecular representation learning, an auto-encoder model using positional encoding as atomic identifiers. We also propose a new training objective named 3D Cloze Test to make the model learn better atom spatial relationships from real molecular substructures. Empirical results demonstrate that MO_SCPLOWOLC_SCPLOW-AE achieves a large margin performance gain compared to the current state-of-the-art 3D molecular modeling approach. The source codes of MO_SCPLOWOLC_SCPLOW-AE are publicly available at https://github.com/yjwtheonly/MolAE.

bioinformatics↗

Multi-Scale Protein Language Model for Unified Molecular Modeling

Protein language models have demonstrated significant potential in the field of protein engineering. However, current protein language models primarily operate at the residue scale, which limits their ability to provide information at the atom level. This limitation prevents us from fully exploiting the capabilities of protein language models for applications involving both proteins and small molecules. In this paper, we propose ESM-AA (ESM All-Atom), a novel approach that enables atom-scale and residue-scale unified molecular modeling. ESM-AA achieves this by pretraining on multi-scale code-switch protein sequences and utilizing a multi-scale position encoding to capture relationships among residues and atoms. Experimental results indicate that ESM-AA surpasses previous methods in proteinmolecule tasks, demonstrating the full utilization of protein language models. Further investigations reveal that through unified molecular modeling, ESM-AA not only gains molecular knowledge but also retains its understanding of proteins.1

bioinformatics↗

Biallelic pathogenic variants in DNAH3 cause male infertility in humans and mice

Axonemal protein complexes, including the outer and inner dynein arms (ODA/IDA), are highly ordered structures of the sperm flagella that drive sperm motility. Deficiencies in several axonemal proteins have been associated with male infertility, which is characterized by asthenozoospermia or asthenoteratozoospermia. Dynein axonemal heavy chain 3 (DNAH3) resides in the IDA and is highly expressed in the testis. However, the relationship between DNAH3 and male infertility is still unclear. Herein, we identified biallelic variants of DNAH3 in four unrelated Han Chinese infertile men with asthenoteratozoospermia through whole-exome sequencing (WES). These variants contributed to deficient DNAH3 expression in the patients sperm flagella. Importantly, the patients represented the anomalous sperm flagellar morphology, and the flagellar ultrastructure was severely disrupted. Intriguingly, Dnah3 knockout (KO) male mice were also infertile, especially showing the severe reduction in sperm movement with the abnormal IDA and mitochondrion structure. Mechanically, nonfunctional DNAH3 expression resulted in decreased expression of IDA-associated proteins in the spermatozoa flagella of patients and KO mice, including DNAH1, DNAH6, and DNALI1, the deletion of which has been involved in disruption of sperm motility. Moreover, the infertility of patients with DNAH3 variants and Dnah3 KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment. Our findings indicated that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and may further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.

genetics↗

The Role of Rhizosphere Microorganisms and CNPS Genes in Shaping Nutritional Traits of Capsicum

The rhizosphere microbiota plays crucial roles in biogeochemical cycling and primary production. However, there is a lack of research exploring the complex relationships between microbiota and their functional traits in pepper rhizospheres, as well as their impact on nutrient cycling processes. Here, we investigated the effects of pepper species on the rhizomicrobiota and functional genes (C/N/P/S) on nutrient absorptions and accumulations in pepper organs. The results revealed that Pepper YZ/BE had higher N content in all compartments, which could be attributed to the presence of enriched N-metabolic microbes (Gaiellales/Leifsonia) and higher expression of N availability-promoting genes (ureC/amoA2/nxrA/napA) in rhizospheres. Additionally, we utilized co-occurrence network analysis and partial least squares path modeling (PLS-PM) to understand the interactions among the variables. The bacterial network exhibited more associations than the fungal network, and the abundance of certain modules positively correlated with the expression of CNPS genes, which thus significantly influenced pepper nutrient content. The PLS-PM analysis demonstrated that taxa abundance in network modules, functional genes, and rhizospheric soil properties collectively explained 92% of the variance in pepper nutrient content. Overall, this study provides valuable experimental and theoretical insights into the effects of rhizosphere microorganisms and CNPS genes on the nutritional traits of Capsicum. HighlightThe rizho-bacterial community harbored more robust relationships than the fungal ones, which formed the functional clusters highly linking to the below- and aboveground nutrient properties of pepper species.

microbiology↗

Lithocholic acid targets TULP3 to activate sirtuins and AMPK to retard ageing

Lithocholic acid (LCA), accumulated in the body during calorie restriction (CR), can confer administered metazoans with the ability to activate AMP-activated protein kinase (AMPK) and retard ageing. However, how LCA is signalled to activate AMPK and elicit the biological effects is unclear. Here, we show that LCA can enhance sirtuins (SIRTs) to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), thereby triggering AMPK activation via the lysosomal glucose-sensing pathway. Through proteomic analysis of SIRT1-coimmunoprecipitated proteins, we identify and validate that TUB like protein 3 (TULP3) is a constitutive component of SIRTs. Surprisingly, we found that TULP3 is an LCA receptor, and that the LCA-bound TULP3 activates SIRTs. The activated SIRTs in turn deacetylate the V1E1 subunit of v-ATPase on K52, K99 and K191 residues. Muscle-specific expression of the 3KR mutant of V1E1, mimicking the deacetylated state, dominantly activates AMPK and rejuvenates muscles in aged mice. Moreover, LCA once administered also activates AMPK and extends lifespan and healthspan in nematodes and flies, depending on the TULP3 homologues tub-1 and ktub, respectively. Our study thus elucidates that LCA triggers the TULP3-sirtuin-v-ATPase- AMPK route to manifest benefits of calorie restriction.

physiology↗

Lithocholic acid phenocopies rejuvenating and life-extending effects of calorie restriction

Calorie restriction (CR) is a dietary intervention to promote health and longevity. CR causes various metabolic changes in both the production and circulation of metabolites; however, it remains unclear which of the changed metabolite(s) can account for the physiological benefits of CR. Through metabolomic analysis of metabolites undergoing abundance changes during CR and subsequent functional validation, we found that lithocholic acid (LCA) is the only metabolite that alone can recapitulate the effects of CR, including activation of AMPK and the rejuvenating effects of muscle regeneration, grip strength and running capacity in mice. Interestingly, LCA also activates AMPK and exerts life- and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster, indicating that these animal models are able to transmit the signalling of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes, in nematodes and flies, as well as in mice. Together, we have identified that administration of the CR-upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans, in an AMPK-dependent manner.

physiology↗

The Toxoplasma monocarboxylate transporters are involved in the metabolism within the apicoplast and are linked to parasite survival

The apicoplast is a four-membrane plastid found in the apicomplexans, which harbors biosynthesis and organelle housekeeping activities in the matrix. However, the mechanism driving the flux of metabolites, in and out, remains unknown. Here we used TurboID and genome engineering to identify apicoplast transporters in Toxoplasma gondii. Among the many novel transporters, we show that one pair of apicomplexan monocarboxylate transporters (AMTs) appears to have evolved from a putative host cell that engulfed a red alga. Protein depletion showed that AMT1 and AMT2 are critical for parasite growth. Metabolite analyses supported the notion that AMT1 and AMT2 are associated with biosynthesis of isoprenoids and fatty acids. However, stronger phenotypic defects were observed for AMT2, including in the inability to establish T. gondii parasite virulence in mice. This study clarifies, significantly, the mystery of apicoplast transporter composition and reveals the importance of the pair of AMTs in maintaining the apicoplast activity in apicomplexans.

microbiology↗