Biology subjects

Dang, S.

Publications and source records attributed to Dang, S..

At least 19 recordsLinked to original sources

bioRxiv2026

MICROSTRUCTURAL ORGANIZATION OF CORTICO-SUBCORTICAL FUNCTIONAL CONVERGENCE

The human subcortex integrates information from distributed cortical regions through functionally organized cortico-subcortical systems. Using the publicly available MICA-MICs multimodal MRI dataset of 50 healthy adults, we characterized the microstructural organization of functionally converging cortical regions. First, using resting-state fMRI., we identified cortical regions converging on subcortical targets, including thalamic, basal ganglia, and subcortical limbic structures. Then, using depth-resolved quantitative T1 profiles, we constructed a convergence-restricted microstructural profile covariance matrix, followed by diffusion-map embedding. The first microstructural gradient predominantly differentiated primary and association cortex, whereas the second gradient showed target-related differentiation beyond differences in primary versus association cortex. Cytoarchitectural analysis further revealed target-related differences in cortical composition. Together, these findings reveal complementary dimensions of cortico-subcortical functional organization, spanning broad cortical hierarchy, target-related microstructural differentiation, and cytoarchitectural composition.

neuroscience↗

bioRxiv2026

KlinkPPI: Single Point of Access to Protein-Protein Interactions Across Databases

Protein-protein interaction (PPI) information is distributed across resources that differ in organism coverage, identifier systems, evidence models, confidence scores and access mechanisms, so assembling and comparing evidence for a protein requires source-specific queries, identifier conversion and extensive post-processing. We present KlinkPPI, a web server that retrieves, compares and exports PPI evidence from STRING, BioGRID, IntAct, CORUM, HuRI and Predictomes from a single query. KlinkPPI accepts UniProtKB accessions, NCBI Gene and Ensembl identifiers and gene names, and performs taxonomy-aware mapping to a common identifier space. Users can query individual proteins across all resources available for an organism, or retrieve organism-wide interaction sets. Results are presented per source so that database-specific evidence, annotations and confidence values are retained, while an integrated view exposes coverage and agreement between resources. KlinkPPI deliberately does not merge heterogeneous confidence scores, nor collapse functional associations, complex co-membership, binary interactions and structural predictions into a single consensus network. Results can be exported in PSI-MI TAB 2.8-compatible or Apache Parquet format with user-selected evidence fields. KlinkPPI is freely available at https://rappsilberlab.org/KlinkPPI/ and the source code at https://github.com/Rappsilber-Laboratory/KlinkPPI. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/742057v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@12dcaceorg.highwire.dtl.DTLVardef@15d9d0aorg.highwire.dtl.DTLVardef@f0fc39org.highwire.dtl.DTLVardef@13f172e_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Distinct Computational and Temporal Mechanisms Underlie the Joint Effects of Motivation and Working Memory on Perceptual Sensitivity

Human perception is continuously shaped by internal cognitive states, yet how motivation and working memory jointly influence perceptual sensitivity remains poorly understood. Here, we combined behavioural experiments, computational modelling, and pupillometry to determine whether motivation enhances perception by amplifying working memory (WM)-driven facilitation or whether both exert independent influences. Participants performed a near-threshold visuospatial discrimination task under systematically manipulated motivational and WM states. Behaviourally, both motivation and WM independently improved perceptual performance, producing the greatest enhancement when both were present. A Bayesian generalized linear psychometric model revealed that these improvements were best explained by independent additive contributions to effective perceptual sensitivity, rather than motivational amplification of WM. Consistent with this computational framework, pupil dynamics tracked trial-by-trial fluctuations in effective perceptual sensitivity while revealing temporally dissociable influences of WM and motivation during perceptual decision making. Together, our findings demonstrate that the joint effects of motivation and working memory arise from distinct computational and temporal mechanisms, providing a unified framework for understanding top-down regulation of human perception.

neuroscience↗

bioRxiv2026

Pupil responses reveal temporally distinct signatures of value updating and decision strategy

Adaptive decision making depends on dopaminergic and noradrenergic systems supporting value learning and exploratory decision strategies, respectively, yet their contributions remain difficult to dissociate non-invasively. Here, we investigated whether pupil dynamics provide dissociable readouts of computational processes underlying value-based decision making across sensory modalities, potentially reflecting distinct neuromodulatory processes. Human participants performed a dynamic foraging task in which they chose between auditory, visual, or audio-visual options based on their estimated value, alongside a control task where choices were instructed. Behavior in the value-based task was well captured by a probabilistic choice model, revealing adaptive integration of reward history and a balance between exploration and exploitation. Pupil responses revealed temporally distinct computational signatures of decision strategy and value updating. Reaction time was associated with sustained pupil dilation throughout the decision process, whereas value differences between chosen and unchosen options selectively modulated pupil responses during stimulus evaluation and following feedback. These findings are consistent with computational processes linked to noradrenergic regulation of exploration-exploitation behavior and dopaminergic value updating, respectively. Both effects were significantly stronger during value-based than instructed decisions, indicating enhanced engagement of these computational processes when choices depended on learned reward values. Importantly, these effects were largely modality-independent, indicating a domain-general encoding of computational variables. Together, these findings identify pupil dynamics as a temporally sensitive and non-invasive marker of distinct computational stages underlying adaptive decision making and establish a framework for linking pupillometry to neuromodulatory theories of value learning and uncertainty processing.

neuroscience↗

bioRxiv2026

Higher-order intrinsic routes support flexible task-evoked communication

Flexible task-evoked communication requires the brain to transiently establish functional interactions that are not evident during rest, yet the network mechanisms supporting these newly formed connections remain unresolved. Using whole-brain functional MRI from 92 participants performing six cognitive tasks, we show that task-evoked communication is implemented within a constrained intrinsic network architecture rather than through large-scale rewiring. Across tasks, we found that approximately 70% of functional connections were preserved from rest, forming a dominant stable core, while task engagement selectively reconfigured a smaller subset of connections, primarily at the between-network level. While existing activity-flow models explain task-evoked information transfer primarily through direct stable core connections, we demonstrate that newly formed connections between regions lacking direct resting-state coupling were supported by selectively strengthened indirect higher-order resting-state routes embedded within the intrinsic scaffold. Network-level analyses revealed a multiscale organization of information transfer: we observed that direct stable routes dominated within-network communication, most prominently in sensory-motor and default mode systems, whereas indirect higher-order routes preferentially supported between-network integration through control and attentional systems. By extending activity-flow modelling to incorporate these higher-order intrinsic routes, we show a significant improvement in the prediction of task-evoked activity at the global, between-network scale, confirming their functional recruitment during task performance. Together, our findings identify higher-order intrinsic routes as a key mechanism enabling flexible task-evoked communication within a stable large-scale network architecture.

neuroscience↗

bioRxiv2025

Sequencing-free whole genome spatial transcriptomics at molecular resolution in intact tissue

Recent breakthroughs in spatial transcriptomics technologies have enhanced our understanding of diverse cellular identities, compositions, interactions, spatial organizations, and functions. Yet existing spatial transcriptomics tools are still limited in either transcriptomic coverage or spatial resolution. Leading spatial-capture or spatial-tagging transcriptomics techniques that rely on in-vitro sequencing offer whole-transcriptome coverage, in principle, but at the cost of lower spatial resolution compared to image-based techniques. In contrast, high-performance image-based spatial transcriptomics techniques, which rely on in situ hybridization or in situ sequencing, achieve single-molecule spatial resolution and retain sub-cellular morphologies, but are limited by probe libraries that target only a subset of the transcriptome, typically covering several hundred to a few thousand transcript species. Together, these limitations hinder unbiased, hypothesis-free transcriptomic analyses at high spatial resolution. Here we develop a new image-based spatial transcriptomics technology termed Reverse-padlock Amplicon Encoding FISH (RAEFISH) with whole-genome level coverage while retaining single-molecule spatial resolution in intact tissues. We demonstrate image-based spatial transcriptomics targeting 23,000 human transcript species or 22,000 mouse transcript species, including nearly the entire protein-coding transcriptome and several thousand long-noncoding RNAs, in single cells in cultures and in tissue sections. Our analyses reveal differential subcellular localizations of diverse transcripts, cell-type-specific and cell-type-invariant tissue zonation dependent transcriptome, and gene expression programs underlying preferential cell-cell interactions. Finally, we further develop our technology for direct spatial readout of gRNAs in an image-based high-content CRISPR screen. Overall, these developments provide the research community with a broadly applicable technology that enables high-coverage, high-resolution spatial profiling of both long and short, native and engineered RNA species in many biomedical contexts.

genetics↗

bioRxiv2025

Cortico-subcortical converging organization at rest

Higher-order cognitive function relies on information convergence between functionally specialized communities. It is unknown how subcortex configures itself with respect to the local segregation and global integration dynamics at rest. Using functional MRI, we revealed three non-overlapping communities confined anatomically to thalamus, basal ganglia, and subcortical limbic structures and network "hubs". Further, using statistical modelling we quantified the extent of convergence and found multiple, widespread cortical regions converging onto individual subcortical regions. We revealed a topographic organization of cortical convergence within subcortical resting state networks, such that thalamic, basal ganglia, subcortical limbic networks received convergence from cortical areas involved in sensorimotor integration, associative and motor control, limbic functions, respectively. Further, we found functional diversity of cortex to be the major driving factor behind cortical convergence within subcortex and that the absence of subcortical regions significantly impacted the information-transmission efficiency within the converging organization, underscoring the subcortical contributions to brain dynamics.

neuroscience↗

bioRxiv2024

Clathrin-associated carriers enable recycling through a kiss-and-run mechanism

Endocytosis and recycling control the uptake and retrieval of various materials, including membrane proteins and lipids, in all eukaryotic cells. These processes are crucial for cell growth, organization, function, and environmental communication. However, the mechanisms underlying efficient, fast endocytic recycling remain poorly understood. Here, by utilizing a biosensor and imaged-based screening, we uncover a novel recycling mechanism that couples endocytosis and fast recycling, which we name the clathrin-associated fast endosomal recycling pathway (CARP). Clathrin-associated tubulovesicular carriers containing clathrin, AP1, Arf1, Rab1, and Rab11, while lacking the multimeric retrieval complexes, are generated at subdomains of early endosomes, and then transported along actin to cell surfaces. Unexpectedly, the clathrin-associated recycling carriers undergo partial fusion with the plasma membrane. Subsequently, they are released from the membrane by dynamin and reenter cells. Multiple receptors utilize and modulate CARP for fast recycling following endocytosis. Thus, CARP represents a novel endocytic recycling mechanism with kiss-and-run membrane fusion.

cell biology↗

bioRxiv2024

Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions

The class I PI3K-AKT signaling pathway is the master regulator of cell survival, growth, and proliferation, and among the most frequently mutated pathways in cancer. However, where and how the PI3K-AKT signaling is spatially activated and organized in mammalian cells remain poorly understood. Here, we identified focal adhesions (FAs) as the subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P3-AKT signaling in mammalian cells. We found that class IA PI3Ks are preferentially and dynamically recruited to FAs for activation, resulting in localized production of the critical signaling lipid PI(3,4,5)P3 around FAs. As the effector protein of PI(3,4,5)P3, AKT molecules are dynamically recruited around FAs for activation. Mechanistically, the spatial recruitment/activation of PI3K-PI(3,4,5)P3-AKT cascade are regulated by the activated FAK. Furthermore, combined inhibition of class I PI3K and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P3-AKT signaling.

cell biology↗

bioRxiv2024

Logic-based modeling of biological networks with Netflux

Molecular signaling networks drive a diverse range of cellular decisions, including whether to proliferate, how and when to die, and many processes in between. Such networks often connect hundreds of proteins, genes, and processes. Understanding these complex networks is aided by computational modeling, but these tools require extensive programming knowledge. In this article, we describe a user-friendly, programming-free network simulation tool called Netflux (https://github.com/saucermanlab/Netflux). Over the last decade, Netflux has been used to construct numerous predictive network models that have deepened our understanding of how complex biological networks make cell decisions. Here, we provide a Netflux tutorial that covers how to construct a network model and then simulate network responses to perturbations. Upon completion of this tutorial, you will be able to construct your own model in Netflux and simulate how perturbations to proteins and genes propagate through signaling and gene-regulatory networks.

bioengineering↗

bioRxiv2024

Spatiotemporal recruitment of the ubiquitin-specific protease USP8 directs endosome maturation

The spatiotemporal transition of small GTPase Rab5 to Rab7 is crucial for early-to-late endosome maturation, yet the precise mechanism governing Rab5-to-Rab7 switching remains elusive. USP8, a ubiquitin-specific protease, plays a prominent role in the endosomal sorting of a wide range of transmembrane receptors and is a promising target in cancer therapy. Here, we identified that USP8 is recruited to Rab5-positive carriers by Rabex5, a guanine nucleotide exchange factor (GEF) for Rab5. The recruitment of USP8 dissociates Rabex5 from early endosomes (EEs) and meanwhile promotes the recruitment of the Rab7 GEF SAND-1/Mon1. In USP8-deficient cells, the level of active Rab5 is increased, while the Rab7 signal is decreased. As a result, enlarged EEs with abundant intraluminal vesicles accumulate and digestive lysosomes are rudimentary. Together, our results reveal an important and unexpected role of a deubiquitinating enzyme in endosome maturation.

cell biology↗

bioRxiv2023

Cryo-EM structure of TMEM63C suggests it functions as a monomer

The TMEM63 family proteins (A, B, and C), calcium-permeable channels in animals that are preferentially activated by hypo-osmolality, have been implicated in various physiological functions. Deficiency of these channels would cause many diseases including hearing loss. However, their structures and physiological roles are not yet well understood. In this study, we determined the cryo-EM structure of the mouse TMEM63C at 3.56 [A], and revealed structural differences compared to its plant orthologues OSCAs. Further structural guided mutagenesis and electrophysiological studies demonstrated the important roles of the coupling of TM0 and TM6 in channel activity. Additionally, we confirmed that the physiological state of TMEM63C is monomer, while TMEM63B is a mix of monomer and dimer in cells, suggesting that oligomerization is a novel regulatory mechanism for TMEM63 proteins.

biophysics↗

bioRxiv2023

Structural study of membrane proteins using vesicles

Membrane proteins play crucial roles in numerous biological processes and are important drug targets. However, structural studies of memebrane proteins heavily rely on solubilization by detergents, which may not reflect their native states in the cellular context. Moreover, identifying suitable detergents for individual membrane proteins is a tedious and costly screening process. Here, we developed a vesicle-based method that enables membrane protein structure determination in their native lipid environment, thereby bypassing the limitations of detergent solubilization. Using this approach, we isolated vesicles containing the multidrug efflux transporter AcrB and solved its structure by cryo-electron microscopy. Intriguingly, the AcrB trimer in the vesicle exhibited a loose assembly compared to the detergent-solubilized and nanoparticle structures. Our method presents a promising approach for studying structure and function of membrane protein in their native environment without the need for detergent screening and protein purification.

biophysics↗

bioRxiv2023

Distinct mechanisms underlie value-driven modulation of visual cortex by previously rewarded visual and auditory stimuli

Past reward associations may be signaled by stimuli from different sensory modalities, however it remains unclear how different types of reward-associated stimuli modulate perception. In this human fMRI study, we employed a paradigm involving a visual discrimination task, where a visual target was simultaneously presented with either an intra-(visual) or a cross-modal (auditory) cue that was previously associated with rewards. We hypothesized that depending on the sensory modality of the cues distinct neural pathways underlie the value-driven modulation of visual areas. Two steps of analyses were conducted: first, using a multivariate approach, we confirmed that previously reward-associated cues enhanced the target representation in the early visual areas. Then, using effective connectivity analysis, we tested three possible patterns of communication across the brain regions that could underlie the modulation of visual cortex: a direct pathway from the frontal valuation areas to the visual areas, a mediated pathway through the attention-related areas, and a mediated pathway that additionally involved distinct sensory association areas for auditory and visual rewards. We found evidence for the third model and demonstrate that reward-related information is communicated across the valuation and attention-related brain regions such as the intraparietal sulcus across for both visual and auditory cues. Additionally, the long-range communication of reward information also involved the superior temporal areas in case of auditory reward-associated stimuli. These results suggest that in the presence of previously rewarded stimuli from different sensory modalities, a combination of domain-general and domain-specific mechanisms are recruited across the brain to adjust visual processing.

neuroscience↗

bioRxiv2022

Modality-specific and modality-general representations of reward value in frontal cortex

Standard neuroeconomics theories state that the value of different classes of stimuli, for instance the hedonic value of food versus music, is transformed to a common reference scale that is independent of their sensory properties. However, adaptive behaviour in a multimodal dynamic environment requires that our brain also encodes information about the sensory features of rewarding stimuli. How these two processes, i.e. deriving a common reference scale for valuation and maintaining sensitivity to the sensory contexts for goal-directed behaviour, are implemented in the brain remains inadequately understood. Here, we acquired fMRI data while human participants were engaged in a dynamic foraging task requiring them to integrate the reward history of auditory or visual choice options and update the subjective value assigned to each sensory modality. Univariate fMRI analysis revealed modality-specific and modality-general value representations in orbitofrontal cortex (OFC) and ventromedial prefrontal cortex (vmPFC), respectively. Crucially, modality-specific value representations were absent when the task involved instruction-based rather than value-based choices. The analysis of effective connectivity further demonstrated that the modality-specific value representations emerged as a result of selective bidirectional interactions across the auditory and visual sensory cortices, the corresponding OFC clusters and the vmPFC. These results show how a valuation process that is sensitive to the sensory context of rewarding stimuli is enabled in the brain.

neuroscience↗

bioRxiv2022

Application of metallo-supramolecular branched polymer improves particle distribution and orientation in single-particle cryo-EM

Recent technological breakthroughs in single-particle cryo-electron microscopy (cryo-EM) enabled rapid atomic structure determination of biological macromolecules. A major bottleneck in the current single particle cryo-EM pipeline is the preparation of good quality frozen cryo-EM grids, which is mostly a trial-and-error process. Among many issues, preferred particle orientation and sample damage by air-water interface (AWI) are common practical problems. Here we reported a method of applying metallo-supramolecular branched polymer (MSBP) in the cryo-sample preparation for high-resolution single-particle cryo-EM. Our data shows that MSBP keeps a majority of particles away from air-water interface and mitigates preferred orientation as verified by the analyses of apoferritin, hemagglutinin (HA) trimer and various sample proteins. The use of MSBP is a simple method to improve particle distribution for high-resolution structure determination in single-particle cryo-EM.

biophysics↗

bioRxiv2021

Integration of the cyanophage-encoded phosphate binding protein into the cyanobacterial phosphate uptake system

To acquire phosphorus, cyanobacteria use the typical bacterial ABC-type phosphate transporter, which is composed of a periplasmic high-affinity phosphate-binding protein PstS and a channel formed by two transmembrane proteins PstC and PstA. The pstS gene has been identified in the genomes of cyanophages that infect the unicellular cyanobacteria Prochlorococcus and Synechococcus. However, it is unknown how the cyanophage PstS interplays with the host PstC and PstA to function as a chimeric ABC transporter. Here we showed that the cyanophage P-SSM2 PstS protein was abundant in the infected Prochlorococcus NATL2A cells and the host phosphate uptake rate was enhanced after infection. This is consistent with our biochemical and structural analyses showing that the phage PstS protein is indeed a high-affinity phosphate-binding protein. We further modeled the complex structure of phage PstS with host PstCA and revealed three putative interfaces that may facilitate the formation of the chimeric ABC transporter. Our results provide insights into the molecular mechanism by which cyanophages enhance the phosphate uptake rate of cyanobacteria. Phosphate acquisition by infected bacteria can increase the phosphorus contents of released cellular debris and virus particles, which together constitute a significant proportion of the marine dissolved organic phosphorus pool.

microbiology↗

bioRxiv2021

The effects of host availability and fitness on Aedes albopictus blood feeding patterns in New York

Aedes albopictus is a competent vector of numerous pathogens, representing a range of transmission cycles involving unique hosts. Despite the important status of this vector, variation in its feeding patterns is poorly understood. We examined the feeding patterns of Ae. albopictus utilizing resting collections in Long Island, New York, and contextualized blood meal sources with host availability measured by household interviews and camera traps. We identified 90 blood meals, including 29 human, 22 cat, 16 horse, 12 opossum, 5 dog, 2 goat, and 1 rabbit, rat, squirrel and raccoon. Our study is the first to quantitatively assess Ae. albopictus feeding patterns in the context of host availability of wild animals in addition to humans and domestic animals. Host feeding indices showed that cats and dogs were fed upon disproportionately often compared to humans. Forage ratios suggested a tendency to feed on cats and opossums and to avoid raccoons, squirrels, and birds. This feeding pattern was different from another published study from Baltimore, where Ae. albopictus fed more often on rats than humans. To understand if these differences were due to host availability or mosquito population variation, we compared the fitness of Long Island and Baltimore Ae. albopictus after feeding on rat and human blood. In addition, we examined fitness within the Long Island population after feeding on human, rat, cat, horse, and opossum blood. Together, our results do not show major mosquito fitness differences by blood hosts, suggesting that fitness benefits do not drive Northeastern Ae. albopictus feeding patterns.

ecology↗