Biology subjects

Peng, A.

Publications and source records attributed to Peng, A..

13 recordsLinked to original sources

bioRxiv2026

Intrinsic fluctuations modulate thalamic gating during the emergence of human conscious perception

Human conscious perception is not determined solely by external sensory input but is also shaped by moment-to-moment fluctuations in intrinsic brain states. However, how these intrinsic states directly function after stimulus onset to shape the emergence of conscious perception remains unclear. We recorded sEEG activity in thalamus and five other consciousness-related cortical regions, while 32 patients (n= 2,023 recording sites) conscious percept a near-threshold visual stimulus. Preceding the extensively evoked consciousness-related activities, there are early activities (0-200ms after stimulus onset) exclusively appeared in high-order thalamus. These early activities inversely associated with stimulus strength, which reflected an intrinsic state that compensated for the stimulus-evoked response to reach the conscious threshold. These early activities were closer to the critical state in conscious trials, which enables more efficient information processing. These results suggest that intrinsic fluctuations in the high-order thalamus directly modulate thalamic gating during the emergence of conscious perception.

neuroscience↗

bioRxiv2026

ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity

Natural Killer (NK) cell desensitization induced by persistent stimulation limits durable antitumor immunity, yet the molecular mechanisms governing this dysfunctional state remain poorly defined. To identify conserved regulators of NK cell desensitization, we performed comparative transcriptomic analyses across multiple murine models of persistent activation and dysfunction. This approach defined a shared transcriptional program of desensitization and identified Itpkb to be upregulated across multiple distinct contexts. Genetic and pharmacological inhibition of ITPKB enhanced degranulation, cytokine production, and cytotoxicity in both murine and human NK cells under multiple desensitization settings. Mechanistically, ITPKB regulated signaling downstream of persistent activation through the IP3/IP4 axis, limiting calcium mobilization and NFAT-dependent transcriptional responses in desensitized NK cells. Furthermore, inhibition or deletion of ITPKB enhanced NK-cell mediated tumor control in vivo and improved the efficacy of adoptively transferred CAR-NK cells, underscoring the translational potential of targeting this pathway. Together, these findings identify ITPKB as a cell-intrinsic regulator of NK cell desensitization and support targeting the IP3/IP4 signaling axis to enhance NK cell-mediated antitumor immunity.

immunology↗

bioRxiv2026

Rapid gene exchange explains differences in bacterial pangenome structure

The size and diversity of bacterial gene repertoires, known as pangenomes, vary widely across species. The evolutionary forces driving the maintenance of pangenomes is an open topic of debate, with contradictory theories suggesting that pangenomes exist as a result of neutral evolution, with all genes gained and lost at random, or that all genes provide a fitness benefit to the host and are maintained by positive selection. Modelling of pangenome dynamics has provided insight into how gene exchange explains observed gene frequency distributions, and stands as the only means of jointly inferring contributions of individual gene selection effects and mobility on the maintenance of pangenomes. However, previous modelling studies have not included both gene-level selection and mobility, and do not consider broadly sampled genome datasets for many species. To differentiate neutral and selective forces maintaining pangenomes, we developed a mechanistic model of gene-level evolution, Pansim, and a scalable model fitting framework, PopPUNK-mod. Together, these tools leverage rapid genome distance calculation to fit models of pangenome dynamics to datasets containing hundreds of thousands of genomes. We used this framework to compare the pangenome dynamics of over 400 different bacterial species, using over 600,000 genomes. We find that diversity in pangenome characteristics between species is driven predominantly by variation in the number of rapidly exchanged genes, while the rate of exchange of remaining genes is conserved. We find that bacterial phylogeny, rather than ecology, correlates with pangenome dynamics. We express that pan-species gene-level analyses are now needed to understand selection across accessory genes. Our work highlights the importance of gene exchange rate differences in governing differences in pangenome characteristics between species.

bioinformatics↗

bioRxiv2025

Recovery of retinal terminal fields after traumatic brain injury: evidence of collateral sprouting and sexual dimorphism

The central nervous system is characterized by its limited regenerative potential, yet striking examples of functional recovery after injury in animal models and humans highlight its capacity for repair. Little is known about repair of pathways/circuits after traumatic brain injury (TBI), which results in disruption of connectivity. Here we utilize a mouse model of diffuse traumatic axonal injury (Impact-acceleration TBI) in order to explore, for the first time, the evolution of structural and functional changes in the terminal fields of the injured visual system. Retinal ganglion cell (RGC) axons and synapses were genetically labeled via AAV transduction, while anterograde and transsynaptic tracers were used to mark terminals and postsynaptic cells. Functional connectivity and visual integrity were assessed by monitoring c-Fos expression following light stimulation and pattern-reversal visual evoked potentials (pVEPs). Our findings demonstrate that, although TAI results in approximately a 50% loss of RGC axons and terminals, surviving RGCs undergo collateral sprouting, a form of compensatory branching of surviving axons, that restores terminal density to pre-injury levels. Transsynaptic tracing and c-Fos mapping confirmed the reestablishment of connectivity, which was also associated with significant improvements in visual function as measured by pVEPs. Interestingly, the recovery process exhibited sexual dimorphism, with female mice showing delayed or incomplete repair. Moreover, collateral sprouting proceeded normally in Sarm1 knockout mice, evidence of some independence from Wallerian degeneration. Our findings show that collateral sprouting may be an important mechanism of circuit repair in TAI and may represent a promising target for therapeutic interventions. SignificanceHomotypic collateral sprouting -the process by which uninjured axons from the same neuronal source extend new branches to reinnervate targets deprived of their original connections- is a fundamental yet understudied mechanism for CNS repair following injury. Unlike heterotypic sprouting, involving sprouting from unrelated pathways, homotypic sprouting offers potential to restore circuit architecture after partial lesions. Here, we employed a model of diffuse axonal injury in the mouse visual system to examine this mechanism. Our research demonstrates surviving retinal ganglion cell axons can re-establish terminal fields, achieving structural and functional connectivity. Importantly, we discovered significant sex differences: female mice showed delayed/incomplete recovery compared to males. These findings provide evidence of repair of brain circuits perturbed by TBI and the role of homotypic sprouting.

neuroscience↗

bioRxiv2025

Exploring sustainability through the lens of the Lotka-Volterra model in population ecology

The Lotka-Volterra equations, a cornerstone of predator-prey modeling, offer a versatile framework for understanding population dynamics in the context of sustainability. This chapter explores how these equations, through the analysis of dynamic equilibrium and stability, illuminate principles of both sustainable ecological interactions and the mechanisms leading to detrimental long-term out-comes in various systems (negative sustainability). We first analyze predator-prey interactions to gain insights into population management, resource conservation, and the delicate balance of ecosystems. Furthermore, we extend the Lotka-Volterra model to discuss its broader implications for complex systems dynamics in diverse fields, such as in modeling economic competition and arms races, where the framework helps identify pathways that lead to unsustainable resource consumption, increased risk, or collapse.

ecology↗

bioRxiv2024

DnaB and DciA: Mechanisms of Helicase Loading and Translocation on ssDNA

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/622779v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@b0641dorg.highwire.dtl.DTLVardef@7caf59org.highwire.dtl.DTLVardef@1dc0fccorg.highwire.dtl.DTLVardef@913ce2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO The Vibrio cholerae (Vc) DnaB replicative helicase structure bound to single-stranded (ss) DNA is depicted in the ribbon (top left) and sphere-cylinder representation (top right). In the bottom center is a native mass spectrum showing Vc DnaB helicase loading onto single-stranded DNA (ssDNA). C_FIG Replicative helicases are assembled on chromosomes by helicase loaders before initiation of DNA replication. Here, we investigate mechanisms used by the bacterial Vibrio cholerae (Vc) DnaB replicative helicase and the DciA helicase loader. Structural analysis of the ATP{gamma}S form of the VcDnaB-ssDNA complex reveals a configuration distinct from that seen with GDP*AlF4. With ATP{gamma}S, the amino-terminal (NTD) tier, previously found as an open spiral in the GDP*AlF4 complex, adopts a closed planar arrangement. Further, the DnaB subunit at the top of the carboxy-terminal spiral (CTD) tier is displaced by [~]25 [A] between the two forms. We suggest that remodeling the NTD layer between closed planar and open spiral configurations and migration of two distinct CTDs to the top of the DnaB spiral, repeated three times, mediates hand-over-hand translocation. Biochemical analysis suggests that VcDciA leverages its Lasso domain to contact DnaB near its Docking-Linker-Helix interface. Up to three copies of VcDciA bind to VcDnaB and suppress its ATPase activity during loading onto physiological DNA substrates. Our data suggest that DciA loads DnaB onto DNA using the ring-opening mechanism.

biochemistry↗

bioRxiv2024

Corticostriatal Maldevelopment in the R6/2 Mouse Model of Juvenile Huntington Disease

There is a growing consensus that brain development in Huntingtons disease (HD) is abnormal, leading to the idea that HD is not only a neurodegenerative but also a neurodevelopmental disorder. Indeed, structural and functional abnormalities have been observed during brain development in both humans and animal models of HD. However, a concurrent study of cortical and striatal development in a genetic model of HD is still lacking. Here we report significant alterations of corticostriatal development in the R6/2 mouse model of juvenile HD. We examined wildtype (WT) and R6/2 mice at postnatal (P) days 7, 14, and 21. Morphological examination demonstrated early structural and cellular alterations reminiscent of malformations of cortical development, and ex vivo electrophysiological recordings of cortical pyramidal neurons (CPNs) demonstrated significant age- and genotype-dependent changes of intrinsic membrane and synaptic properties. In general, R6/2 CPNs had reduced cell membrane capacitance and increased input resistance (P7 and P14), along with reduced frequency of spontaneous excitatory and inhibitory synaptic events during early development (P7), suggesting delayed cortical maturation. This was confirmed by increased occurrence of GABAA receptor-mediated giant depolarizing potentials at P7. At P14, the rheobase of CPNs was significantly reduced, along with increased excitability. Altered membrane and synaptic properties of R6/2 CPNs recovered progressively, and by P21 they were similar to WT CPNs. In striatal medium-sized spiny neurons (MSNs), a different picture emerged. Intrinsic membrane properties were relatively normal throughout development, except for a transient increase in membrane capacitance at P14. The first alterations in MSNs synaptic activity were observed at P14 and consisted of significant deficits in GABAergic inputs, however, these also were normalized by P21. In contrast, excitatory inputs began to decrease at this age. We conclude that the developing HD brain is capable of compensating for early developmental abnormalities and that cortical alterations precede and are a main contributor of striatal changes. Addressing cortical maldevelopment could help prevent or delay disease manifestations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=170 HEIGHT=200 SRC="FIGDIR/small/618500v1_ufig1.gif" ALT="Figure 1000"> View larger version (38K): org.highwire.dtl.DTLVardef@16db9eborg.highwire.dtl.DTLVardef@c9329borg.highwire.dtl.DTLVardef@1198fc1org.highwire.dtl.DTLVardef@12ce530_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

The X-Linked Intellectual Disability gene, ZDHHC9, is important for oligodendrocyte maturation and myelin formation

Two percent of patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a concurrent disruption in white matter integrity. In this study, we demonstrate that deletion of Zdhhc9 in mice disrupts the balance of mature oligodendrocyte subtypes within the corpus callosum. While overall mature oligodendrocyte numbers are unchanged, there is a marked increase in MOL5/6 cells that are enriched in genes associated with cell adhesion and synapses, and a concomitant decrease in MOL2/3 cells that are enriched in genes associated with myelination. In line with this, we observed a decrease in the density of myelinated axons and disruptions in myelin compaction in the corpus callosum of Zdhhc9 knockout mice. RNA sequencing and proteomic analysis further unveiled a reduction in genes and proteins essential for lipid metabolism, cholesterol synthesis, and myelin compaction. These findings reveal a previously under-appreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte subtype determination and myelinogenesis, offering mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.

neuroscience↗

bioRxiv2023

The ATM-E6AP-MASTL axis mediates DNA damage checkpoint recovery

Checkpoint activation after DNA damage causes a transient cell cycle arrest by suppressing CDKs. However, it remains largely elusive how cell cycle recovery is initiated after DNA damage. In this study, we discovered the upregulated protein level of MASTL kinase hours after DNA damage. MASTL promotes cell cycle progression by preventing PP2A/B55-catalyzed dephosphorylation of CDK substrates. DNA damage-induced MASTL upregulation was caused by decreased protein degradation, and was unique among mitotic kinases. We identified E6AP as the E3 ubiquitin ligase that mediated MASTL degradation. MASTL degradation was inhibited upon DNA damage as a result of the dissociation of E6AP from MASTL. E6AP depletion reduced DNA damage signaling, and promoted cell cycle recovery from the DNA damage checkpoint, in a MASTL-dependent manner. Furthermore, we found that E6AP was phosphorylated at Ser-218 by ATM after DNA damage and that this phosphorylation was required for its dissociation from MASTL, the stabilization of MASTL, and the timely recovery of cell cycle progression. Together, our data revealed that ATM/ATR-dependent signaling, while activating the DNA damage checkpoint, also initiates cell cycle recovery from the arrest. Consequently, this results in a timer-like mechanism that ensures the transient nature of the DNA damage checkpoint.

cell biology↗

bioRxiv2023

MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva

Circulating cell-free mitochondrial DNA (cf-mtDNA) is an emerging biomarker of psychobiological stress and disease which predicts mortality and is associated with various disease states. To evaluate the contribution of cf-mtDNA to health and disease states, standardized high-throughput procedures are needed to quantify cf-mtDNA in relevant biofluids. Here, we describe MitoQuicLy: Mitochondrial DNA Quantification in cell-free samples by Lysis. We demonstrate high agreement between MitoQuicLy and the commonly used column-based method, although MitoQuicLy is faster, cheaper, and requires a smaller input sample volume. Using 10 {micro}L of input volume with MitoQuicLy, we quantify cf-mtDNA levels from three commonly used plasma tube types, two serum tube types, and saliva. We detect, as expected, significant inter-individual differences in cf-mtDNA across different biofluids. However, cf-mtDNA levels between concurrently collected plasma, serum, and saliva from the same individual differ on average by up to two orders of magnitude and are poorly correlated with one another, pointing to different cf-mtDNA biology or regulation between commonly used biofluids in clinical and research settings. Moreover, in a small sample of healthy women and men (n=34), we show that blood and saliva cf-mtDNAs correlate with clinical biomarkers differently depending on the sample used. The biological divergences revealed between biofluids, together with the lysis-based, cost-effective, and scalable MitoQuicLy protocol for biofluid cf-mtDNA quantification, provide a foundation to examine the biological origin and significance of cf-mtDNA to human health.

molecular biology↗

bioRxiv2022

Spatial compartmentalization of signalling imparts source-specific functions on secreted factors

Efficient regeneration requires multiple cell types acting in a coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profiled the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. A time-resolved computational model of interactions was generated, and VEGFA-driven endothelial engagement was identified as a key differentiating feature in models of successful and failed regeneration. In addition, it revealed that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we deleted VEGFA from two cell types residing in close proximity, stromal and myogenic progenitors. By comparing responses to different types of damage, we found that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks. HighlightsO_LILigand-receptor signaling redundancy during skeletal muscle regeneration C_LIO_LIInflammatory cells, and muscle and fibro/adipogenic progenitors produce VEGFA C_LIO_LIVEGFA from muscle progenitors control their proliferation after muscle damage C_LIO_LIVEGFA from FAP controls angiogenesis only after ischemic damage C_LI eTOC blurbGroppa et al. performed a novel time-resolved bioinformatics analysis that revealed extensive ligand-receptor redundancy among the cell types contributing to skeletal muscle regeneration. They focused on one of these pathways, and showed that VEGFA from different cell types has distinct roles in regeneration.

cell biology↗

bioRxiv2020

A peptide-signal amplification strategy for the detection and validation of neoepitope presentation on cancer biopsies

Targeting the right cancer-specific peptides presented by Human Leukocyte antigen (HLA) class I and II molecules on the tumor cell surface is a crucial step in cancer immunotherapy. Numerous approaches have been proposed to predict the presentation of potential neoepitopes that may be targeted through immune-based therapies. Often founded on patient specific somatic mutations, the routine validation of their actual appearance on the tumor cell surface is a significant barrier to realising personalized cancer immunotherapy. This can be attributed to the lack of robust and adaptable assays for antigen presentation that offer the required sensitivity to deal with the limited amounts of patient tumor tissue available. Rather than personalize individual assays we propose the use mass spectrometry to identify tumor neoepitopes from HLA-bound peptides directly isolated form the surface of tumor biopsies. We have developed a microscale HLA-peptide complex immunoprecipitation protocol combined with tandem mass tagging (TMT) to directly sequence HLA-bound peptides using mass spectrometry. Using this strategy, we identified HLA-bound peptides from as few as ~1000 cultured cells and from a small piece (~1 mg) of whole melanoma tumour tissue, encompassing epitopes derived from Melanoma-associated antigens and potential neoantigens.

immunology↗

bioRxiv2019

Overexpressing CsGH3.1 and CsGH3.1L reduces susceptibility to Xanthomonas citri subsp. citri by repressing auxin signaling in citrus (Citrus sinensis Osbeck)

The auxin early response gene Gretchen Hagen3 (GH3) plays dual roles in plant development and responses to biotic or abiotic stress. It functions in regulating hormone homeostasis through the conjugation of free auxin to amino acids. In citrus, GH3.1 and GH3.1L play important roles in responding to Xanthomonas citri subsp. citri (Xcc). Here, in Wanjingcheng orange (C. sinensis Osbeck), the overexpression of CsGH3.1 and CsGH3.1L caused increased branching and drooping dwarfism, as well as smaller, thinner and upward curling leaves compared with wild-type. Hormone determinations showed that overexpressing CsGH3.1 and CsGH3.1L decreased the free auxin contents and accelerated the Xcc-induced decline of free auxin levels in transgenic plants. A resistance analysis showed that transgenic plants had reduced susceptibility to citrus canker, and a transcriptomic analysis revealed that hormone signal transduction-related pathways were significantly affected by the overexpression of CsGH3.1 and CsGH3.1L. A MapMan analysis further showed that overexpressing either of these two genes significantly downregulated the expression levels of the annotated auxin/indole-3-acetic acid family genes and significantly upregulated biotic stress-related functions and pathways. Salicylic acid, jasmonic acid, abscisic acid, ethylene and zeatin levels in transgenic plants displayed obvious changes compared with wild-type. In particular, the salicylic acid and ethylene levels involved in plant resistance responses markedly increased in transgenic plants. Thus, the overexpression of CsGH3.1 and CsGH3.1L reduces plant susceptibility to citrus canker by repressing auxin signaling and enhancing defense responses. Our study demonstrates auxin homeostasis potential in engineering disease resistance in citrus.

plant biology↗