Biology subjects

He, Q.

Publications and source records attributed to He, Q..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Engineering a mouse-adapted SADS-CoV and establishing a neonatal mouse model to study its infection

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an emerging bat-origin alphacoronavirus causing severe disease in neonatal piglets, with significant economic losses to the swine industry as a consequence. The virus exhibits a broad species tropism, infecting cells derived from pigs, humans and mice, highlighting its potential for cross-species transmission. Due to drawbacks associated with the use of young piglets, there is a need for an appropriate small animal model to study SADS-CoV biology. Here we established a mouse infection model based on a murinized mutant of the virus, mSADS-CoV, in which the ectodomain of the viral spike protein was replaced by that of the murine coronavirus mouse hepatitis virus (MHV). This chimeric virus, generated through targeted RNA recombination, replicated efficiently in murine cell cultures and exhibited an age-dependent infection in neonatal mice that was lethal in 2-day-old BALB/c mice affecting various organs, notably the intestine. We validated our infection model by successfully verifying the efficacy of the RNA-dependent RNA polymerase inhibitor remdesivir (RDV). The model will serve as a valuable tool for studying SADS-CoV pathogenesis and for elucidating the roles of host factors in viral replication as well as for preclinical evaluation of vaccine candidates and antiviral compounds targeting the viral replication machinery. Author SummarySADS-CoV poses a dual threat to the swine industry and public health because of its broad species tropism and potential for cross-species transmission. The emergence of other bat-derived coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV), underscores the need for robust models to study these pathogens. The successful rescue of mSADS-CoV and the development of a mouse infection model represent significant advancements in SADS-CoV research. This model not only enables the evaluation of antiviral therapeutics such as RDV but also provides a powerful platform for investigating viral replication mechanisms and host-pathogen interactions, offering critical insights for pandemic preparedness.

microbiology↗

bioRxiv2025

Biophysical modeling for accurate T cell specificity prediction of viral and tumor antigens

Accurate predictions of T cell receptor (TCR) specificity remain an important open problem in immunology, with broad implications for vaccine design, optimal immunotherapy, and improved management of autoimmune diseases. However, diversity in peptide antigens and TCR sequences at the level of individual patient repertoires remains a formidable computational challenge. Here, we develop a joint experimental and computational approach for predicting the antigen specificity of clinically-derived TCR sequences. Our model is trained on a combination of experimentally pre-identified and in silico-predicted TCR-pMHC structures using AlphaFold3. We apply our structural model in the clinical setting of hematopoietic stem cell transplant (HSCT) and demonstrate that our model is able to effectively discern the specificity of previously unseen donor and patient-derived TCR sequences against tumor associated and viral antigens. Model performance was further enhanced through the integration of sequence-based clustering and structurally diverse training templates. Our results highlight the predictive capabilities of structurally guided machine learning frameworks, trained on a minority test dataset, for antigen specificity prediction on unseen TCR sequences and their potential impact on a wide range of immunological applications.

immunology↗

bioRxiv2025

Prg4+ fibro-adipogenic progenitors in muscle are crucial for bone fracture repair

Clinically, compromised fracture healing often occurs at sites with less muscle coverage and muscle flaps can provide the necessary healing environment for appropriate healing in severe bone loss. However, the underlying mechanisms are largely unknown. Here, we established a mouse reporter model for studying muscle cell contribution to bone fracture repair. Analyzing skeletal muscle scRNA-seq datasets revealed that Prg4 marks a fibro-adipogenic progenitor (FAP) subpopulation. In mice, Prg4+ cells were specifically located in the skeletal muscle, but not at the periosteum or inside cortical bone. These cells expressed FAP markers, responded to muscle injury, and became periosteal cells under normal and muscle injury conditions. Fracture fragmented muscle fibers, rapidly expanded Prg4+ FAPs at the injury site and promoted their migration into the fracture site. Later, they gave rise to many chondrocytes, osteoblasts, and osteocytes in the outer periphery of callus next to muscle. In repaired bones, the descendants of Prg4+ FAPs were detected as mesenchymal progenitors in the periosteum and osteocytes at the prior fracture site. A second fracture activated those cells and stimulated them to become osteoblasts in the inner part of callus. Importantly, ablation of Prg4+ FAPs impaired fracture healing and functional repair. In an intramembranous bone injury model (drill-hole), Prg4+ FAPs became periosteal cells, but their contribution to bone defect repair was significantly less than in fractures. Taken together, we demonstrate the critical role of FAPs in endochondral bone repair and uncover a novel mechanism by which mesenchymal progenitors transform from muscle to cortical bone. Significance statementFracture healing is often impaired in areas with less muscle coverage, but the mechanisms behind this are poorly understood. In this work, we uncovered a critical role of specific muscle cells, known as Prg4+ fibro-adipogenic progenitors (FAPs), in bone regeneration. Using mouse models, we show that these muscle-resident mesenchymal progenitors expand after bone injury, migrate to the fracture site, transform into various bone cells in the fracture callus, and eventually become bone surface progenitors after the bone is healed. This finding highlights the importance of muscle cells in endochondral fracture repair and reveals a novel crosstalk mechanism between muscle and bone tissues. Future studies targeting these muscle progenitor cells could develop new treatments for delayed and nonunion fractures.

cell biology↗

bioRxiv2025

Structural Basis of Herpesvirus Helicase-Primase Inhibition by Pritelivir and Amenamevir

Widespread herpesvirus infections are associated with various diseases. DNA replication of human herpes simplex virus type 1 (HSV-1) requires a helicase-primase (HP) complex of three core proteins: UL5, UL52, and UL8. This complex unwinds viral DNA and synthesizes primers for DNA replication, making it an attractive antiviral target. Although HP inhibitors pritelivir and amenamevir were identified through screening, their binding mechanisms remain unclear. Here, we report cryo-EM structures of HSV-1 HP bound to a forked DNA template alone, and in complex with pritelivir or amenamevir. The structures reveal a bilobed architecture highlighting helicase-primase coordinated action at the replication fork and providing a structural basis for HP inhibition by illustrating precisely how pritelivir and amenamevir block helicase activity. Data lays a solid foundation for the development of improved antiviral therapies.

biochemistry↗

bioRxiv2025

The proofreading mechanism of the human leading strand DNA polymerase ϵ holoenzyme

Significance StatementReplicative DNA polymerases (Pol) function with a sliding clamp and their proofreading exonuclease provides high fidelity. Thus, study of the proofreading mechanism must both contain the Pol-clamp complex and generate the mismatch in situ to ensure the mismatched primer follows a physiological route from the pol to exo site. Despite numerous previous studies, none satisfy both criteria. This study on human Pol{varepsilon}-PCNA meets both criteria. Cryo-EM analysis captured proofreading intermediates that reveal an unexpected proofreading process. The primer is unwound by 6 nucleotides that scrunches to form out-of-register base pairs with the template. These findings provide new insights and calls for reevaluation of proofreading mechanisms performed without a sliding clamp or with an existing mismatch. The eukaryotic leading strand DNA polymerase epsilon is a dual function enzyme with a proofreading exonuclease site located 40 angstroms from the DNA synthesizing polymerase site. Errors in Pol epsilon proofreading can cause various mutations, including C to G transversions, the most prevalent mutation in cancers and genetic diseases. Pol epsilon interacts with all three subunits of the PCNA ring to assemble a functional holoenzyme. Despite previous studies on proofreading of several polymerases, how Pol epsilon, or any Pol complexed with its sliding clamp proofreads a mismatch generated in situ has been unknown. We show here by cryo-EM that a template/primer DNA substrate with a pre-existing mismatch cannot enter the exo site of Pol epsilon/PCNA holoenzyme, but a mismatch generated in the Pol site yields three proofreading intermediates of Pol epsilon/PCNA holoenzyme. These intermediates reveal how the mismatch is dislodged from the Pol site, how the DNA unwinds 6 base pairs and how the unpaired primer 3'-end is inserted into the exo site for cleavage. These results unexpectedly demonstrate that PCNA imposes strong steric constraints that extend unwinding and direct the trajectory of mismatched DNA, and that this trajectory is dramatically different than for Pol epsilon in the absence of PCNA. These findings suggest a physiologically relevant proofreading mechanism for the human Pol epsilon/PCNA holoenzyme.

biochemistry↗

bioRxiv2025

Lysosomal cathepsin D regulates bone turnover through distinct mode of actions of the autophagy pathways in osteoblasts and osteoclasts

Insufficiency in nutrient availability, oxidative stress and autophagy failure are fundamental factors for the decline of bone mass and strength with aging. Accumulating evidence indicates that these factors affect normal autophagosomal or lysosomal activities which are the major force in clearance of aggregated or damaged proteins. Cathepsin D (CtsD), the principal lysosomal aspartate protease and a main endopeptidase, exists in the skeleton during development or homeostasis. However, the molecular and cellular mechanisms of CtsD mediated autophagosome or lysosome function in the skeletal homeostasis remain unclear. In the present study, we showed that deletion of CtsD dramatically decreased bone mass in the 3-week old mutant mice compared with their control littermates as indicated by decreased bone volume (BV), bone volume / total volume (BV/TV), bone surface (BS), trabecular number, trabecular thickness and increase trabecular separation in the microCT analysis. Histomorphometry analysis revealed that the phenotype was characterized by decreased osteoblast numbers, osteoblast surface/bone surface and mineral apposition rate, increased osteoclast numbers, osteoclast surface/bone surface and erosion surface/bone surface. At molecular level, siRNA medicated inactivation of CtsD in MC3T3E1 cells attenuated osteoblastic differentiation and downregulated LC3B expression, which was accompanied by decreased levels of P62, p-Akt and p-GSK3beta in osteoblasts. Intriguingly, inactivation of CtsD in RAW264.7 cells increased osteoclast differentiation with decreased LC3B expression but upregulated P62 level. This was accompanied by alterations in the formation of autophagosome and differential transcription profiles associated with the autophagy pathway during the differentiation of osteoblasts and osteoclasts. The results suggest that CtsD mediated autophagy pathway plays important roles in regulation of bone mass and homeostasis through distinct mode of actions in osteoblasts and osteoclasts, and CtsD may serve as a potential therapeutic target for the maintenance of bone mass.

cell biology↗

bioRxiv2025

CDK12 condensation in nuclear speckles confers sensitivity to cyclin K molecular glue degraders

Transcriptional machinery often operates in the configuration of biomolecular condensates, presenting emerging opportunities to develop therapies targeting transcriptionally addicted malignancies. In this study, we discovered that cyclin-dependent kinase 12 (CDK12), a key regulator of transcription elongation, formed dynamic liquid-like droplets within nuclear speckles, a process enhanced by high CDK12 expression and CDK12 inhibitor treatment. Recognizing this unique property, we rationally designed ZSQ253, a modular cyclin K molecular glue degrader that coupled binding moieties for both CDK12 and DDB1. By promoting phase separation-driven assembly and subsequent proteasomal degradation of the CDK12-cyclin K complex, ZSQ253 interfered with oncogenic transcription and demonstrated potent antitumor capability. Further structure-guided optimization yielded HQY1428, a derivative with a multi-site gluing effect and improved drug activity. Given the frequent genomic co-amplification of CDK12 and ERBB2 across diverse human cancers, we showed that combining HQY1428 with HER2 inhibitors provided synergistic therapeutic benefits. Collectively, our findings establish CDK12 condensation within nuclear speckles as an exploitable vulnerability, and introduce a novel mechanism of action underlying cyclin K molecular glue degraders.

cancer biology↗

bioRxiv2025

A Single-Cell Atlas of RNA Alternative Splicing in the Glioma-Immune Ecosystem

Single-cell analysis has refined our understanding of cellular heterogeneity in glioma, yet RNA alternative splicing (AS)--a critical layer of transcriptome regulation--remains underexplored at single-cell resolution. Here, we present a pan-glioma single-cell AS analysis in both tumor and immune cells through integrating seven SMART-seq2 datasets of human gliomas. Our analysis reveals lineage-specific AS across glioma cellular states, with the most divergent AS landscapes between mesenchymal- and neuronal-like glioma cells, exemplified by AS in TCF12 and PTBP2. Comparison between core and peripheral glioma cells highlights AS-redox co-regulation of cytoskeleton organization. Further analysis of glioma-infiltrating immune cells reveals potential isoform-level regulation of protein glycosylation in regulatory T cells and a link between MS4A7 AS in macrophages and clinical response to anti-PD-1 therapy. This study emphasizes the role of AS in glioma cellular heterogeneity, highlighting the importance of an isoform-centric approach to better understand the complex biological processes driving tumorigenesis.

genomics↗

bioRxiv2025

Adaptive learning via BG-thalamo-cortical circuitry

People adjust their use of feedback over time through a process referred to as adaptive learning. We have recently proposed that the underlying mechanisms of adaptive learning are rooted in how the brain organizes time into similarly credited units, which we refer to as latent states. Here we develop a basal ganglia-thalamo-cortical circuit model of this process and show that it captures both the commonalities and heterogeneity in human adaptive learning behavior. Our model learns incrementally through synaptic plasticity in prefrontal-basal ganglia (PFC-BG) connections, but upon observing discordant information, produces thalamocortical reset signals that alter PFC connectivity, driving attractor state transitions that facilitate rapid updating of behavioral policy. We demonstrate that this mechanism can give rise to optimized learning dynamics in the context of either change-points or reversals, and that under reasonable biological assumptions the model is able to generalize efficiently across these conditions, adjusting behavior in a context-appropriate manner. Taken together, our results provide a biologically plausible mechanistic model for adaptive learning that explains existing behavioral data and makes testable predictions about the computational roles of different brain regions in complex learning behaviors.

neuroscience↗

bioRxiv2025

Evidence of inbreeding depression on stature in Brown Swiss cattle

BackgroundSmall effective population size and the disproportionately large use of few genetically superior bulls in artificial insemination lead to extensive runs of homozygosity and an increased risk of homozygosity for deleterious alleles in domestic cattle, which may cause inbreeding depression. The adverse effects of inbreeding on phenotypic performance are well established, but the genetic variants contributing to inbreeding depression remain largely unknown. This study aimed to analyse the impacts of inbreeding on stature (measured as height at the sacral bone) in a cohort of 15,306 Brown Swiss (BS) cows that have imputed genotypes at 20 million sequence variants and stature measurements as height at the sacral bone. ResultsThe average genomic inbreeding coefficient of the 15,306 BS cows estimated from runs of homozygosity (ROH) was 0.369 ({+/-} 0.022). We found a loss in stature, decreasing from a height of 0.076 cm at the sacral bone per 1% increase in inbreeding (p = 1.94e-09). Contributions to inbreeding depression were significant for long (> 2 Mb), medium (0.1 - 2 Mb), and short (50 kb - 0.1 Mb) ROH (p = 1.29e-12, p = 3.20e-04 and p = 1.77e-06, respectively), suggesting that both ancient and recent inbreeding have negative effects on stature. Non-additive association testing identified a novel recessive quantitative trait locus (QTL) for stature on chromosome 25 with the most significantly (p = 2.35e-21) associated SNP residing at 14,535,327 bp. Cows homozygous for the alternate allele of the top associated SNP were 2 cm shorter than heterozygous and reference allele homozygotes. Fine mapping of the QTL identified a splice donor variant (rs447836030 at 25:14,515,474) of the gene ABCC6 encoding ATP binding cassette subfamily C member 6 which causes exon skipping as both a positional and functional candidate causal variant. ConclusionsOur study reveals evidence for inbreeding depression on stature in a large cohort of BS cattle. We also uncover a recessive QTL that decreases stature through non-additive association testing. This QTL harbors a high-impact variant affecting a splice donor site of ABCC6 which leads to exon skipping, thereby possibly contributing to inbreeding depression. Accumulating non-lethal deleterious alleles in ROH may reduce the overall fitness of the BS cattle population.

genomics↗

bioRxiv2025

Evidence for evolution of a new sex chromosome within the Marchantiales haploid plant lineage

Sex chromosomes have evolved independently in numerous lineages across the tree of life, in both diploid-dominant species, including many animals and plants, and the less studied haploid-dominant plants and algae. Strict genetic sex determination ensures that individuals reproduce by outcrossing. However, species with separate sexes (termed dioecy in diploid plants, and dioicy in haploid plants) may sometimes evolve different sex systems, and become monoicous, with the ability to self-fertilize. Here, we study dioicy-monoicy transitions in the ancient liverwort haploid plant lineage, using three telomere-to-telomere gapless chromosome-scale reference genome assemblies from the Ricciaceae group of Marchantiales. Ancestral liverworts are believed to have been dioicous, with U and V chromosomes (chromosome 9) determining femaleness and maleness, respectively. We confirm the finding that monoicy in Ricciocarpos natans evolved from a dioicous ancestor, and most ancestrally U chromosomal genes have been retained on autosomes in this species. We also describe evidence suggesting the possible re-evolution of dioicy in the genus Riccia, with probable de novo establishment of a sex chromosome from an autosome (chromosome 5), and further translocations of genes from the new sex chromosome to autosomes. Our results also indicated that m-chromosomes are consistent genomic features, and may have evolved independently from sex chromosomes in Ricciocarpos and Riccia lineages.

evolutionary biology↗

bioRxiv2024

Dissociable neurofunctional and molecular characterizations of reward and punishment sensitivity

While the hyper-and hypo-reward or punishment sensitivities (RS, PS) have received considerable attention as prominent transdiagnostic features of psychopathology, the lack of an overarching neurobiological characterization currently limits their early identifications and neuromodulations. Here we combined microarray data from the Allen Human Brain Atlas with a multimodal fMRI approach to uncover the neurobiological signatures of RS and PS in a discovery-replication design (N=655 participants). Both RS and PS were mapped separately in the brain, with the intrinsic functional connectome in the fronto-striatal network encoding reward responsiveness, while the fronto-insular system was particularly engaged in punishment sensitivity. This dissociable functional connectome patterns related to RS and PS were also specific in differentiating decisions driven by social or monetary reward and punishment motivations. Further imaging transcriptomic analyses revealed that functional connectome variations for RS and PS were associated with topography of specific gene sets enriched in ontological pathways, including synaptic transmission, dopaminergic metabolism, immune response and stress adaptation. On the neurotransmitter level, the serotonin neuromodulator was identified as a pivotal hub regulating the intrinsic functional connectome patterns of RS and PS, with this process critically dependent on its interactions with dopaminergic, opioid and GABAergic systems. Overall, these findings indicate dissociable neural connectome mapping of RS and PS and highlight their linkage with transcriptomic profiles, which may offer valuable insights into the treatment evaluation for symptomatology relevant to reward/punishment processing deficits.

neuroscience↗

bioRxiv2024

STAT1 Promotes PD-L1 Activation and Tumor Growth in Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a cystic lung disease that primarily affects women. LAM is caused by the invasion of metastatic smooth muscle-like cells into the lung parenchyma, leading to abnormal cell proliferation, lung remodeling and progressive respiratory failure. LAM cells have TSC gene mutations, which occur sporadically or in people with Tuberous Sclerosis Complex. Although it is known that hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to TSC2 gene mutations contributes to aberrant cell growth in LAM lung, tumor origin and invasive mechanism remain unclear. To determine molecular drivers responsible for aberrant LAM cell growth, we performed integrative single-cell transcriptomic analysis and predicted that STAT1 interacts with Pre-B cell leukemia transcription factor (PBX1) to regulate LAM cell survival. Here, we show activation of STAT1 and STAT3 proteins in TSC2- deficient LAM models. Fludarabine, a potent STAT1 inhibitor, induced the death of TSC2- deficient cells, increased caspase-3 cleavage, and phosphorylation of necroptosis marker RIP1. Fludarabine treatment impeded lung colonization of TSC2-deficient cells and uterine tumor progression, associated with reduced percentage of PCNA-positive cells in vivo. Interestingly, IFN-{gamma} treatment increased STAT1 phosphorylation and PD-L1 expression, indicating that STAT1 aids TSC2-deficient tumor cells in evading immune surveillance in LAM. Our findings indicate that STAT1 signaling is critical for LAM cell survival and could be targeted to treat LAM and other mTORC1 hyperactive tumors.

cancer biology↗

bioRxiv2024

TurboID-based proximity labeling discovers ABCF2 as an adhesion receptor for the zoonotic pathogen Pasteurella multocida

Pasteurella multocida is a zoonotic pathogen that can cause fatal infections in both animals and humans. A significant number of putative adhesive factors have been predicted to contribute to the pathogenesis of P. multocida, but their interactive proteins on host cells remain unclear. In this study, we experimentally verified the roles of three previously proposed proteins (PlpE, PtfA, Hsf-2) in the adherence of P. multocida. Through turboID-based proximity labeling screening, we identified ATP-binding cassette sub-family F member 2 (ABCF2) as a host interactive protein for PlpE/PtfA/Hsf-2. Crucial amino acid residues in PlpE, PtfA, and/or Hsf-2 that are essential for interacting with ABCF2 included Asp-123 (PlpE), Lys-88 (PtfA), Asp-136 (PtfA), Ala-464 (Hsf-2), Glu-473 (Hsf-2), and Arg-489 (Hsf-2). Knocking down or knocking out ABCF2 significantly reduced the adherence and invasion of P. multocida to host cells, while overexpression of ABCF2 markedly increased these effects. However, ABCF2 did not contribute to the adherence of other bacterial species such as Klebsiella pneumoniae and Bordetella bronchiseptica. Additionally, we demonstrated that P. multocida infection upregulated the expression of host ABCF2 by activating the p38 MAPK and NF-{kappa}B signaling pathways. Furthermore, we showed that ABCF2 was involved in the P. multocida-induced p53-dependent apoptotic signaling pathway. To the best of our knowledge, this is the first identification of ABCF2 as a host factor contributing to the adherence of P. multocida and only the second report of ABCF2s involvement in bacterial pathogenesis. ImportanceP. multocida can cause fatal infections in both animals and humans, yet the mechanisms related to its pathogenesis remain to be fully explored. In this study, we identified ABCF2 as a crucial host interactive protein for three adhesive proteins encoded by P. multocida and experimentally verified its role in the adherence and invasion of P. multocida. Furthermore, we elucidated how P. multocida modulates ABCF2 during its infection and revealed p53-dependent apoptosis as a downstream effect of ABCF2 during P. multocida infection. Given the absence of reports on ABCF2 contributing to the pathogenesis of P. multocida and only one previous report on the involvement of ABCF2 in bacterial pathogenesis prior to this study, this research could be valuable for comprehending the interactions between bacteria and hosts during bacterial infections.

microbiology↗

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

Water use efficiency of Cupressus gigantea is higher in mountain slope habitats compared to riverside habitats

Cupressus gigantea is an endemic species of the Yarlung Zangbo River in Tibet, China, and is designated as a national key protected wild plant. It is only distributed in the narrow area along Yarlung Zangbo River from Jiacha County to Danniang village Milin City in various habitats such as the waterline along the Yarlung Zangbo River, terraces, and mountain slopes. In this study, we utilized stable isotope technology ({delta}D, {delta}18O, and {delta}13C), combined with the IsoSource model, to quantitatively determined the sources of water absorption and the water use efficiency of C. gigantea in various habitats, including riverside area, terraces and mountain slopes. The results showed that the content of soil total nitrogen, soil nitrate nitrogen, soil ammonium nitrogen, and soil organic carbon are significantly higher on mountain slope than in the other two habitats, while the total carbon content, water content, and total nitrogen content of C. gigantea leaves are significantly lower on mountain slope than in the other two habitats (P<0.05). The water use efficiency (WUE) of C. gigantea in the mountain slope habitats is 107.8 mol mol-1, which is significantly higher than that of other habitats (P<0.05), with the WUE of C. gigantea in the riverside habitat being the lowest at 35.7 mol mol-1. C. gigantea distributed on the mountain slope and terrace uses soil water as the main water source. During the normal rainy season, the proportion of soil water utilization is the highest, accounting for more than 60%; in the dry season, the utilization of river water and groundwater increases, while soil water utilization decreases. C. gigantea distributed along the riverside mainly absorbs water from the Yarlung Zangbo River, about 63%. In August when the rainfall increases in the rainy season, the use of soil moisture increases, and in the dry season, river water becomes the main water source. This indicates that with the alternation of rainy and dry seasons, the water absorption sources and strategies of C.gigantea adjusted accordingly. The research results provide an important scientific basis for the protection and management measures of the C. gigantea population.

ecology↗

bioRxiv2024

Distinct duration and diet dependent lipid profiles and renal complicationsin GCK-MODY

Heterozygous inactivating mutations in the glucokinase (GCK) gene cause one of the most common types of maturity-onset diabetes of the young type 2 (MODY2), also named GCK-MODY. Studies suggest that, unlike other types of diabetes, patients with GCK-MODY do not have increased risk of diabetic complications and therefore do not typically require antihyperglycemic therapy. However, long-term outcomes of GCK-MODY on lipid profiles and chronic complications under different dietary scenarios remain unclear. Herein, using a knock-in mouse model expressing a novel MODY causing mutation GCK-Q26L (GCKMut), we examined age- and diet-related lipid profiles and diabetic complications. We found that, although GCKMut mice exhibited mild elevated blood glucose, the lipid profiles, body fat composition, and diabetic kidney disease (DKD) were initially improved in high-fat-diet (HFD) fed mice at the age of 28 weeks, supporting potential beneficial effects of GCKMut on lipid metabolism and kidney health. Unexpectedly however, those protective effects diminished by 40 weeks, and became more severe dyslipidemia and kidney injury associated with renal fibrosis and inflammation at 60-week-old mice fed with normal diet (ND) or HFD. Those findings revealed distinct duration- and diet-dependent effects of inactivating GCK mutation on lipid profiles and DKD, highlighting previously unrealized long-term chronic complications in GCK-MODY.

physiology↗

bioRxiv2024

Tetanizing wakeful consolidation: ten-hertz repetitive visual stimulation enhances the offline gain of visual learning

Consolidation of encoded information is vital for learning and memory, often explored during sleep. However, the consolidation during post-encoding offline wakefulness remains largely uncharted, especially regarding its modulation and brain mechanisms. Here, we unraveled frequency-dependent modulatory effects of repetitive visual stimulation (RVS) on wakeful consolidation of visual learning and investigated the underlying neural substrates. After training on an orientation discrimination task, exposure to 10-Hz grating-form RVS enhanced, while 1-Hz RVS deteriorated, the discrimination performance in a subsequent retest. However, 10-Hz uniform-disk RVS failed to facilitate wakeful consolidation, suggesting that alpha entrainment alone was not the facilitative mechanism. Using neuroimaging of multiple modalities, we observed augmented event-related potential and heightened neural excitation in the early visual cortex after 10-Hz grating-form RVS, implying an involvement of long-term potentiation-like (LTP-like) plasticity. Collectively, we provide a new photic method for modulating the offline processing of encoded sensory information and suggest a role of sensory tetanization in the modulation.

neuroscience↗