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Zou, J.

Publications and source records attributed to Zou, J..

At least 127 records · Page 7Linked to original sources

Broadband aperiodic components of local field potentials reflect inherent differences between cortical and subcortical activity

Information flow in brain networks is reflected in intracerebral local field potential (LFP) measurements that have both periodic and aperiodic components. The 1/f{chi} broadband aperiodic component of the power spectra has been shown to track arousal level and to correlate with other physiological and pathophysiological states, with consistent patterns across cortical regions. Previous studies have focused almost exclusively on cortical neurophysiology. Here we explored the aperiodic activity of subcortical nuclei from the human thalamus and basal ganglia, in relation to simultaneously recorded cortical activity. We elaborated on the FOOOF (fitting of one over f) method by creating a new parameterization of the aperiodic component with independent and more easily interpretable parameters, which allows seamlessly fitting spectra with and without an aperiodic knee, a component of the signal that reflects the dominant timescale of aperiodic fluctuations. First, we found that the aperiodic exponent from sensorimotor cortex in Parkinsons disease (PD) patients correlated with disease severity. Second, although the aperiodic knee frequency changed across cortical regions as previously reported, no aperiodic knee was detected from subcortical regions across movement disorders patients, including the ventral thalamus (VIM), globus pallidus internus (GPi) and subthalamic nucleus (STN). All subcortical region studied exhibited a relatively low aperiodic exponent ({chi}STN=1.3{+/-}0.2, {chi}VIM=1.4{+/-}0.1, {chi}GPi=1.4{+/-}0.1) that differed markedly from cortical values ({chi}Cortex=3.2{+/-}0.4, fkCortex=17{+/-}5 Hz). These differences were replicated in a second dataset from epilepsy patients undergoing intracranial monitoring that included thalamic recordings. The consistently lower aperiodic exponent and lack of an aperiodic knee from all subcortical recordings may reflect cytoarchitectonic and/or functional differences between subcortical nuclei and the cortex. Significance StatementThe broadband aperiodic component of local field potentials is a useful and reproducible index of neural activity. Here we refined a widely used phenomenological model for extracting aperiodic parameters, with which we fit cortical, basal ganglia and thalamic intracranial local field potentials, recorded from unique cohorts of movement disorders and epilepsy patients. We found that the aperiodic exponent in motor cortex is higher in Parkinsons disease patients with more severe motor symptoms, suggesting that aperiodic features may have potential as electrophysiological biomarkers for movement disorders symptoms. Remarkably, we found conspicuous differences in the broadband aperiodic components of basal ganglia and thalamic signals compared to those from neocortex, suggesting that the aperiodic neural timescale of subcortical LFPs is slower than that in cortex.

neuroscience↗

The impact of extracellular matrix on the precision medicine utility of pancreatic cancer patient-derived organoids

The use of patient-derived organoids (PDOs) to characterize therapeutic sensitivity and resistance (pharmacotyping) is a promising precision medicine approach. The potential of this approach to inform clinical decisions is now being tested in several large multi-institutional clinical trials. PDOs are cultivated in extracellular matrix from basement membrane extracts (BMEs) that are most commonly acquired commercially. Each clinical site utilizes distinct BME lots and may be restricted due to the availability of commercial BME sources. However, the impact of different sources and lots of BMEs on organoid drug response is unknown. Here, we tested the impact of BME source and lot on proliferation, chemotherapy and targeted therapy drug response, and gene expression in mouse and human pancreatic ductal adenocarcinoma (PDA) organoids. Both human and mouse organoids displayed increased proliferation in Matrigel (Corning) compared to Cultrex (RnD) and UltiMatrix (RnD). However, we observed no substantial impact on drug response when oragnoids were cultured in Matrigel, Cultrex, or UltiMatrix. We also did not observe major shifts in gene expression across the different BME sources, and PDOs maintained their Classical or Basal-like designation. Overall, we find that BME source (Matrigel, Cultrex, UltiMatrix) does not shift PDO dose-response curves and drug testing results, indicating that PDO pharmacotyping is a robust approach for precision medicine.

cancer biology↗

Biallelic Variants in MAD2L1BP (p31comet) Cause Female Infertility Characterized by Oocyte Maturation Arrest

Human oocyte maturation arrest represents one of the severe conditions for female patients with primary infertility. However, the genetic factors underlying this human disease remain largely unknown. The spindle assembly checkpoint (SAC) is an intricate surveillance mechanism that ensures accurate segregation of chromosomes throughout cell cycles. Once the kinetochores of chromosomes are correctly attached to bipolar spindles and the SAC is satisfied, the MAD2L1BP, best known as p31comet, binds MAD2 and recruits the AAA+-ATPase TRIP13 to disassemble the mitotic checkpoint complex (MCC), leading to the cell cycle progression. In this study, by whole-exome sequencing (WES), we identified homozygous and compound heterozygous MAD2L1BP variants in three families with female patients diagnosed with primary infertility owing to oocyte metaphase I (MI) arrest. Functional studies revealed that the protein variants resulting from the C-terminal truncation of MAD2L1BP lost their binding ability to MAD2. cRNA microinjection of full-length or truncated MAD2L1BP uncovered their discordant roles in driving the extrusion of polar body 1 (PB1) in mouse oocytes. Furthermore, the patients oocytes carrying the mutated MAD2L1BP variants resumed polar body extrusion (PBE) when rescued by microinjection of full-length MAD2L1BP cRNAs. Together, our studies identified and characterized novel biallelic variants in MAD2L1BP responsible for human oocyte maturation arrest at MI, and thus prompted new therapeutic avenues for curing female primary infertility.

developmental biology↗

How random is the review outcome? A systematic study of the impact of external factors on eLife peer review

The advance of science rests on a robust peer review process. However whether or not a paper is accepted can depend on random external factors--e.g. the timing of the submission, the matching of editors and reviewers--that are beyond the quality of the work. This article systematically investigates the impact of these random factors independent of the papers quality on peer review outcomes in a major biomedical journal, eLife. We analyzed all of the submissions to eLife between 2016 to 2018, with 23,190 total submissions. We examined the effects of random factors at each decision point in the review process, from the gatekeeping senior editors who may desk-reject papers to review editors and reviewers who recommend the final outcome. Our results suggest that the peer-review process in eLife is robust overall and that random external factors have relatively little quantifiable bias.

bioinformatics↗

Predicting Immune Escape with Pretrained Protein Language Model Embeddings

Assessing the severity of new pathogenic variants requires an understanding of which mutations enable escape of the human immune response. Even single point mutations to an antigen can cause immune escape and infection by disrupting antibody binding. Recent work has modeled the effect of single point mutations on proteins by leveraging the information contained in large-scale, pretrained protein language models (PLMs). PLMs are often applied in a zero-shot setting, where the effect of each mutation is predicted based on the output of the language model with no additional training. However, this approach cannot appropriately model immune escape, which involves the interaction of two proteins--antibody and antigen-- instead of one protein and requires making different predictions for the same antigenic mutation in response to different antibodies. Here, we explore several methods for predicting immune escape by building models on top of embeddings from PLMs. We evaluate our methods on a SARS-CoV-2 deep mutational scanning dataset and show that our embedding-based methods significantly outperform zero-shot methods, which have almost no predictive power. We also highlight insights gained into how best to use embeddings from PLMs to predict escape. Despite these promising results, simple statistical and machine learning baseline models that do not use pretraining perform comparably, showing that computationally expensive pretraining approaches may not be beneficial for escape prediction. Furthermore, all models perform relatively poorly, indicating that future work is necessary to improve escape prediction with or without pretrained embeddings1.

bioinformatics↗

Improved Neutralization of Omicron BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent BA.4/5 Vaccine

The BNT162b2 bivalent BA.4/5 COVID-19 vaccine has been authorized to mitigate COVID-19 due to current Omicron and potentially future variants. New sublineages of SARS-CoV-2 Omicron continue to emerge and have acquired additional mutations, particularly in the spike protein, that may lead to improved viral fitness and immune evasion. The present study characterized neutralization activities against new Omicron sublineages BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 after a 4th dose (following three doses of BNT162b2) of either the original monovalent BNT162b2 or the bivalent BA.4/5 booster in individuals >55 years of age. For all participants, the 4th dose of monovalent BNT162b2 vaccine induced a 3.0x, 2.9x, 2.3x, 2.1x, 1.8x, and 1.5x geometric mean neutralizing titer fold rise (GMFR) against USA/WA1-2020 (a strain isolated in January 2020), BA.4/5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1, respectively; the bivalent vaccine induced 5.8x, 13.0x, 11.1x, 6.7x, 8.7x, and 4.8x GMFRs. For individuals without SARS-CoV-2 infection history, BNT162b2 monovalent induced 4.4x, 3.0x, 2.5x, 2.0x, 1.5x, and 1.3x GMFRs, respectively; the bivalent vaccine induced 9.9x, 26.4x, 22.2x, 8.4x, 12.6x, and 4.7x GMFRs. These data suggest the bivalent BA.4/5 vaccine is more immunogenic than the original BNT162b2 monovalent vaccine against circulating Omicron sublineages, including BQ.1.1 that is becoming prevalent globally.

microbiology↗

Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1, and XBB.1 by 4 doses of parental mRNA vaccine or a BA.5-bivalent booster

The newly emerged SARS-CoV-2 Omicron BQ.1.1, XBB.1, and other sublineages have accumulated additional spike mutations that may affect vaccine effectiveness. Here we report neutralizing activities of three human serum panels collected from individuals 1-3 months after dose 4 of parental mRNA vaccine (post-dose-4), 1 month after a BA.5-bivalent-booster (BA.5-bivalent-booster), or 1 month after a BA.5-bivalent-booster with previous SARS-CoV-2 infection (BA.5-bivalent-booster-infection). Post-dose-4 sera neutralized USA-WA1/2020, BA.5, BF.7, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 SARS-CoV-2 with geometric mean titers (GMTs) of 1533, 95, 69, 62, 26, 22, and 15, respectively; BA.5-bivalent-booster sera improved the GMTs to 3620, 298, 305, 183, 98, 73, and 35; BA.5-bivalent-booster-infection sera further increased the GMTs to 5776, 1558,1223, 744, 367, 267, and 103. Thus, although BA.5-bivalent-booster elicits better neutralization than parental vaccine, it does not produce robust neutralization against the newly emerged Omicron BA.2.75.2, BQ.1.1, and XBB.1. Previous infection enhances the magnitude and breadth of BA.5-bivalent-booster-elicited neutralization.

microbiology↗

A Spectral Method for Assessing and Combining Multiple Data Visualizations

Dimension reduction and data visualization aim to project a high-dimensional dataset to a low-dimensional space while capturing the intrinsic structures in the data. It is an indispensable part of modern data science, and many dimensional reduction and visualization algorithms have been developed. However, different algorithms have their own strengths and weaknesses, making it critically important to evaluate their relative performance for a given dataset, and to leverage and combine their individual strengths. In this paper, we propose an efficient spectral method for assessing and combining multiple visualizations of a given dataset produced by diverse algorithms. The proposed method provides a quantitative measure - the visualization eigenscore - of the relative performance of the visualizations for preserving the structure around each data point. Then it leverages the eigenscores to obtain a consensus visualization, which has much improved quality over the individual visualizations in capturing the underlying true data structure. Our approach is flexible and works as a wrapper around any visualizations. We analyze multiple simulated and real-world datasets from diverse applications to demonstrate the effectiveness of the eigenscores for evaluating visualizations and the superiority of the proposed consensus visualization. Furthermore, we establish rigorous theoretical justification of our method based on a general statistical framework, yielding fundamental principles behind the empirical success of consensus visualization along with practical guidance.

bioinformatics↗

Proteomics of resilience to Alzheimer's disease identifies brain regional soluble Aβ levels, actin filament processes, and response to injury

Resilience to Alzheimers disease (RAD) is an uncommon combination of high disease burden without dementia that may provide critical insights into limiting the clinical impact of this incurable disease. In this study, we used mass spectrometry-based proteomics to quantify regional protein differences that characterize RAD. Starting with over 700 brain donations, we identified 43 extensively annotated research participants who met stringent inclusion exclusion criteria and analyzed matched isocortical regions, hippocampus, and caudate nucleus. Differential expression analysis of 7,115 soluble proteins identified lower isocortical and hippocampal soluble A{beta} peptide levels as a significant feature of RAD. Protein co-expression analysis revealed a group of 181 densely-interacting proteins significantly associated with RAD that were enriched for actin filament-based process, cellular detoxification, and wound healing in isocortex and hippocampus. We further support our findings using data from 689 human isocortical samples from four independent external cohorts that were the closest approximations of our clinico-pathologic groups. The molecular basis of RAD, a widely replicated state in older adults for which there is no experimental model, likely holds important insights into therapeutic interventions for Alzheimers disease.

neuroscience↗

Stress vesicles are induced by acute mechanical force and precede the commitment of epidermal stem cells to terminal differentiation

The skin has a pronounced ability to adapt to physical changes in the environment by exhibiting plasticity at the cellular level. Transient mechanical deformations applied to the skin are accommodated without permanent changes to tissue structure. However, sustained physical stress induces long-lasting alterations in the skin, which are mediated by shifts in the fates of epidermal stem cells. To investigate this phenomenon, we implemented two-photon intravital imaging to capture the responses of epidermal cells when an acute mechanical force is applied to the live skin. We show that mechanical stress induces the formation of intracellular vesicles in epidermal stem cells, which are filled with extracellular fluid and gradually enlarge, causing the deformation of the cell nucleus. By lineage tracing analysis we demonstrate that the degree of nuclear deformation is linked to cell fate. Utilizing a fluorescent in vivo reporter, to capture intracellular calcium dynamics, we show that mechanical force induces a sustained increase in intracellular calcium within basal epidermal stem cells. Conditional deletion of Piezo1, a mechanosensitive ion channel, alters intracellular calcium dynamics and increases the number of stress vesicles in epidermal stem cells. Using a human skin xenograft model, we show that stress vesicles are a conserved phenomenon in mammalian skin. This study uncovers stress vesicles as key manifestations of the mechanism that regulates the fate of epidermal stem cells under conditions of mechanical stress, in which Piezo1 and calcium dynamics are also involved.

cell biology↗

Transgressive and parental dominant gene expression and cytosine methylation during seed development in Brassica napus hybrids

The enhanced performance of hybrids though heterosis remains a key aspect in plant breeding, however the underlying mechanisms are still not fully elucidated. To investigate the potential role of transcriptomic and epigenomic patterns in early expression of hybrid vigour, we investigated gene expression, small RNA abundance and genome-wide methylation in hybrids from two distant Brassica napus ecotypes during seed and seedling developmental stages using next-generation sequencing technologies. A total of 71217, 773, 79518 and 31825 differentially expressed genes, microRNAs, small interfering RNAs and differentially methylated regions were identified, respectively. Approximately 70% of the differential expression and methylation patterns observed could be explained due to parental dominance levels. Via gene ontology enrichment and microRNA-target association analyses during seed development we found copies of reproductive, developmental and meiotic genes with transgressive and paternal dominance patterns. Interestingly, maternal dominance was more prominent in hypermethylated and downregulated features during seed formation. This contrasts to the general maternal gamete demethylation reported during gametogenesis in most plant species. Associations between methylation and gene expression allowed identification of putative epialleles with diverse pivotal biological functions during seed formation. Furthermore, most differentially methylated regions, differentially expressed siRNAs and transposable elements were found in regions flanking genes that had no differential expression. This suggests that differential expression and methylation of epigenomic features may help maintain expression of pivotal genes in a hybrid context. Differential expression and methylation patterns during seed formation in an F1 hybrid provide novel insight into genes and mechanisms with a potential role in early heterosis. Key messageTranscriptomic and epigenomic profiling of gene expression and small RNAs during seed and seedling development reveals expression and methylation dominance levels with implications on early stage heterosis in oilseed rape.

plant biology↗

H3K36M provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis

Epigenetic dysregulation is pervasive in cancer, frequently impairing normal tissue development and differentiation1. Beyond alterations in histone modifying enzymes, "oncohistone" mutations have been described across a variety of cancers2-4, although the in vivo effects and underlying mechanisms behind these observations have not been well- studied and remain unclear. Here, by inducing the in vivo expression of histone H3.3 carrying a lysine to methionine (K to M) mutation at position 36 (H3K36M) in self- renewing stratifying epithelial tissues, we show that the H3K36M oncohistone dramatically disrupts normal epithelial differentiation, leading to extensive tissue dysplasia characterized by a significant increase in mitotic, proliferative basal stem cells. Furthermore, this differentiation blockade promotes increased cellular plasticity and enrichment of alternate cell fates, and in particular the aberrant generation of excessive glandular tissue including both hypertrophic salivary, sebaceous, and meibomian glands. Upon carcinogen stress, H3K36M mice display markedly enhanced squamous tumorigenesis. These aberrant phenotypic and gene expression manifestations are associated with global loss of H3K36me2 and concomitant gain of H3K27me3. Collectively, these results have revealed a previously unknown critical role for H3K36 methylation in both the in vivo maintenance of proper epithelial cell fate decisions and the prevention of squamous carcinogenesis. Additionally, they suggest that H3K36 methylation modulation may offer new avenues for the regulation of numerous common disorders driven by over- or under-active glandular function.

cancer biology↗

Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro

The SARS-CoV-2 virus is the causal agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). There is an urgent need for potent, specific antiviral compounds against SARS-CoV-2. The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses, and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, non-covalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment. One-Sentence SummaryA oral non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication.

microbiology↗

Chromatin state modeling across individuals reveals global patterns of histone modifications

Epigenetic mapping studies across individuals have identified many positions of epigenetic variation in various human tissues and conditions. However the relationships between these positions, and in particular global patterns that recur in many regions of the genome remains understudied. In this study, we use a stacked chromatin state model to systematically learn global patterns of epigenetic variation across individuals and annotate the human genome based on them. We applied this framework to histone modification data across individuals in lymphoblastoid cell lines and across autism spectrum disorder cases and controls in prefrontal cortex tissue. We find that global patterns are correlated across multiple histone modifications and with gene expression. We used the global patterns as a framework to predict transregulators, identify trans-QTL, and study complex disease. The frameworks for identifying and analyzing global patterns of epigenetic variation are general and we expect will be useful in other systems.

bioinformatics↗

Neutralization of SARS-CoV-2 Omicron sublineages by 4 doses of mRNA vaccine

Since the initial emergence of SARS-CoV-2 Omicron BA.1, several Omicron sublineages have emerged, leading to BA.5 as the current dominant sublineage. Here we report the neutralization of different Omicron sublineages by human sera collected from individuals who had distinct mRNA vaccination and/or BA.1 infection. Four-dose-vaccine sera neutralize the original USA-WA1/2020, Omicron BA.1, BA.2, BA.212.1, BA.3, and BA.4/5 viruses with geometric mean titers (GMTs) of 1554, 357, 236, 236, 165, and 95, respectively; 2-dose-vaccine-plus-BA.1-infection sera exhibit GMTs of 2114, 1705, 730, 961, 813, and 274, respectively; and 3-dose-vaccine-plus-BA.1-infection sera show GMTs of 2962, 2038, 983, 1190, 1019, and 297, respectively. Thus, 4-dose-vaccine elicits the lowest neutralization against BA.5; 2-dose-vaccine-plus-BA.1-infection elicits significantly higher GMTs against Omicron sublineages than 4-dose-vaccine; and 3-dose-vaccine-plus-BA.1-infection elicits slightly higher GMTs (statistically insignificant) than the 2-dose-vaccine-plus-BA.1-infection. Finally, compared with BA.5, the newly emerged BA.2.75 is equally evasive of 4-dose-vaccine-elicited neutralization, but more susceptible to 3-dose-vaccine-plus-BA.1-infection-elicited neutralization.

microbiology↗

Acoustic Correlates of the Syllabic Rhythm of Speech: Modulation Spectrum or Local Features of the Temporal Envelope

The speech envelope is considered as a major acoustic correlate of the syllable rhythm since the peak frequency in the speech modulation spectrum matches the mean syllable rate. Nevertheless, it has not been quantified whether the peak modulation frequency can track the syllable rate of individual utterances and how much variance of the speech envelope can be explained by the syllable rhythm. Here, we address these problems by analyzing large speech corpora (>1000 hours of recording of multiple languages) using advanced sequence-to-sequence modeling. It is found that, only when averaged over minutes of speech recordings, the peak modulation frequency of speech reliably correlates with the syllable rate of a speaker. In contrast, the phase-locking between speech envelope and syllable onsets is robustly observed within a few seconds of recordings. Based on speaker-independent linear and nonlinear models, the timing of syllable onsets explains about 13% and 46% variance of the speech envelope, respectively. These results demonstrate that local temporal features in the speech envelope precisely encodes the syllable onsets but the modulation spectrum is not always dominated by the syllable rhythm.

neuroscience↗

Kynurenic acid promotes A1 to A2 astrocyte conversion against HIV-associated neurocognitive disorder

Although extensive astrocyte activation is present in the CNS of patients suffering from HIV-associated neurocognitive disorder (HAND), little is known about the contribution of reactive astrocytes to HAND neuropathology. Here, we report that the imbalance between neurotoxic (A1 astrocytes) and protective astrocytes (A2 astrocytes) occurring in HIV-1 gp120 transgenic mice impedes the resolution of inflammation in the CNS, perpetuating neuron damage and cognitive deficits. Kynurenic acid (KYNA), a tryptophan metabolite with 7 nicotinic acetylcholine receptors (7nAChR) inhibitory property, blunts gp120-induced A1 astrocyte activation while promoting A2 astrocyte formation through blockade of 7nAChR/JAK2/STAT3 signaling activation. Meanwhile, we provide evidence that 7nAChR deletion and tryptophan administration convert astrocyte phenotypes, ultimately facilitating neuronal and cognitive improvement in the gp120tg mice. These initial and determinant findings mark a turning point in our understanding of the role of 7nAChR in gp120-mediated astrocyte activation, which opens new opportunities to control reactive astrocyte generation through KYNA and tryptophan administration as a pharmacological approach for treating HAND.

microbiology↗

Metformin Alleviates Arthrofibrosis in Rat via Fibroblast Metabolic Reprogramming and Lactate-Mediated Macrophage Polarization

BackgroundEmerging studies have suggested an essential role of fibroblast metabolic reprogramming in the pathogenesis of arthrofibrosis. The metabolic modulator metformin appears to be a therapeutic candidate for fibrotic disorders. However, whether metformin could alleviate arthrofibrosis has not been defined. In this study we have determined if treatment with metformin has the beneficial effect on arthrofibrosis and its underlying mechanism. MethodsArticular capsule samples were collected from patients with/without arthrofibrosis to perform gene and protein expression analysis. Arthrofibrosis animal model was established to examine the anti-fibrotic effect of metformin. Cell culture experiments were conducted to determine the mechanism by which metformin inhibits fibroblast activation. ResultsWe found that glycolysis was upregulated in human fibrotic articular capsules. In an arthrofibrosis animal model, intra-articular injection of metformin mitigated inflammatory reactions, downregulated expression of both fibrotic and glycolytic markers, improved range of motion of the joint, and reduced capsular fibrosis and thickening. At the cellular level, metformin inhibited the activation of fibroblasts and mitigated the abundant influx of glucose into activated fibroblasts. Interestingly, metformin prompted a metabolic shift from oxidative phosphorylation to aerobic glycolysis in activated fibroblasts, resulting in the anti-fibrotic effect of metformin. ConclusionMetformin decreased glycolysis, causing a metabolic shift toward aerobic glycolysis in activated fibroblasts and has beneficial effect on the treatment of arthrofibrosis. The translational potential of this articleThe finding of this study demonstrated the therapeutic effect of metformin on arthrofibrosis and defined novel targets for the treatment of articular fibrotic disorders.

cell biology↗