Biology subjects

Zhu, J.

Publications and source records attributed to Zhu, J..

At least 307 records · Page 17Linked to original sources

bioRxiv2024

TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport

Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employed a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. Over 300 proteins were identified, forming different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown solid inclusion at the ER exit sites (ERES). TDP43-ERES coaggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delayed ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.

cell biology↗

bioRxiv2024

Effects of different feeding methods on serum biochemical indexes, metabolic indexes, immune indexes, and intestinal microorganisms of Nanjiang yellow goats

The intestinal microbiota significantly influences the intake, storage, and absorption of nutrients in animals, thereby greatly impacting the growth and development of the animals. Factors such as diet, animal breed, growth stage, and feeding methods may affect variations in the composition of the intestinal microbiota. However, research on the variations in the intestinal microbiota and metabolites of Nanjiang Yellow goats under different feeding methods is still unclear. We measured various serum biochemical indicators and immune biochemical indicators and found that the triglyceride (TC) content in the grazing group (the FMMF) was significantly lower than in the barn-feeding group (the SSMF) (P<0.05). Serum levels of immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin G (IgM) were higher in the FMMF group. At the phylum level, the most abundant bacteria were Firmicutes, Bacteroidota, and Verrucomicrobiota. At the genus level, the most abundant microbial groups were Christensenellaceae_R-7_group, UCG-005, and Rikenellaceae_RC9_gut_group. Differential metabolite enrichment analysis through KEGG pathways revealed that the most remarkably enriched pathway was "Metabolic pathways," including Steroid hormone biosynthesis and Arachidonic acid metabolism, among others. Analyzed by multi-omics association, we identified notably different microbial features correlated with immune indicators and metabolites after different feeding methods. We observed a significant negative correlation (P<0.05) between the concentrations of serum immune factors interleukin-2 (IL-2), interleukin-4 (IL-4), and g__probable_genus_10. The concentration of IgM in serum showed a highly significant positive correlation (P<0.01) with the relative abundance of g__Erysipelatoclostridium in the intestine. Interestingly, most differential metabolites were significantly associated with intestinal microbiota. This experiment indicates that different feeding methods may influence the diversity and relative abundance of the intestinal microbiota in Nanjiang Yellow goats. The intestinal microbiota is correlated with immune indicators and metabolism, and regulating the diversity and relative abundance of the intestinal microbiota can be a way to adjust metabolism, thereby promoting the healthy growth of the Nanjiang Yellow goats.

microbiology↗

bioRxiv2023

Comprehensive characterization of the integrin family across 32 cancer types

Integrin genes widely involve in tumorigenesis. Yet, a comprehensive characterization of integrin family and their interactome on the pan-cancer level is lacking. Here, we systematically dissect integrin family in nearly 10000 tumors across 32 cancer types. Globally, integrins represent a frequently altered and misexpressed pathway, with alteration and dysregulation overall being protumorigenic. Expression dysregulation, better than mutational landscape, of integrin family successfully identifies a subgroup of aggressive tumors demonstrating a high level of proliferation and stemness. We identify that several molecular mechanisms jointly regulate integrin expression in a context-dependent manner. For potential clinical usage, we construct a weighted score, integrinScore, to measure integrin signaling patterns in individual tumors. Remarkably, integrinScore consistently correlates with predefined molecular subtypes in multiple cancers, with integrinScore high tumors being more aggressive. Importantly, integrinScore is cancer-dependently and closely associated with proliferation, stemness, tumor microenvironment, metastasis, and immune signatures. IntegrinScore also predicts patients response to immunotherapy. By mining drug databases, we unravel an array of compounds that may serve as integrin signaling modulators. Finally, we build a user-friendly database to facilitate researchers to explore integrin-related knowledge. Collectively, we provide a comprehensive characterization of integrins across cancers, which offers gene- and cancer-specific rationales for developing integrin-targeted therapy.

bioinformatics↗

bioRxiv2023

Role of Ribeye PXDLS/T-binding cleft in normal synaptic ribbon function

Non-spiking sensory hair cells of the auditory and vestibular systems encode a dynamic range of graded signals with high fidelity by vesicle exocytosis at ribbon synapses. Ribeye, the most abundant protein in the synaptic ribbon, is composed of a unique A domain specific for ribbons and a B-domain nearly identical to the transcriptional corepressor CtBP2. CTBP2 and the B-domain of Ribeye contain a surface cleft that binds to proteins harboring a PXDLS/T peptide motif. Little is known about the importance of this binding site in synaptic function. Piccolo has a well-conserved PVDLT motif and we find that overexpressed Ribeye exhibits striking co-localization with Piccolo in INS-cells, while two separate mutants containing mutations in PXDLS/T-binding region, fail to co-localize with Piccolo. Similarly, co-transfected Ribeye and a piccolo fragment containing the PVDLT region co-localize in HEK cells. Expression of wild-type Ribeye-YFP in zebrafish neuromast hair cells returns electron densities to ribbon structures and mostly rescued normal synaptic transmission and morphological phenotypes in a mutant zebrafish lacking most Ribeye. By contrast, Ribeye-YFP harboring a mutation in the PXDLS/T-binding cleft resulted in ectopic electron dense aggregates that did not collect vesicles and the persistence of ribbons lacking electron densities. Furthermore, overexpression failed to return capacitance responses to normal levels. These results point toward a role for the PXDLS/T-binding cleft in the recruitment of Ribeye to ribbons and in normal synaptic function. Significance statementHair cell synaptic ribbons are evolutionarily conserved structures that appear dense in electron micrographs, extend from the release site into the cytoplasm and tether synaptic vesicles for release. Here, we show that Ribeye, the major component of the synaptic ribbon electron density is directed to ribbons via its PXDLS/T-binding site and that mutant isoforms of Ribeye with point mutations disrupting these interactions fail to rescue normal function in mutant zebrafish lacking most Ribeye.

neuroscience↗

bioRxiv2023

Functional Connectivity, Tissue Microstructure And T2 At 11.1 Tesla Distinguishes Neuroadaptive Differences In Two Contusive Brain Injury Models In Rats

Traumatic brain injuries (TBIs), particularly contusive types, are associated with disruptions in neuronal communication due to focal and diffuse axonal injury, as well as alterations in the neuronal chemical environment. These changes can negatively impact neuronal networks beyond the primary injury site. In this Translational Outcomes Project in NeuroTrauma (TOP-NT) UG3 phase study, we sought to use multimodal neuroimaging biomarker approach to assess functional connectivity and brain tissue microstructure, along with T2 relaxometry, in two experimental rat models of TBI: controlled cortical impact (CCI) and lateral fluid percussive injury (LFPI). Rats underwent imaging using an 11.1 Tesla scanner at 2 and 30 days post-injury. Naive controls were scanned once to establish baseline comparisons for both TBI groups. Imaging modalities included functional magnetic resonance imaging (fMRI), diffusion-weighted imaging (DWI), and multi-echo T2 imaging. fMRI data were analyzed to evaluate functional connectivity across lateral and medial regions of interest (ROIs) in the cortical mantle, hippocampus, and dorsal striatum. DWI scans were used to generate maps of fractional anisotropy (FA) and mean, axial, and radial diffusivities (MD, AD, RD), focusing on cortical and white matter (WM) regions near the injury epicenter. Our findings revealed significantly increased contralateral intra-cortical connectivity at 2 days post-injury in both CCI and LFPI models, localized to similar cortical areas. This increased connectivity persisted at day 30 in the CCI model but not in LFPI. Changes in WM and cortical FA and diffusivities were observed in both models, with WM alterations predominating in CCI and cortical changes being more pronounced in LFPI. These results highlight the utility of multimodal MR imaging for characterizing distinct injury mechanisms in contusive and skull-penetrating TBI models.

neuroscience↗

bioRxiv2023

Population suppression with dominant female-lethal alleles is boosted by homing gene drive

Methods to suppress pest insect populations using genetic constructs and repeated releases of male homozygotes have recently been shown to be an attractive alternative to older sterile insect technique based on radiation. Female-specific lethal alleles have substantially increased power, but still require large, sustained transgenic insect releases. Gene drive alleles bias their own inheritance to spread throughout populations, potentially allowing population suppression with a single, small-size release. However, suppression drives often suffer from efficiency issues, and the most well-studied type, homing drives, tend to spread without limit. In this study, we show that coupling female-specific lethal alleles with homing gene drive allowed substantial improvement in efficiency while still retaining the self-limiting nature (and thus confinement) of a lethal allele strategy. Using a mosquito model, we show the required releases sizes for population elimination in a variety of scenarios, including different density growth curves, with comparisons to other systems. Resistance alleles reduced the power of this method, but these could be overcome by targeting an essential gene with the drive while also providing rescue. A proof-of-principle demonstration of this system in Drosophila melanogaster was effective in both basing its inheritance and achieving high lethality among females that inherit the construct in the absence of antibiotic. Overall, our study shows that substantial improvements can be achieved in female-specific lethal systems for population suppression by combining them with a gene drive.

synthetic biology↗

bioRxiv2023

Development of attenuated coxsackievirus B3 vectored intranasal pre-emptive pan-coronavirus vaccine

SARS-CoV-2 has the ability to evade immunity, resulting in breakthrough infections even after vaccination. Similarly, zoonotic coronaviruses pose a risk of spillover to humans. There is an urgent need to develop a pre-emptive pan-coronavirus vaccine that can induce systemic and mucosal immunity. Here, we employed a combination of immune-informatics approaches to identify shared immunodominant linear B- and T-cell epitopes from SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs), as well as zoonotic coronaviruses. Epitope-guided vaccine were designed and the attenuated coxsackievirus B3 vectored intranasal vaccines rCVB3-EPI and rCVB3-RBD-trimer were constructed. The immunogenicity of these candidate vaccines was evaluated using Balb/c mice. The results demonstrated effective immune responses, including the production of SARS-CoV-2-specific IgG and sIgA antibodies, as well as T cell-mediated responses. However, further verification is required to assess cross-reactivity with various variants. Our intranasal pre-emptive pan-coronavirus vaccine design framework offers an appealing candidate for future vaccine development.

microbiology↗

bioRxiv2023

Feedback inhibition by a descending GABAergic neuron regulates timing of escape behavior in Drosophila larvae

Escape behaviors help animals avoid harm from predators and other threats in the environment. Successful escape relies on integrating information from multiple stimulus modalities (of external or internal origin) to compute trajectories toward safe locations, choose between actions that satisfy competing motivations, and execute other strategies that ensure survival. To this end, escape behaviors must be adaptive. When a Drosophila melanogaster larva encounters a noxious stimulus, such as the focal pressure a parasitic wasp applies to the larval cuticle via its ovipositor, it initiates a characteristic escape response. The escape sequence consists of an initial abrupt bending, a corkscrew-like rolling, and finally rapid crawling. Previous work has shown that the detection of noxious stimuli primarily relies on class IV multi dendritic arborization neurons (Class IV neurons) located beneath the body wall, and more recent studies have identified several important components in the nociceptive neural circuitry involved in rolling. However, the neural mechanisms that underlie the rolling-escape sequence remain unclear. Here we present both functional and anatomical evidence suggesting that bilateral descending neurons within the subesophageal zone of D. melanogaster larva play a crucial role in regulating the termination of rolling and subsequent transition to escape crawling. We demonstrate that these descending neurons (designated SeIN128) are inhibitory and receive inputs from a second-order interneuron upstream (Basin-2) and an ascending neuron downstream of Basin-2 (A00c). Together with optogenetic experiments showing that co-activation of SeIN128 neurons and Basin-2 influence the temporal dynamics of rolling, our findings collectively suggest that the ensemble of SeIN128, Basin-2, and A00c neurons forms a GABAergic feedback loop onto Basin-2, which inhibits rolling and thereby facilitates the shift to escape crawling.

neuroscience↗

bioRxiv2023

Development of an Engineered Mycobacterium tuberculosis Strain for a Safe and Effective Tuberculosis Human Challenge Model

Human challenge experiments could greatly accelerate the development of a tuberculosis (TB) vaccine. Human challenge for tuberculosis requires a strain that can both replicate in the host and be reliably cleared. To accomplish this, we designed Mycobacterium tuberculosis (Mtb) strains featuring up to three orthogonal kill switches, tightly regulated by exogenous tetracyclines and trimethoprim. The resultant strains displayed immunogenicity and antibiotic susceptibility similar to wild-type Mtb under permissive conditions. In the absence of supplementary exogenous compounds, the strains were rapidly killed in axenic culture, mice and nonhuman primates. Notably, the strain that contained three kill switches had an escape rate of less than 10-10 per genome per generation and displayed no relapse in a SCID mouse model. Collectively, these findings suggest that this engineered Mtb strain could be a safe and effective candidate for a human challenge model.

microbiology↗

bioRxiv2023

Sleep Disruption in a Mouse Model of Chronic Traumatic Brain Injury

Chronic sleep/wake disturbances are strongly associated with traumatic brain injury (TBI) in patients and are being increasingly recognized. However, the underlying mechanisms are largely understudied and there is an urgent need for animal models of lifelong sleep/wake disturbances. The objective of this study was to develop a chronic TBI rodent model and investigate the lifelong chronic effect of TBI on sleep/wake behavior. We performed repetitive midline fluid percussion injury (rmFPI) in four months old mice and monitored their sleep/wake behavior using the non-invasive PiezoSleep system. The sleep/wake states were recorded before injury (baseline) and then monthly thereafter. We found that TBI mice displayed a significant decrease in sleep duration in both the light and dark phases, beginning at three months post-TBI and continuing throughout the study. Consistent with the sleep phenotype, these TBI mice showed circadian locomotor activity phenotypes and exhibited reduced anxiety-like behavior. TBI mice also gained less weight, and had less lean mass and total body water content, compared to sham controls. Furthermore, TBI mice showed extensive brain tissue loss and increased GFAP and IBA1 levels in the hypothalamus and the vicinity of the injury, indicative of chronic neuropathology. In summary, our study identified a critical time window of TBI pathology and associated circadian and sleep/wake phenotypes. Future studies should leverage this mouse model to investigate the molecular mechanisms underlying the chronic sleep/wake phenotypes following TBI early in life.

neuroscience↗

bioRxiv2023

Investigation of contributions from cortical and subcortical brain structures for speech decoding

Language impairments often arise from severe neurological disorders, prompting the development of neural prosthetics based on electrophysiological signals for the restoration of comprehensible language information. Previous decoding efforts have focused mainly on signals from the cerebral cortex, neglecting the potential contributions of subcortical brain structures to speech decoding in brain-computer interfaces (BCIs). This study aims to explore the role of subcortical structures for speech decoding by utilizing stereotactic electroencephalography (sEEG). Two native Mandarin Chinese speakers, who underwent sEEG implantation for pharmaco-resistant epilepsy, participated in this study. sEEG contacts were primarily located in the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, thalamus, hippocampus, insular gyrus, amygdala, and parahippocampal gyrus. The participants were asked to read Chinese text, which included 407 Chinese characters (covering all Chinese syllables), displayed on a screen after receiving prompts. 1-30, 30-70 and 70-150 Hz frequency band powers of sEEG signals were used as key features. A deep learning model based on long short-term memory (LSTM) was developed to evaluate the contribution of different brain structures during encoding of speech. Prediction of speech characteristics of consonants (articulatory place and manner) and tone within single words based on the selected features and electrode contact locations was made. Cortical signals were generally better at articulatory place prediction (86.5% accuracy, chance level = 12.5%), while cortical and subcortical signals predicted articulatory manner at similar level (51.5% vs 51.7% accuracy, respectively, chance level = 14.3%). Subcortical signals generated better prediction for tone (around 58.3% accuracy, chance level = 25%). Superior temporal gyrus remains highly relevant during speech decoding for both consonants and tone. Prediction reached the highest level when cortical and subcortical inputs were combined, especially for tone prediction. Our findings indicate that both cortical and subcortical structures can play crucial roles for speech decoding, each contributing to different aspects of speech.

neuroscience↗

bioRxiv2023

A high-performance brain-sentence communication designed for logosyllabic language

Many severe neurological diseases, such as stroke and amyotrophic lateral sclerosis, can impair or destroy the ability of verbal communication. Recent advances in brain-computer interfaces (BCIs) have shown promise in restoring communication by decoding neural signals related to speech or motor activities into text. Existing research on speech neuroprosthesis has predominantly focused on alphabetic languages, leaving a significant gap of logosyllabic languages such as Mandarin Chinese which are spoken by more than 15% of the world population. Logosyllabic languages pose unique challenges to brain-to-text decoding due to extended character sets (e.g., 50,000+ for Mandarin Chinese) and complex mapping between characters and pronunciation. To address these challenges, we established a speech BCI designed for Mandarin, decoding speech-related stereoelectroencephalography (sEEG) signals into coherent sentences. We leverage the unique acoustic features of Mandarin Chinese syllables, constructing prediction models for syllable components (initials, tones, and finals), and employ a language model to resolve pronunciation to character ambiguities according to the semantic context. This method leads to a high-performance decoder with a median character accuracy of 71.00% over the full character set, demonstrating huge potentials for clinical application. To our knowledge, we are the first to report brain-to-sentence decoding for logosyllabic languages over full character set with a large intracranial electroencephalography dataset.

neuroscience↗

bioRxiv2023

Attenuating amyloid-beta pathology in mice with in situ programmed astrocytes

Astrocytes are abundant cells in the central nervous system that provide trophic support for neurons and clear detrimental factors, such as A{beta} oligomers (A{beta}Os). However, in the brains of Alzheimers disease (AD) patients, astrocytes lose these physiological functions. Here, we genetically engineered astrocytes with an anti-A{beta}O chimeric antigen receptor (CAR), constructed by replacing the antigen-binding domain of MerTK with an A{beta}O-specific single-chain variable fragment, to direct their phagocytic activity against A{beta}Os. CAR-engineered astrocytes (CAR-As) showed significantly enhanced phagocytosis of A{beta}Os due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased release of pro-inflammatory cytokines due to inhibition of the NF-{kappa}B and cytokine receptor signalling pathways. Consistently, in situ CAR-As markedly ameliorated the cognitive deficits of APP/PS1 transgenic mice possibly by clearing A{beta}Os and creating a non-inflammatory microenvironment for neuronal survival and the restoration of microglia to a healthy phenotype. Our present study is the first to introduce a CAR-A-based therapy, validate its feasibility and effectiveness, and highlight its potential application for the treatment of AD and other brain disorders.

neuroscience↗

bioRxiv2023

An exploration of mechanisms underlying Desemzia incerta colonization resistance to methicillin-resistant Staphylococcus aureus on the skin

Colonization of human skin and nares by methicillin-resistant Staphylococcus aureus (MRSA) leads to community spread of MRSA. This spread is exacerbated by transfer of MRSA between humans and livestock, particularly swine. Here we capitalized on the shared features between human and porcine skin, including shared MRSA colonization, to study novel bacterial mediators of MRSA colonization resistance. We focused on the poorly studied bacterial species Desemzia incerta, which we found to exert antimicrobial activity through a secreted product and exhibited colonization resistance against MRSA in an in vivo murine skin model. Using parallel genomic and biochemical investigation, we discovered that D. incerta secretes an antimicrobial protein. Sequential protein purification and proteomics analysis identified 24 candidate inhibitory proteins, including a promising peptidoglycan hydrolase candidate. Aided by transcriptional analysis of D. incerta and MRSA cocultures, we found that exposure to D. incerta leads to decreased MRSA biofilm production. These results emphasize the value in exploring microbial communities across a spectrum of hosts, which can lead to novel therapeutic agents as well as increased understanding of microbial competition. IMPORTANCEMethicillin-resistant Staphylococcus aureus causes significant healthcare burden and can be spread to the human population via livestock transmission. Members of the skin microbiome can prevent MRSA colonization via a poorly-understood phenomenon known as colonization resistance. Here, we studied colonization resistance of S. aureus by bacterial inhibitors previously identified from a porcine skin model. We identify a pig skin commensal, Desemzia incerta, that reduced MRSA colonization in a murine model. We employ a combination of genomic, proteomic, and transcriptomic analyses to explore the mechanisms of inhibition between D. incerta and S. aureus. We identify 24 candidate antimicrobial proteins secreted by D. incerta that could be responsible for its antimicrobial activity. We also find that exposure to D. incerta leads to decreased S. aureus biofilm formation. These findings show that the livestock transmission of MRSA can be exploited to uncover novel mechanisms of MRSA colonization resistance.

microbiology↗

bioRxiv2023

Hybrid hydrogel-extracellular matrix scaffolds identify distinct ligand and mechanical signatures in cardiac aging

Extracellular matrix (ECM) remodeling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Aberrant secretion, structural perturbations, and degradation of specific ECM components lead to significant alterations in ECM properties that disrupt healthy cell and tissue homeostasis. These changes in ECM are multifaceted, as alterations in ligand presentation, including both biochemical and architectural aspects, are often accompanied by stiffness changes, clouding our understanding of how and which ECM properties contribute to a dysfunctional state. To identify the specific roles of these interconnected ECM cues and elucidate their mechanistic regulation in cellular function, we developed a material system that can independently present these two distinct matrix properties, i.e., ligand presentation and stiffness, to cultured cells in vitro. We describe a decellularized ECM-synthetic hydrogel hybrid scaffold that maintains native matrix composition and organization of young or aged murine cardiac tissue with independently tunable scaffold mechanics that mimic young or aged tissue stiffness. Seeding these scaffolds with primary cardiac fibroblasts (CFs) from young or aged mice, we identify distinct age- and ECM-dependent mechanisms of CF activation. Importantly, we show that ligand presentation of young ECM can outweigh profibrotic stiffness cues typically present in aged ECM in maintaining or driving CF quiescence, thereby highlighting the unique roles of ECM in aging. Ultimately, these tunable scaffolds can enable the discovery of specific ECM targets to prevent aging dysfunction and promote rejuvenation. DECIPHER: DECellularized In Situ Polyacrylamide Hydrogel-ECM hybRid

bioengineering↗

bioRxiv2023

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling

Inflammation-associated fibroblasts (IAFs) are associated with the progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial function and architecture is unknown. In this study, we developed an in vitro model whereby human colon fibroblasts are induced to become IAFs by specific cytokines and recapitulate key features of IAFs in vivo. When co-cultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid swelling and barrier disruption due to swelling and rupture of individual epithelial cells. Epithelial cells co-cultured with IAFs also exhibit increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated through a paracrine pathway involving prostaglandin E2 (PGE2) and the PGE2 receptor EP4, leading to PKA-dependent activation of the CFTR chloride channel. Importantly, EP4-specific chemical inhibitors effectively prevented colonoid swelling and restored normal proliferation and genome stability of IAF-exposed epithelial cells. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a potential treatment to mitigate inflammation-associated epithelial injury. TeaserInflammation-associated fibroblasts compromise colon epithelial barrier integrity and genome stability via PGE2-EP4 signaling.

cell biology↗

bioRxiv2023

Differential effects of aneuploidy on growth and differentiation in human intestinal stem cells

Aneuploidy, a near ubiquitous genetic feature of tumors, is a context-dependent driver of cancer evolution; however, the mechanistic basis of this role remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigate how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Single-cell RNA sequencing reveals that the gene expression signature across over 100 unique aneuploid karyotypes is enriched with p53 responsive genes. The primary driver of p53 activation is karyotype complexity. Complex aneuploid cells with multiple unbalanced chromosomes activate p53 and undergo G1 cell-cycle arrest, independent of DNA damage and without evidence of senescence. By contrast, simple aneuploid cells with 1-3 chromosomes gained or lost continue to proliferate, demonstrated by single cell tracking in colonoids. Notably, simple aneuploid cells exhibit impaired differentiation when niche factors are withdrawn. These findings suggest that while complex aneuploid cells are eliminated from the normal epithelium due to p53 activation, simple aneuploid cells can escape this checkpoint and may contribute to niche factor-independent growth of cancer-initiating cells.

cell biology↗

bioRxiv2023

Voxelated bioprinting of modular double-network bio-ink droplets

Analogous of pixels to two-dimensional pictures, voxels -- in the form of either small cubes or spheres -- are the basic building blocks of three-dimensional (3D) objects. However, precise manipulation of viscoelastic bio-ink voxels in 3D space represents a grand challenge in both soft matter science and biomanufacturing. Here, we present a voxelated bioprinting technology that enables the digital assembly of interpenetrating alginate and polyacrylamide (PAM) double-network (DN) hydrogel droplets. The hydrogel is crosslinked via additive-free bioorthogonal chemistry involving a pair of stoichiometrically matched polymers. We develop theoretical frameworks to describe the crosslinking kinetics and stiffness of the hydrogels, and construct a diagram-of-state to delineate their mechanical properties. Multi-channel print nozzles are developed to allow on-demand mixing of highly viscoelastic bio-inks without significantly impairing cell viability. Further, we showcase the distinctive capability of voxelated bioprinting by creating highly complex 3D structures such as a hollow sphere composed of interconnected yet distinguishable hydrogel particles. Finally, we validate the cytocompatibility and in vivo stability of the printed DN scaffolds through cell encapsulation and animal transplantation.

bioengineering↗