Biology subjects

Lin, J.

Publications and source records attributed to Lin, J..

At least 271 records · Page 15Linked to original sources

bioRxiv2022

Brevicidine, a bacterial non-ribosomally produced cyclic antimicrobial lipopeptide with a unique modus operandi

Due to the accelerated appearance of antibiotic-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately-needed. Brevicidine, a bacterial non-ribosomally produced cyclic lipopeptide, has shown potent and selective antimicrobial activity against Gram-negative pathogens. However, before our investigations, little was known about how brevicidine exerts its potent bactericidal effect against Gram-negative pathogens. In this study, we find that brevicidine has potent antimicrobial activity against AMR Enterobacteriaceae pathogens, with a MIC value ranging between 0.5M (0.8mg/L) and 2M (3.0mg/L). In addition, brevicidine showed potent anti-biofilm activity against the Enterobacteriaceae pathogens, with same 100% inhibition and 100% eradication concentration of 4M (6.1mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity via interacting with lipopolysaccharide in the outer membrane, targeting phosphatidylglycerol and cardiolipin in the inner membrane, and dissipating the proton motive force of bacteria. This results in metabolic perturbation, including inhibition of adenosine triphosphate synthesis, inhibits the dehydrogenation of nicotinamide adenine dinucleotides, accumulation of reactive oxygen species in bacteria, and inhibition of protein synthesis. Lastly, brevicidine showed a good therapeutic effect in a mouse peritonitis-sepsis model. Our findings pave the way for further research on clinical applications of brevicidine, to combat the prevalent infections caused by AMR Gram-negative pathogens worldwide.

microbiology↗

bioRxiv2022

Small Molecule Assembly Modulators with Pan-Cancer Therapeutic Efficacy

Two structurally-unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951 with antiviral activity in cell culture against monkeypox virus (MPXV) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity, reasonable pharmacokinetics, and non-toxicity in mice at active concentrations. Anti-tumor properties of both chemotypes, were validated in mouse xenografts against A549 human lung cancer and, for one of the chemotypes, against HT-29 colorectal cancer. The targets of these compounds are unconventional: each binds to a different transient, energy-dependent multi-protein complex containing the protein TRIM28/KAP1, an allosteric modulator known to regulate mechanisms underlying viral and nonviral disease states including cancer. Treatment with these compounds alters the target multi-protein complexes in a manner consistent with allosteric modulation as their mechanism of action. These compounds appear to remove a block, crucial for cancer survival and progression, on the homeostatic linkage of uncontrolled cellular proliferation to apoptosis. These compounds provide starting points for development of next-generation non-toxic, pan-cancer therapeutics.

cancer biology↗

bioRxiv2022

Haplotype-resolved assemblies and variant benchmark of a Chinese Quartet

As the state-of-the-art sequencing technologies and computational methods enable investigation of challenging regions in the human genome, an update variant benchmark is demanded. Herein, we sequenced a Chinese Quartet, consisting of two monozygotic twin daughters and their biological parents, with multiple advanced sequencing platforms, including Illumina, BGI, PacBio, and Oxford Nanopore Technology. We phased the long reads of the monozygotic twin daughters into paternal and maternal haplotypes using the parent-child genetic map. For each haplotype, we utilized advanced long reads to generate haplotype-resolved assemblies (HRAs) with high accuracy, completeness, and continuity. Based on the ingenious quartet samples, novel computational methods, high-quality sequencing reads, and HRAs, we established a comprehensive variant benchmark, including 3,883,283 SNVs, 859,256 Indels, 9,678 large deletions, 15,324 large insertions, 40 inversions, and 31 complex structural variants shared between the monozygotic twin daughters. In particular, the preciously excluded regions, such as repeat regions and the human leukocyte antigen (HLA) region, were systematically examined. Finally, we illustrated how the sequencing depth correlated with the de novo assembly and variant detection, from which we learned that 30 x HiFi is a balance between performance and cost. In summary, this study provides high-quality haplotype-resolved assemblies and a variant benchmark for two Chinese monozygotic twin samples. The benchmark expanded the regions of the previous report and adapted to the evolving sequencing technologies and computational methods.

genomics↗

bioRxiv2022

Distinct selection signatures during domestication and improvement in crops: a tale of two genes in mungbean

Domestication and improvement are two crucial processes underlying the evolution of crops. Domestication transformed wild plants into a utilizable form for humans; improvement refined cultivars adapting to distinct environments and local preferences. Using whole-genome re-sequencing of Vigna radiata, we investigated the demographic history and compared the genetic footprints of domestication and improvement. The Asian wild population migrated to Australia at about 50 kya, and domestication happened in Asia about 9 kya selecting for non-shattering pods. The key candidate gene for this trait, VrMYB26a, has lower expression in cultivars, consistent with the reduced polymorphism in the promoter region reflecting hard selective sweep. The determinate stems were later selected as an improvement phenotype and associated with the gene VrDet1. Two ancient haplotypes reducing gene expression exhibit intermediate frequencies in cultivars, consistent with selection favoring independent haplotypes in soft selective sweep. Our results suggest domestication and improvement may leave different genomic signatures of selection, reflecting the fundamental differences in the two processes and highlighting the limitations of genome-scan methods relying on hard selective sweep.

plant biology↗

bioRxiv2022

Identification of the Metaphyseal Skeletal Stem Cell

Identification of novel regional skeletal stem cells (SSCs) will provide a new cellular paradigm for bone physiology and dysfunction. Several populations of SSCs have been identified at distinct skeletal sites. However, a bona fide SSC population has not yet been formally characterized in the bone marrow. Here, we identify a metaphyseal SSCs (mpSSCs) population whose transcriptional landscape is distinct from other bone mesenchymal stromal cells (bMSCs) in the bone marrow. These mpSSCs emerge at the postnatal stage and reside just underneath the growth plate, consistent with the fact that these mpSSCs are exclusively derived from hypertrophic chondrocytes (HCs). These mpSSCs possess SSC properties such as self-renewal and multipotency in vitro and in vivo, stand at the top of the HC de-differentiation path, and produce most HC progeny. Genetic block of the conversion from HCs to mpSSCs significantly compromises trabecular bone formation and bone regeneration. Thus, metaphysis houses a unique HC-derived SSC population, which is a major source of osteoblasts and bMSCs supporting postnatal trabecular bone formation.

developmental biology↗

bioRxiv2022

Dual control of lysogeny and phage defense by a phosphorylation-based toxin/antitoxin system

Regulatory systems that maintain prophage quiescence integrate phage and host gene expression with environmental conditions1,2. In the opportunistic bacterial pathogen Pseudomonas aeruginosa, Pf filamentous bacteriophages play critical roles in biofilm formation and virulence3-5, but mechanisms governing Pf prophage activation in biofilms are largely unknown. Here, we report a new type of prophage regulatory module in a widely-distributed P. aeruginosa lineage that not only controls virion production of co-resident Pf prophages, but also mediates defense against diverse lytic phages. By comparing two lineages of the prototype P. aeruginosa strain PAO1 that harbor different Pf prophages, we identified a prophage-encoded kinase-kinase-phosphatase (KKP) system that controls Pf production in biofilms. KKP components exhibit dynamic stoichiometry, where high kinase levels in planktonic conditions maintain phosphorylation of the host H-NS protein MvaU, repressing prophage activation. During biofilm formation, phosphatase expression is heightened, leading to MvaU dephosphorylation and alleviating repression of prophage gene expression. KKP clusters are present in hundreds of diverse temperate prophages and other mobile elements across Gram-negative bacteria. Characterization of KKP modules from different species revealed that, in addition to regulating Pf phage lysogeny, KKP functions as a tripartite toxin-antitoxin system that mediates host defense from predatory lytic phages. KKP represents a new phosphorylation-based mechanism for prophage regulation and for phage defense. The dual function of this module raises the question of whether other newly described phage defense systems6-9 also regulate intrinsic prophage biology in diverse hosts.

microbiology↗

bioRxiv2022

Comparison and benchmark of long-read based structural variant detection strategies

BackgroundRecent advances in long-read callers and assembly methods have greatly facilitated structural variants (SV) detection via read-based and assembly-based detection strategies. However, the lack of comparison studies, especially for SVs at complex genomic regions, complicates the selection of proper detection strategy for ever-increasing demand of SV analysis. ResultsIn this study, we compared the two most widely-used strategies with six long-read datasets of HG002 genome and benchmarked them with well curated SVs at genomic regions of different complexity. First of all, our results suggest that SVs detected by assembly-based strategy are slightly affected by assemblers on HiFi datasets, especially for its breakpoint identity. Comparably, though read-based strategy is more versatile to different sequencing settings, aligners greatly affect SV breakpoints and type. Furthermore, our comparison reveals that 70% of the assembly-based calls are also detectable by read-based strategy and it even reaches 90% for SVs at high confident regions. While 60% of the assembly-based calls that are totally missed by read-based callers is largely due to the challenges of clustering ambiguous SV signature reads. Lastly, benchmarking with SVs at complex genomic regions, our results show that assembly-based approach outperforms read-based calling with at least 20X coverage, while read-based strategy could achieve 90% recall even with 5X coverage. ConclusionsTaken together, with sufficient sequencing coverage, assembly-based strategy is able to detect SVs more consistently than read-based strategy under different settings. However, read-based strategy could detect SVs at complex regions with high sensitivity and specificity but low coverage, thereby suggesting its great potential in clinical application.

bioinformatics↗

bioRxiv2022

Brassinosteroids signaling component SlBZR1 promotes fruit ripening in tomato

Fruit ripening evolved to be attractive to frugivores that derive energy and nutrition from the fruits in exchange for assisting seed dispersal, which is accompanied by the dramatically change of fruit characteristics, including color, aroma, and texture. The plant hormone ethylene plays a key role in climacteric fruit ripening, while the role of other phytohormones as well as their cross talk with ethylene in modulating fruit ripening remains elusive. Here, we report growth-promoting phytohormone brassinosteroids promote fruit ripening in tomato through regulation of ethylene biosynthesis. Exogenous BR treatment and the increase of endogenous BR content in SlCYP90B3-OE promoted ethylene production and fruit ripening. SlBZR1, a central component and positive regulator of BR signaling pathway, promotes ethylene production and carotenoid accumulation through direct transcriptional regulation of SlACO1, SlACO3 and SlPSY1. Furthermore, SlBIN2, a negative regulator of BR signaling upstream of SlBZR1, decreases ethylene production and carotenoid accumulation. Together, our results demonstrate that BR signaling integrates ethylene and carotenoid biosynthetic pathway to regulate fruit ripening.

plant biology↗

bioRxiv2022

A Long-Circulating Vector for Aptamers Based upon Polyphosphodiester-Backboned Molecular Brushes

Aptamers face challenges for use outside the ideal conditions in which they are developed. These difficulties are most palpable in vivo due to nuclease activities, rapid clearance, and off-target binding. Herein, we demonstrate that a polyphosphodiester-backboned molecular brush can suppress enzymatic digestion, reduce non-specific cell uptake, enable long blood circulation, and rescue the bioactivity of a conjugated aptamer in vivo. The backbone along with the aptamer is assembled via solid-phase synthesis, followed by installation of poly(ethylene glycol) (PEG) side chains using a two-step process with near-quantitative efficiency. The synthesis allows for precise control over polymer size and architecture. Consisting entirely of building blocks that are generally recognized as safe for therapeutics, this novel molecular brush is expected to provide a highly translatable route for aptamer-based therapeutics.

pharmacology and toxicology↗

bioRxiv2022

An atypical F-actin capping protein modulates cytoskeleton behaviors crucial to colonization of Trichomonas vaginalis

Cytoadherence and consequential migration are crucial for pathogens to establish colonization in the host. In contrast to the nonadherent isolate of Trichomonas vaginalis, the adherent one expresses more actin-related machinery proteins with more active flagellate-amoeboid morphogenesis, amoeba migration, and cytoadherence, activities that were abrogated by an actin assembly blocker. By immunoprecipitation coupled with label-free quantitative proteomics, an F-actin capping protein (TvFACP) was identified from the actin-centric interactome, with an atypically greater binding preference to G-actin than F-actin. TvFACP partially colocalized with F-actin at the parasite pseudopodia protrusion and formed the protein complexes with -actin through its c-terminal domain. Meanwhile, TvFACP overexpression suppresses F-actin polymerization, amoeboid morphogenesis, and cytoadherence in this parasite. Ser2 phosphorylation of TvFACP enriched in the amoeboid stage of adhered trophozoites was reduced by a CKII inhibitor. The site-directed mutagenesis and CKII inhibitor treatment revealed that Ser2 phosphorylation acts as a switching signal to alter TvFACP actin-binding activity and consequent actin cytoskeleton behaviors. Through CKII signaling, TvFACP also controls the conversion of adherent trophozoite from amoeboid migration to flagellate form with axonemal motility. Together, CKII-dependent Ser2 phosphorylation regulates TvFACP binding actin to fine-tune cytoskeleton dynamics and drive crucial behaviors underlying host colonization of T. vaginalis.

microbiology↗

bioRxiv2022

Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants

The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike(S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the Wild-type, B.1.1.7, B.1.351, B.1.617.2, and the omicron B.1.1.529 variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. We also proved the safety of RQ3013 in NHP models. Our results provided key support for the evaluation of RQ3013 in clinical trials.

immunology↗

bioRxiv2022

Chemotherapy drugs induce different gut microbiota disorder pattern and NODs/RIP2/NF-κB signaling pathway activation that lead to different degrees of intestinal injury

5-Fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (L-OHP) and calcium folinate (CF) are the widely used chemotherapy drugs to treat colorectal cancer. However, the use of chemotherapy is often accompanied by intestinal inflammation and gut microbiota disorder. Moreover, the change of gut microbiota may lead to destruction of the intestinal barrier, which contributes to the severity of intestinal injury. There was no detailed comparison of intestinal injury and gut microbiota disorder among 5-FU, CPT-11, L-OHP and CF, which is not benefit for the development of targeted detoxification therapy after chemotherapy. In this project, a model of chemotherapy-induced intestinal injury in tumor-bearing mice was established by intraperitoneal injection of chemotherapy drugs at a clinically equivalent dose. 16S rDNA sequencing was used to detect gut microbiota. We found that 5-FU, CPT-11 and L-OHP caused intestinal injury, inflammatory cytokine (IFN-{gamma}, TNF-, IL-1{beta}, and IL-6) secretion, and gut microbiota disorder. Importantly, we established a complex but clear network between the gut microbiota change pattern and intestinal damage degree induced by different chemotherapy drugs. L-OHP caused the most severe damage in intestine and disorder of gut microbiota, and showed considerable overlap of the microbiota change pattern with 5-FU and CPT-11. The phylogenetic investigation of communities by reconstruction of unobserved states, V1.0 (PICRUSt) analysis showed that the microbiota disorder pattern induced by 5-FU, CPT-11 and L-OHP was related to the NOD like signaling pathway. Therefore, we detected the protein expression of the NODs/RIP2/NF-{kappa}B signaling pathway and found that L-OHP activated that pathway highest. Furthermore, by RDA/CCA analysis, we found that Bifidobacterium, Akkermansia, Allobaculum, Catenibacterium, Mucispirillum, Turicibacter, Helicobacter, Proteus, Escherichia Shigella, Alloprevotealla, Vagococcus, Streptococcus and Candidatus Saccharimonas were highly correlated with the NODs/RIP2/NF-{kappa}B signaling pathway, and influenced by chemotherapy drugs. IMPORTANCEThe chemotherapy-induced intestinal injury limit drugs clinical use. Intestinal injury involves multiple signaling pathways and the disruption of microbiota. Our results suggest that the degree of intestinal injury caused by different drugs of the first-line colorectal chemotherapy regimen is related to the change pattern of microbiota. Moreover, the NODs/RIP2/NF-{kappa}B signaling pathway was activated in different degrees is also related to the change pattern of microbiota. We found L-OHP caused the most severe change of gut microbiota, and showed considerable overlap of the microbiota changes pattern with 5-FU and CPT-11. Here, we have established a network of different chemotherapy drugs, gut microbiota and NODs/RIP2/NF-{kappa}B signaling pathway, which may provide a new basis for further elucidating the mechanism and clinical treatment of intestinal injury caused by chemotherapy.

molecular biology↗

bioRxiv2022

A molecular plugin rescues GroEL/ES substrates from pre-folding oxidation

Hsp60 chaperonins and their Hsp10 cofactors assist protein folding in all living cells, constituting the paradigmatic example of molecular chaperones. Despite extensive investigations of their structure and mechanism, crucial questions regarding how these chaperonins promote folding remain unsolved. Here, we report that the bacterial Hsp60 chaperonin GroEL forms a stable, functionally relevant complex with the chaperedoxin CnoX, a protein combining a chaperone and a redox function. Binding of GroES (Hsp10) to GroEL induces CnoX release. Cryo-electron microscopy provided crucial structural information on the GroEL-CnoX complex, showing that CnoX binds GroEL outside the substrate-binding site via a highly conserved C-terminal -helix. Furthermore, the identification of complexes in which CnoX, bound to GroEL, forms mixed-disulfides with GroEL substrates indicates that CnoX likely functions as a redox quality-control plugin for GroEL. Proteins sharing structural features with CnoX exist in eukaryotes, which suggests that Hsp60 molecular plugins have been conserved through evolution.

biochemistry↗

bioRxiv2022

Structure and mechanism of a mitochondrial AAA+ disaggregase CLBP

The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space and functions to promote the solubilization of various mitochondrial proteins. CLPB deficiency by mutations is associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. The mechanism of CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo- tetradecamers in apo-state and is remodeled into homo-dodecamers upon binding to substrates. Conserved pore- loops on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of two amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.

molecular biology↗

bioRxiv2022

Chronic Glucocorticoid Stress Reveals Increased Energy Expenditure and Accelerated Aging as Cellular Features of Allostatic Load

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by [~]60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

cell biology↗

bioRxiv2022

Hinokitiol alters Gene Expression in Aspergillus fumigatus, protects against fungal keratitis by Reducing Fungal Load, LOX-1, Proinflammatory cytokines and Neutrophil Infiltration

Hinokitiol (HK), a tropolone-related compound found in cupressaceous plants, has antifungal and anti-inflammatory properties. But its roles in Aspergillus fumigatus ( A.F. ) keratitis remains unknown. This study examined the antifungal activity of HK against A.F. and investigated its possible mechanisms at the ultrastructural and transcriptional levels. We tested the minimum inhibitory concentration (MIC) of HK against A.F.. Our data showed that the MIC50 was 2 g/ml and MIC90 was 8 g/ml, and HK could significantly inhibit the spore germination and mycelial growth of A.F.. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations showed that HK induced significant changes in hyphal morphology and microstructure, including cell membrane rupture and intracellular structural disorder. Adhesion assay and biofilm assay experiments showed that HK reduced the adhesion of spores to human corneal epithelial cells (HCECs) and inhibited the formation of biofilms. The genetic changes of A.F. after HK treatment were analyzed by RNA sequencing, and a total of 2487 differentially expressed genes (DEGs) were identified, including the down-regulated DEGs related to carbohydrate and various amino acid metabolism, ribosome biogenesis, asexual reproduction, and up-regulated DEGs related to steroid biosynthesis through GO and KEGG enrichment analysis. RNA-seq results suggested that HK may play an antifungal effect by destroying the structural integrity of its wall and membrane, inhibiting protein biosynthesis and the growth and reproduction of A.F..10 g/ml HK, which had no effect on proliferation and migration of HCECs, was used in the treatment of murine fungal keratitis (FK). We found that HK eyedrop treatment could reduce the severity of FK by reducing corneal fungal burden, neutrophil infiltration, and the expression of LOX-1 and pro-inflammatory factors. HK is expected to be a safe and effective new drug for FK treatment. Author summaryFK is a serious common blind-causing eye disease. The current clinical antifungal drugs have the disadvantages of low bioavailability and high corneal toxicity, which greatly limit the clinical effectiveness. Therefore, there is an urgent need for a new, safe and effective treatment for FK. HK had shown great antifungal capacity against A.F., amazingly well anti-inflammatory effect and real improvement in murine FK in our research. These findings provide a theoretical basis for the application of HK as an antifungal drug and reveal the potential of HK to be applied in the clinical treatment of FK.

microbiology↗

bioRxiv2022

DJ-1 glyoxalase activity makes a modest contribution to cellular defense against methylglyoxal damage in neurons

Human DJ-1 is a cytoprotective protein whose absence causes Parkinsons disease and is also associated with other diseases. DJ-1 has an established role as a redox-regulated protein that defends against oxidative stress and mitochondrial dysfunction. Multiple studies have suggested that DJ-1 is also a protein/nucleic acid deglycase that plays a key role in the repair of glycation damage caused by methylglyoxal (MG), a reactive -keto aldehyde formed by central metabolism. Contradictory reports suggest that DJ-1 is a glyoxalase but not a deglycase and does not play a major role in glycation defense. Resolving this issue is important for understanding how DJ-1 protects cells against insults that can cause disease. We find that DJ-1 reduces levels of reversible adducts of MG with guanine and cysteine in vitro. The steady-state kinetics of DJ-1 acting on reversible hemithioacetal substrates are fitted adequately with a computational kinetic model that requires only a DJ-1 glyoxalase activity, supporting the conclusion that deglycation is an apparent rather than a true activity of DJ-1. Sensitive and quantitative isotope-dilution mass spectrometry shows that DJ-1 modestly reduces the levels of some irreversible guanine and lysine glycation products in primary and cultured neuronal cell lines and whole mouse brain, consistent with a small but measurable effect on total neuronal glycation burden. However, DJ-1 does not improve cultured cell viability in exogenous MG. In total, our results suggest that DJ-1 is not a deglycase and has only a minor role in protecting neurons against methylglyoxal toxicity.

biochemistry↗

bioRxiv2022

Elasticity generates indissoluble biomolecular condensates

While biomolecular condensates are often liquid-like, many experiments found that condensates also exhibit solid-like behaviors, making them indissoluble in conditions liquid condensates dissolve. Despite the biological significance of indissoluble condensates to cellular fitness, the mechanisms underlying the indissolubility of solid-like condensates are still unclear. In this work, we study the effects of elasticity on the dissolution of biomolecular condensates. We demonstrate that the bulk stress inside condensates may prevent the condensates from dissolution and obtain a new mechanical equilibrium condition of elastic condensates. Moreover, we theoretically predict a phase diagram of indissolubility for biomolecular condensates and identify a minimum bulk modulus for the condensates to be indissoluble. To verify our theories, we simulate the two-fluid model in which the slow component corresponding to biomolecules generates elastic stress. Our theoretical predictions are nicely confirmed and independent of microscopic details. Our works show that elasticity makes biomolecular condensates less prone to dissolution.

biophysics↗