Biology subjects

Zhu, L.

Publications and source records attributed to Zhu, L..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

Cryo-EM structure of monomeric CXCL12-bound CXCR4 in active state

CXC chemokine receptor 4 (CXCR4) and its chemokine ligand CXCL12 are crucial to embryonic development, bone marrow retention of hematopoietic progenitor cells, cancer metastasis, angiogenesis and HIV-1 infection. Yet the structural basis for CXCR4 recognition of full-length CXCL12 remains unknown despite available structures of CXCR4 in complex with small molecule antagonists and a viral chemokine. Here we present a cryo-EM structure of monomeric CXCL12-CXCR4 in complex with heterotrimeric Gi proteins at a resolution of 2.65 [A]. The CXCL12-CXCR4 interaction at their N termini is stabilized by a polar interaction between the PC motif (C28NT in CXCR4) and CXC motif (the unique P10 in CXCL12). The N terminal 8 amino acids in CXCL12 insert into the transmembrane binding pocket (chemokine recognition site 2, CRS2) of CXCR4 with S4 defining an upward turn of V3, P2 and K1. Polar interactions involving C186ECL2 and D187ECL2, along with hydrogen bonding with E2887,39 and D2626,58 stabilize the N terminus of CXCL12 in CRS2. Hydrophobic interactions between side chains aligning CRS2 and P2, L5 and S6 of CXCL12 further strengthen its binding to the receptor. CXCL12 inserts deep into the binding pocket, and the 3.2[A] distance measured between V3 and the toggle switch W6.48 for G protein activation is among the shortest of all chemokine-receptor pairs. Our findings provide structural insights into the recognition mechanism of CXCR4 for its chemokine ligand CXCL12.

immunology↗

bioRxiv2023

Reproductive life history may modulate selection on the germline mutation rate

Mutation rates vary across the tree of life by many orders of magnitude, with lower mutation rates in species that reproduce quickly and maintain large effective population sizes. A compelling explanation for this trend is that large effective population sizes facilitate selection against weakly deleterious "mutator alleles" such as variants that interfere with the molecular efficacy of DNA repair. However, in multicellular organisms, the relationship of the mutation rate to DNA repair efficacy is complicated by variation in reproductive age. Long generation times leave more time for mutations to accrue each generation, and late reproduction likely amplifies the fitness consequences of any DNA repair defect that creates extra mutations in the sperm or eggs. Here, we present theoretical and empirical evidence that a long generation time amplifies the strength of selection for low mutation rates in the spermatocytes and oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for DNA proofreading and repair in their germ cells. In contrast, species with different generation times accumulate similar mutation loads during embryonic development. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold. Significance StatementAll cells accumulate mutations due to DNA damage and replication errors. When mutations occur in germ tissues including sperm, eggs, and the early embryo, they create changes in the gene pool that can be passed down to future generations. Here, we examine how rates of germline mutations vary within and between mammalian species, and we find that species which reproduce at older ages tend to accumulate fewer mutations per year in their sperm and eggs. This finding suggests that the evolution of humans long reproductive lifespan created evolutionary pressure to improve the fidelity of DNA maintenance in germ tissues, paralleling the pressure to avoid accumulating too many mutations in the body over a long lifespan.

evolutionary biology↗

bioRxiv2023

High-throughput experimental evolution reveals the mutation-driven landscape of high-level clinical resistance acquired under low-level environmental antibiotic stresses

Potential pathogens consistently exposed to low-level environmental antibiotics could derive high-level clinically relevant resistance detrimental to the human health. However, the underlying evolutionary landscapes remain poorly understood. We conducted a high-throughput experimental evolution study by exposing an environmentally isolated pathogenic Escherichia coli strain to 96 typical antibiotics at 10 g l-1 for 200 generations. Antibiotic resistance phenotypic (IC90 against 8 clinically used antibiotics) and genetic changes of the evolved populations were systematically investigated, revealing a universal increase in antibiotic resistance (up to 349-fold), and mutations in 2,432 genes. Transposon sequencing was further employed to verify genes potentially associated with resistance. A core set of mutant genes conferring high-level resistance was analyzed to elucidate their resistance mechanisms by analyzing the functions of interacted genes within the gene co-fitness network and performing gene knockout validations. We developed machine-learning models to predict antibiotic resistance phenotypes from antibiotic structures and genomic mutations, enabling the resistance predictions for another 569 antibiotics. Importantly, 14.6% of the 481 key mutations were observed in clinical and environmental E. coli isolates retrieved from the NCBI database, and several were over-represented in >500 clinical isolates. Deciphering the evolutionary landscapes underlying resistance exposed to low-level environmental antibiotics is crucial for evaluating the emergence and risks of environment-originated clinical antibiotic resistance.

evolutionary biology↗

bioRxiv2023

High-fidelity, high-resolution light-field reconstruction with physics-informed neural representation learning

Light-field microscopy (LFM) captures 3D biological dynamics by single 2D snapshots but suffers from limited resolution and artifacts during 2D-to-3D inversion. Here, we introduce light-field meta neural representation (LFMNR), a novel self-supervised paradigm that utilizes physics-informed light-field implicit neural representation (LFINR) and meta learning for high-quality 3D reconstruction in Fourier-LFM. By developing a physics-based hybrid-rendering model, LFINR achieves artifact-free light-field reconstruction with enhanced spatial resolution (>1.4-fold improvement). Additionally, the integration of meta-learning and progressive sampling strategies mitigates INRs intrinsic limitations in low reconstruction speed caused by scene-specific optimization, enabling a [~]100-fold acceleration in the representation of consecutive volumes and facilitating the visualization of sustained 3D dynamics. These advancements enable LFMNR to deliver superior imaging with high spatiotemporal resolution and low phototoxicity, as demonstrated by capturing instantaneous voltage signals in C. elegans at 100 volumes per second and recording 6000 time points of organelle dynamics over 25 hours.

cell biology↗

bioRxiv2023

Microbiome-based correction of nutrient profiles derived from self-reported dietary assessments

Since dietary intake is challenging to directly measure in large-scale cohort studies, we often rely on self-reported instruments (e.g., food frequency questionnaires, 24-hour recalls, and diet records) developed in nutritional epidemiology. Those self-reported instruments are prone to measurement errors, which can lead to inaccuracies in the calculation of nutrient profiles. Currently, few computational methods exist to address this problem. In the present study, we introduce a deep-learning approach --- Microbiome-based nutrient profile corrector (METRIC), which leverages gut microbial compositions to correct random errors in self-reported dietary assessments using 24-hour recalls or diet records. We demonstrate the excellent performance of METRIC in minimizing the simulated random errors, particularly for nutrients metabolized by gut bacteria in both synthetic and three real-world datasets. Further research is warranted to examine the utility of METRIC to correct actual measurement errors in self-reported dietary assessment instruments.

microbiology↗

bioRxiv2023

The neurons that drive infradian sleep-wake and mania-like behavioral rhythms

Infradian mood and sleep-wake rhythms with periods of 48 hr and beyond have been observed in bipolar disorder (BD) subjects that even persist in time isolation, indicating an endogenous origin. Here we show that mice exposed to methamphetamine (Meth) in drinking water develop infradian locomotor rhythms with periods of 48 hr and beyond which extend to sleep length and mania-like behaviors in support of a model for cycling in BD. This cycling capacity is abrogated upon genetic disruption of DA production in DA neurons of the ventral tegmental area (VTA) or ablation of nucleus accumbens (NAc) projecting, dopamine (DA) neurons. Chemogenetic activation of NAc-projecting DA neurons leads to locomotor period lengthening in clock deficient mice, while cytosolic calcium in DA processes of the NAc was found fluctuating synchronously with locomotor behavior. Together, our findings argue that BD cycling relies on infradian rhythm generation that depends on NAc-projecting DA neurons.

neuroscience↗

bioRxiv2023

Structural Insights into Dopamine Receptor-Ligand Interactions: From Agonists to Antagonists

This study explores the intricacies of dopamine receptor-ligand interactions, focusing on the D1R and D5R subtypes. Using molecular modeling techniques, we investigate the binding of the pan-agonist rotigotine, revealing a universal binding mode at the orthosteric binding pocket (OBP). Additionally, we analyze the stability of antagonist-receptor complexes with SKF83566 and SCH23390. By examining the impact of specific mutations on ligand-receptor interactions through computational simulations and thermostability assays, we gain insights into binding stability. Our research also delves into the structural and energetic aspects of antagonist binding to D1R and D5R in their inactive states. These findings enhance our understanding of dopamine receptor pharmacology and hold promise for drug development in central nervous system disorders, opening doors to future research and innovation in this field.

pharmacology and toxicology↗

bioRxiv2023

An injectable in situ crosslinkable platform for ultra-long-acting delivery of hydrophilic therapeutics

Achieving ultra-long-term release of hydrophilic drugs over several months remains a significant challenge for existing long-acting injectables (LAIs). Existing platforms, such as in situ forming implants (ISFI), exhibit high burst release due to solvent efflux and microsphere-based approaches lead to rapid drug diffusion due to significant water exchange and large pores. Addressing these challenges, we have developed an injectable platform that, for the first time, achieves ultra-long-term release of hydrophilic drugs for over six months. This system employs a methacrylated ultra-low molecular weight pre-polymer (polycaprolactone) to create in situ cross-linked depots (ISCD). The ISCDs solvent-free design and dense mesh network, both attributed to the ultra-low molecular weight of the pre-polymer, effectively minimizes burst release and water influx/efflux. In vivo studies in rats demonstrate that ISCD outperforms ISFI by achieving lower burst release and prolonged drug release. We demonstrated the versatility of ISCD by showcasing ultra-long-term delivery of several hydrophilic drugs, including antiretrovirals (tenofovir alafenamide, emtricitabine, abacavir, and lamivudine), antibiotics (vancomycin and amoxicillin) and an opioid antagonist naltrexone. Additionally, ISCD achieved ultra-long-term release of the hydrophobic drug tacrolimus and enabled co-delivery of hydrophilic drug combinations encapsulated in a single depot. We also identified design parameters to tailor the polymer network, tuning drug release kinetics and ISCD degradation. Pharmacokinetic modeling predicted over six months of drug release in humans, significantly surpassing the one-month standard achievable for hydrophilic drugs with existing LAIs. The platforms biodegradability, retrievability, and biocompatibility further underscore its potential for improving treatment adherence in chronic conditions.

bioengineering↗

bioRxiv2023

An immunohistochemical atlas of necroptotic pathway expression

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo. HighlightsO_LI13 automated immunohistochemistry protocols for detecting the necroptotic pathway C_LIO_LINecroptotic pathway expression is confined to fast-cycling immune barriers C_LIO_LINecroptotic pathway expression changes at sites of immunoinflammatory challenge C_LIO_LIImmunodetection of necrosomes in IBD patients is a putative new diagnostic tool C_LI

cell biology↗

bioRxiv2023

Discovery of biaryl macrocyclic peptides with C-terminal beta-keto acid groups

Advances in genome sequencing and bioinformatics methods have identified a myriad of biosynthetic gene clusters (BGCs) encoding uncharacterized molecules. By mining genomes for BGCs containing a prevalent peptide-binding domain used for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), we uncovered a new class involving modifications installed by a cytochrome P450, a multi-nuclear iron-dependent non-heme oxidative enzyme (MNIO, formerly DUF692), a cobalamin- and radical S-adenosyl-L-methionine-dependent enzyme (B12-rSAM), and a methyltransferase. All enzymes encoded by the BGC were functionally expressed in Burkholderia sp. FERM BP-3421. Structural characterization with 2D-NMR and Marfeys method on the resulting RiPP demonstrated that the P450 enzyme catalyzed the formation of a biaryl C-C crosslink between two Tyr residues with the B12-rSAM generating {beta}-methyltyrosine. The MNIO transformed a C-terminal Asp residue into aminopyruvic acid while the methyltransferase acted on the {beta}-carbon of the -keto acid. Exciton-coupled circular dichroism spectroscopy and microcrystal electron diffraction (MicroED) were used to elucidate the stereochemical configurations of the atropisomer that formed upon biaryl crosslinking. The conserved Cys residue in the precursor peptide was not modified as in all other characterized MNIO-containing BGCs; However, mutational analyses demonstrated that it was essential for the MNIO activity on the C-terminal Asp. To the best of our knowledge, the MNIO featured in this pathway is the first to modify a residue other than Cys. This study underscores the utility of genome mining to discover new macrocyclic RiPPs and that RiPPs remain a significant source of previously undiscovered enzyme chemistry.

biochemistry↗

bioRxiv2023

Co-existence of blaKPC-2 and blaVIM-2 in highly carbapenem-resistant Pseudomonas aeruginosa isolated in the ICU of a public hospital

In this study, highly carbapenem-resistant Pseudomonas aeruginosa (h-CRPA) 18102011 [the minimum inhibitory concentration (MIC) value of carbapenem antimicrobial imipenem (IP) for h-CRPA is 4,096 g/mL] was isolated from the bile of an intensive care unit (ICU) burn patient in China, and genomic sequencing revealed a complete genome. The genomes molecular characteristics were analyzed to assess the genetic environment of blaKPC-2 and blaVIM-2. Average nucleotide identity (ANI) comparisons were used for precise species-level identification, while serotyping, multi-locus sequence typing, and the identification of acquired resistance genes, and virulence genes were also carried out. The h-CRPA 18102011 strain carrying blaKPC-2 and blaVIM-2 was identified as strain ST2374 and the O4 serotype. Virulence genes (plcH, exoST) and resistance genes (aph(3)-IIb, aac(6)-Ib-cr, ant(2)-Ia, blaOXA-396, blaPAO, blaKPC-2, blaVIM-2, blaPER-1, sul1, catB7, qnrVC6, fosA) were both identified in the genome. In addition, the IncpRBL16 type mega-plasmid pP2011-1 carrying blaVIM-2 and the IncP6 type plasmid pP2011-2 carrying blaKPC-2 were identified in the strain. The genetic environment of blaVIM-2 and blaKPC-2 was specifically evaluated to assess their origins. blaVIM-2 was located in the region of In2075 (a novel type 1 integron) that was inserted into plasmid pP2011-1, this plasmid contained 3 novel recombination sites, as well as the typical recombination site 2 (umuC) observed for IncpRBL16 type plasmids. However, the core module Tn3-ISKpn27-blaKPC-{Delta}ISKpn6 was identified as the blaKPC-2 platform in plasmid pP2011-2. Conjugation experiments revealed that the plasmids pP2011-1 and pP2011-2 of the h-CRPA 18102011 strain could be transferred into Escherichia coli with a conjugation transfer efficiency of 10-6. The E. coli transconjugant carried blaKPC-2 and blaVIM-2 from the donor and the MIC value of IP to the E. coli transconjugant was 4,096 g/mL, which was the same as observed for the donor. Overall, this study revealed the molecular characteristics of a VIM-2 and KPC-2-co-producing strain that was typed as O4 and ST2374. The continuous monitoring of bacteria, such as the strain investigated here, that co-harbor different types of carbapenemase genes is critical for preventing the spread of these genes.

genomics↗

bioRxiv2023

Potential intrahospital dissemination of Pseudomonas aeruginosa carrying the blaIMP-1 gene within a Tn7-like transposon

We aimed to determine the molecular characteristics of carbapenem-resistant Pseudomonas aeruginosa 18081308 and 18083286 isolated from the urine and sputum of two Chinese patients respectively, and analyzed the formation mechanism of the genetic environment in which it carries blaIMP-1. Bacterial genome sequencing was carried out on strains 18081308 and 18083286 to obtain their whole genome sequence. Average nucleotide identity (ANI) was used for their precise species identification. Serotyping and multilocus sequence typing were performed. Furthermore, the acquired resistance genes, and virulence factors of these strains were identified. The carbapenem-resistant P. aeruginosa strains isolated in the present study were of sequence type ST865 and serotype O6. They all carried the same virulence factors (PLC, ExoSTY) and resistance genes (aacC2, tmrB, and blaIMP-1). Tn6411, a Tn7-like transposon carrying blaIMP-1, was found in both strains. Detailed genetic dissection was applied to this transposon to display the genetic environment of blaIMP-1. The aacC2-tmrB region remnant-Tn6411 backbone was the original structure of this type of transposon. A Tn402-like type 1 integron (intl1-aac(6)-II-blaIMP-1) was inserted into it and formed a stable structure, which was localized in the chromosome by TnsD for transmission within P. aeruginosa; the original structure of Tn7-like transposon was localized on the plasmid by TnsE for horizontal transmission between bacterial species. The intrahospital dissemination of P. aeruginosa ST865 isolated in this study was episodic. The blaIMP-1-carrying Tn7-like transposon might enhance their ability to survive under drug selection pressure and aggravate the difficulty in treating infections.

genomics↗

bioRxiv2023

Neuroprotective Mechanism of Ribisin A on H 2 O 2 -induced PC12 cell injury model

Ribisin A has been shown to have neurotrophic activity. The aim of this study was to evaluate the neuroprotective effect of Ribisin A on injured PC12 cells and elucidate its mechanism. In this project, PC12 cells were induced by H2O2 to establish an injury model. After treatment with Ribisin A, the neuroprotective mechanism of Ribisin A was investigated by methyl tetrazolium (MTT) assay, Enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, fluorescent probe analysis, and western blot. We found that Ribisin A decreased the rate of lactate dehydrogenase (LDH) release, increased cellular superoxide dismutase (SOD) activity, decreased the levels of tumor necrosis factor- (TNF-), interleukin-6 (IL-6), Ca2+ expression and reactive oxygen species (ROS). Moreover, Ribisin A significantly increased mitochondrial membrane potential (MMP) and inhibited apoptosis of PC12 cells. Meanwhile, Ribisin A activated the phosphorylation of ERK1/2 and its downstream molecule CREB by upregulating the expression of Trk A and Trk B, the upstream molecules of the ERK signaling pathway. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/559840v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@ff9604org.highwire.dtl.DTLVardef@1d1ee75org.highwire.dtl.DTLVardef@17e4441org.highwire.dtl.DTLVardef@b347c4_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Polysaccharides from Balanophora harlandii Hook: Isolation, Characterization, and Anti-Inflammation Activities

Balanophora harlandii Hook (B. harlandii), a folk medicine, has been traditionally employed to treat traumatic bleeding, gastroenteritis, icteric hepatitis, hemorrhoids, and other conditions. In this work, polysaccharides with anti-inflammatory effects were extracted and purified from B. harlandii. The extraction conditions were optimized, and the properties of one purified neutral fraction, denoted as BHPs-W-S3, were analyzed. Gel permeation chromatography (GPC) was carried out to measure the molecular weight. The structure of BHPs-W-S3 was assessed based on monosaccharide composition analysis, Fourier transform infrared (FT-IR) spectroscopy, methylation analysis, and nuclear magnetic resonance (NMR) spectroscopy. BHPs-W-S3 has a molecular weight of 14.1 kDa, and its three main monosaccharides are glucose, galactose, and mannose with a molar ratio of 6.4:1.7:1.1. Its main chain consists of [->]6)--D-Glcp-(1[->], [->]4,6)--D-Glcp-(1[->], [->]6)-{beta}-D-Galp-(1[->], [->]3,6)-{beta}-D-Galp-(1[->], and it has branch chains at the O-4 and/or O-3 positions. In addition, in vitro experiments show that the polysaccharides from B. harlandi can decrease the phosphorylation level of p65 and IKB- in LPS-induced RAW264.7 cells to reduce the expression of the pro-inflammatory genes such as TNF-, IL-6, and IL-1{beta}. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/559774v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@17ccfeforg.highwire.dtl.DTLVardef@137726borg.highwire.dtl.DTLVardef@139100dorg.highwire.dtl.DTLVardef@14cce50_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Energetic Demands Regulate Sleep-Wake Rhythm Circuit Development

Sleep and feeding patterns lack strong daily rhythms during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. In Drosophila, circadian sleep patterns are initiated with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar larval period (L2), sleep and feeding are spread across the day; these behaviors become organized into daily patterns by the 3rd instar larval stage (L3). Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms trigger the formation of sleep-circadian circuits and behaviors.

neuroscience↗

bioRxiv2023

Diet composition drives tissue-specific intensity of murine enteric infections

Diet composition plays a large role in regulating of gut health and enteric infection. In particular, synthetic Western-style diets may predispose to disease, whilst whole-grain diets containing high levels of crude fiber are thought to promote gut health. Here we show that, in contrast to this paradigm, mice fed unrefined chow are significantly more susceptible to infection with Trichuris muris, a caecum-dwelling nematode, than mice given refined, semi-synthetic diets (SSD). Moreover, mice fed SSD supplemented with inulin, a fermentable fiber, developed chronic T. muris burdens whereas mice given SSD efficiently cleared the infection. Diet composition significantly impacted infection-induced changes in the host gut microbiome. Mice infected with the bacterium Citrobacter rodentium were also more susceptible to pathogen colonization when fed either chow or inulin-enriched SSD. However, transcriptomic analysis of tissues from mice fed either SSD or inulin-enriched SSD revealed that, in contrast to T. muris, increased C. rodentium infection appeared to be independent of the host immune response. Accordingly, exogenous treatment with IL-25 partially reduced T. muris burdens in inulin-fed mice, whereas IL-22 treatment was unable to restore resistance to C. rodentium colonization. Diet-mediated effects on pathogen burden were more pronounced for large intestine-dwelling pathogens, as effects on small intestinal helminth (Heligmosomoides polygyrus) were less evident, and protozoan (Giardia muris) infection burdens were equivalent in mice fed chow, inulin-enriched SSD, or SSD, despite higher cyst excretion in chow-fed mice. Collectively, our results point to a tissue- and pathogen-restricted effect of dietary fiber levels on enteric infection intensity. ImportanceEnteric infections induce dysbiosis and inflammation and are a major public health burden. As the gut environment is strongly shaped by diet, the role of different dietary components in promoting resistance to infection is of interest. Whilst diets rich in fiber or whole grain are normally associated with improved gut health, we show here that these components predispose the host to higher levels of pathogen infection. Thus, our results have significance for interpreting how different dietary interventions may impact on gastrointestinal infections. Moreover, our results may shed light on our understanding of how gut flora and musical immune function is influenced by the food that we eat.

microbiology↗

bioRxiv2023

Logic Gate Activated Lysosome Targeting DNA Nanodevice for Controlled Proteins Degradation

Targeted protein degradation (TPD) is a powerful technique for regulation of protein homeostasis. Current TPD mainly focuses on the therapeutical consequences rather than the operation processes of the molecular tools. Herein, we construct a platform for precisely manipulate the protein degradation by activatable lysosome targeting DNA nanodevices. In the design, a lysosome-targeting CD63 aptamer is locked by the single-stranded DNA with a photocleavable group and a disulfide bond. This locked CD63 aptamer is connected with the aptamer targeting the protein of interest via double-stranded DNA linkages to form the logic-gate activated lysosome targeting DNA nanodevice (LALTD). With the UV light and endogenous GSH as inputs, AND logic-gate is built to efficiently manipulate the protein delivery processes by LALTD. The protein of interest could be degraded via efficient lysosome hydrolysis. Further studies shows that the logic-gate operation could be used for modulating the T cell-mediated antitumor immunity. The modularly designed activatable lysosome targeting DNA nanodevices exhibits good stability, controllability, programmability and universality, providing a new prospect for accurate protein degradation and precise therapy. Entry for the Table of ContentsThrough rational integration of dual molecular switches with bispecific aptamer systems, a logic-gate activated lysosome targeting DNA nanodevice (LALTD) was developed for precisely controlled process of protein hydrolysis in living cells. The designed LALTD system provide a general platform for designing accurate protein degradation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/555427v1_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@1b3afc1org.highwire.dtl.DTLVardef@1d7c893org.highwire.dtl.DTLVardef@1b14268org.highwire.dtl.DTLVardef@7ed354_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

PRO-LDM: Protein Sequence Generation with Conditional Latent Diffusion Models

AbstractsDeep learning-driven protein design holds enormous potential despite the complexities in sequences and structures. Recent developments in diffusion models yielded success in structure design, but awaits progress in sequence design and are computationally demanding. Here we present PRO-LDM: an efficient framework combining design fidelity and computational efficiency, utilizing the diffusion model in latent space to design proteins with property tuning. The model employs a joint autoencoder to capture latent variable distributions and generate meaningful embeddings from sequences. PRO-LDM (1) learns representations from biological features in natural proteins at both amino-acid and sequence level; (2) generates native-like new sequences with enhanced diversity; and (3) conditionally designs new proteins with tailored properties or functions. The out-of-distribution design enables sampling notably different sequences by adjusting classifier guidance strength. Our model presents a feasible pathway and an integratable tool to extract physicochemical and evolutionary information embedded within primary sequences, for protein design and optimization.

bioengineering↗