Biology subjects

Liu, K.

Publications and source records attributed to Liu, K..

At least 181 records · Page 10Linked to original sources

bioRxiv2023

Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma

Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides a new aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define novel molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.

cancer biology↗

bioRxiv2023

PD-L1 Restrains the PD-1hiNrp1loTGFb+ Treg to block IL6+ Neutrophil tumor infiltration to Suppress Inflammation-driven Colorectal Cancer

PD-L1 functions as a suppressor of T cell activation and colonic inflammation. The consequence of and mechanism underlying these opposite functions of PD-L1 in colorectal cancer remains unknown. We report that global Cd274 deletion promotes inflammation-driven colorectal tumorigenesis. 16S rRNA and shotgun metagenomic sequencing revealed that loss of host PD-L1 leads to expansion of gut Ligilactobacillus murinus and activation of the AhR pathway in tumor-bearing mice. scRNA-seq analysis revealed that PD-L1 regulates PD-189Nrp11215 Treg, IL6+ neutrophils, and B cells in colorectal tumor. Treg expresses high level of TGF{beta} to recruit IL6+ neutrophils. IL6 inhibits activation of B and T cells. IL6 blockade or B cell activation via CD40 agonist increases CTL activation and suppresses colon tumor growth in vivo. Our findings determine that PD-L1 functions as a tumor suppressor in the context of inflammation-driven colorectal cancer and the PD-L1/L. murius/PD-189Nrp11215TGF{beta}+ Treg/IL6+ neutrophils pathway controls host cancer immunosurveillance and colorectal tumorigenesis. Key pointsGlobal deletion of Cd274 promotes inflammation-driven colorectal tumorigenesis. Loss of PD-L1 increases gut L. murinus and activates AhR pathway in colorectal tumor. PD-1hiTGF{beta}+Nrp1lo Treg recruits IL6+ neutrophils to inhibit B and T cell function in colorectal tumor. L. murinus and tryptophan metabolites connect PD-L1 and colorectal tumor immunosurveillance. Graphic summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/562132v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@2d23bcorg.highwire.dtl.DTLVardef@1852c8eorg.highwire.dtl.DTLVardef@304978org.highwire.dtl.DTLVardef@278c5b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

NanoLAS: a Comprehensive Nanobody Database with Data Integration, Consolidation, and Application

Nanobodies, a unique subclass of antibodies first discovered in camelid animals, are composed solely of a single heavy chains variable region (VHH). Their significantly reduced molecular weight, in comparison to conventional antibodies, confers numerous advantages in the treatment of various diseases. As research and applications involving nanobodies expand, the quantity of identified nanobodies is also rapidly growing. However, the existing antibody databases are deficient in type and coverage, failing to satisfy the comprehensive needs of researchers and thus, impeding progress in nanobody research. In response to this, we have amalgamated data from multiple sources to successfully assemble a new and comprehensive nanobody database. This database has currently included the latest nanobody data, provides researchers with an excellent search and data display interface, thus facilitating the progression of nanobody research and their application in disease treatment. In summary, the newly constructed Nanobody Library and Archive System (NanoLAS) may significantly enhance the retrieval efficiency and application potential of nanobodies. We envision that NanoLAS will serve as an accessible, robust, and efficient tool for nanobody research and development, propelling advancements in the field of biomedicine. Database URLhttps://www.nanolas.cloud

bioinformatics↗

bioRxiv2023

Neutralization of SARS-CoV-2 EG.5/EG.5.1 by sera from ZF2001 RBD-dimer and its next-generation vaccines

SARS-CoV-2 Omicron EG.5 and EG.5.1 are surging in several areas of the world, including China. Compared with XBB.1, EG.5 contains additional mutations of F456L and S486P in the spike protein receptor binding domain (RBD) and its subvariant EG.5.1 carries a further spike mutation Q52H. The immune escape potential of EG.5/EG.5.1 is of great concern. In this study, we evaluated the neutralization activities of sera from participants who received COVID-19 inactivated vaccines, protein subunit vaccine ZF2001 or a booster vaccination of Delta-BA.5 RBD-heterodimer protein vaccine, and participants who had a breakthrough infection during a wave of BF.7/BA.5.2 circulation in December 2022. Neutralization profiles elicited by bivalent RBD-heterodimer vaccine candidates containing XBB.1.5 antigen were evaluated in a murine model. We found that EG.5 and EG.5.1 displayed similar immune evasion potential to XBB.1 and XBB.1.5. The Delta-BA.5 RBD-heterodimer booster induced higher neutralizing titers against the tested XBB subvariants, including EG.5 and EG.5.1, than breakthrough infection by BF.7 or BA.5.2. In addition, Delta-XBB.1.5 and BQ.1.1-XBB.1.5 RBD-heterodimer vaccines induced high neutralizing activities against XBB sub-variants in a murine model, suggesting that next-generation COVID-19 vaccines with updated components must be developed to enhance the protection efficacy against the circulating SARS-CoV-2 strains.

immunology↗

bioRxiv2023

Ancient farmer and steppe pastoralist-related founding lineages contributed to the complex landscape of episodes in the diversification of Chinese paternal lineages

Ancient DNA advances have reported the complex genetic history of Eurasians, but how the knowledge of ancient subsistence strategy shifts and population movements influenced the fine-scale paternal genetic structure in East Asia has not been assessed. Here, we reported one integrated Y-chromosome genomic database of 15,530 people, including 1753 ancient people and newly-reported 919 individuals genotyped using our recently-developed targeted sequencing YHSeqY3000 panel, to explore Chinese genomic diversity, population evolutionary tracts and their genetic formation mechanism. We identified four major ancient technological innovations and population movements that shaped the landscape of Chinese paternal lineages. First, the expansion of millet farmers and early East Asians from the Yellow River Basin carrying the major O2/D subclades promoted the formation of the Sino-Tibetan peoples major composition and accelerated the Tibetan Plateaus permanent occupation. Second, rice farmers dispersal from the Yangtze River Valley carrying O1 and some sublineages of O2 contributed significantly to Tai-Kadai, Austronesian, Hmong-Mien, Austroasiatic people and southern Han Chinese. Third, Siberian-related paternal lineages of Q and C originated and boomed from Neolithic hunter-gatherers from the Mongolian Plateau and the Amur River Basin and significantly influenced the gene pools of northern Chinese. Fourth, western Eurasian-derived J, G and R lineages initially spread with Yamnaya steppe pastoralists and other proto-Indo-European people and further widely dispersed via the trans-Eurasian cultural communication along the Eurasian Steppe and the ancient Silk Road, remaining genetic trajectories in northwestern Chinese. Our work provided comprehensive modern and ancient genetic evidence to illuminate the impact of population interaction from the ancient farmer or herder-based societies on the genetic diversity patterns of modern people, revised our understandings of ancestral sources of Chinese paternal lineages, underscored the scientific imperative of the large-scale genomic resources of dense spatiotemporal underrepresented sampling populations to understand human evolutionary history.

genetics↗

bioRxiv2023

Distinct mechanisms by which antioxidant transcription factors Nrf1 and Nrf2 as drug targets contribute to the anticancer efficacy of Cisplatin on hepatoma cells

Cisplatin (cis-Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors. The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion (Cl-) in its structure with H2O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks. To our surprise, it was found there exists a closer relationship of Nrf1 than Nrf2 with DNA repair, but the hyperactive Nrf2 in Nrf1-/-cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive.

cell biology↗

bioRxiv2023

Simulated musculoskeletal optimization for sprinting and marathon running

Musculoskeletal geometry and muscle volumes vary widely in the population and are intricately linked to the performance of tasks ranging from walking and running to jumping and sprinting. However, our ability to understand how these parameters affect task performance has been limited due to the high computational cost of modelling the necessary complexity of the musculoskeletal system and solving the requisite multi-dimensional optimization problem. For example, sprinting and running are fundamental to many forms of sport, but past research on the relationships between musculoskeletal geometry, muscle volumes, and running performance has been limited to observational studies, which have not established cause-effect relationships, and simulation studies with simplified representations of musculoskeletal geometry. In this study, we developed a novel musculoskeletal simulator that is differentiable with respect to musculoskeletal geometry and muscle volumes. This simulator enabled us to find the optimal body segment dimensions and optimal distribution of added muscle volume for sprinting and marathon running. Our simulation results replicate experimental observations, such as increased muscle mass in sprinters, as well a mass in the lower end of the healthy BMI range and a higher leg-length-to-height ratio in marathon runners. The simulations also reveal new relationships, for example showing that hip musculature is vital to both sprinting and marathon running. We found hip flexor and extensor moment arms were maximized to optimize sprint and marathon running performance, and hip muscles the main target when we simulated strength training for sprinters. Our simulation results can help sprint and marathon runners customize strength training, and our simulator can be extended to other athletic tasks, such as jumping, or to non-athletic applications, such as designing interventions to improve mobility in older adults or individuals with movement disorders. AUTHOR SUMMARYOur study addresses the challenge of determining optimal musculoskeletal parameters for tasks like sprinting and marathon running. Existing research has been limited to observational studies and simplified simulations. To overcome these limitations, we developed a differentiable musculoskeletal simulator to optimize running performance. We replicated past findings and uncovered new insights. We confirmed the benefits of increased muscle mass for sprinters and identified key factors for marathon runners, such a mass in the lower end of the healthy BMI range and an increased leg-length-to-height ratio. Hip musculature was found to be critical for both sprinting and marathon running. Our simulation results have practical implications. They can inform customized strength training for sprinters and marathon runners. Additionally, the simulator can be extended to other athletic tasks, benefiting various sporting events. Beyond athletics, our open-source simulator has broader applications. It can determine minimal strength requirements for daily activities, guide strength training in the elderly, and estimate the effects of simulated musculoskeletal surgery.

bioengineering↗

bioRxiv2023

Skeletal progenitor LRP1-mediated endocytosis is critical for synovial joint formation and bone growth

Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor whose dysfunction is linked to developmental dysplasia of the hip, osteoporosis and osteoarthritis. Our work addresses the critical question of how these skeletal pathologies emerge. Here, we show the abundant expression of LRP1 in skeletal progenitor cells at mouse embryonic stage E13.5 and onwards, especially in the perichondrium, the stem cell layer surrounding developing limbs essential for bone formation. Lrp1 deficiency in these stem cells causes joint fusion, malformation of cartilage/bone template and markedly delayed or lack of primary ossification along with aberrant accumulation of some of the LRP1 ligands at as early as E16.5. These early abnormalities result in multiple and persistent skeletal defects including a severe deficit in hip joint and patella, and markedly deformed and low-density long bones leading to dwarfism and impaired mobility. Mechanistically, we show that LRP1 regulates core non-canonical WNT/planar cell polarity (PCP) components that may explain the malformation of long bones. LRP1 directly binds to Wnt5a, facilitates its cell-association and endocytic recycling. Using Xenopus as a model system we show that loss or gain of LRP1 function leads to shortened tadpoles similar to Wnt5a and Wnt11 overexpression, indicating a role for LRP1 in WNT/PCP signalling. Finally, we show the colocalisation LRP1 and Wnt5a in the developing mouse limbs and that Lrp1 deficiency diminishes graded distribution of Wnt5a and Vangl2. We propose that skeletal progenitor LRP1 plays a critical role in formation and maturity of multiple bones and joints by regulating morphogen signalling, providing novel insights into the fundamental processes of morphogenesis and the emergence of skeletal pathologies.

developmental biology↗

bioRxiv2023

Deep-learning Based Pathological Assessment of Frozen Procurement Kidney Biopsies Predicts Graft Loss and Guides Organ Utilization: A Large-scale Retrospective Study

BackgroundLesion scores on procurement donor biopsies are commonly used to guide organ utilization. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. MethodsWe constructed deep-learning based models to recognize kidney tissue compartments in H&E stained sections from procurement biopsies performed at 583 hospitals nationwide in year 2011-2020. The models were trained and tested respectively on 11473 and 3986 images sliced from 100 slides. We then extracted whole-slide abnormality features from 2431 kidneys, and correlated with pathologists scores and transplant outcomes. Finally, a Kidney Donor Quality Score (KDQS) incorporating digital features and the Kidney Donor Profile Index (KDPI) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. ResultsOur model accurately identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis regions; 90% of tubules. Three whole-slide features (Sclerotic Glomeruli%, Arterial Intimal Fibrosis%, and Interstitial Fibrosis%) demonstrated strong correlations with corresponding pathologists scores (n=2431), but had superior associations with post-transplant eGFR (n=2033) and graft loss (n=1560). The combination of KDQS and other factors predicted 1- and 4-year graft loss (discovery: n=520, validation: n=1040). Finally, by matching 398 discarded kidneys due to "biopsy findings" to transplanted population, the matched transplants from discarded KDQS<4 group (110/398, 27.6%) showed similar graft survival rate to unmatched transplanted kidneys (2-, 5-year survival rate: 97%, 86%). KDQS [≥] 7 (37/398, 9.3%) and 1-year survival model score [≥] 0.55 were determined to identify possible discards (PPV=0.92). ConclusionThis deep-learning based approach provides automatic and reliable pathological assessment of procurement kidney biopsies, which could facilitate graft loss risk stratification and organ utilization. Translational StatementThis deep-learning based approach provides rapid but more objective, sensitive and reliable assessment of deceased-donor kidneys before transplantation, and improves the prognostic value of procurement biopsies, thus could potentially reduce inappropriate discard and stratify patients needing monitoring or preventative measures after transplantation. The pipeline can be integrated into various types of scanners and conveniently generates report after slide scanning. Such report can be used in conjunction with pathologists report or independently for centers lacking renal pathologists.

bioinformatics↗

bioRxiv2023

SLC12A9 is a lysosome-detoxifying ammonium - chloride co-transporter

Ammonia is a ubiquitous, toxic by-product of cell metabolism. Its high membrane permeability and proton affinity causes ammonia to accumulate inside acidic lysosomes in its poorly membrane-permeant form: ammonium (NH4+). Ammonium buildup compromises lysosomal function, suggesting the existence of mechanisms that protect cells from ammonium toxicity. Here, we identified SLC12A9 as a lysosomal ammonium exporter that preserves lysosomal homeostasis. SLC12A9 knockout cells showed grossly enlarged lysosomes and elevated ammonium content. These phenotypes were reversed upon removal of the metabolic source of ammonium or dissipation of the lysosomal pH gradient. Lysosomal chloride increased in SLC12A9 knockout cells and chloride binding by SLC12A9 was required for ammonium transport. Our data indicate that SLC12A9 is a chloride-driven ammonium co-transporter that is central in an unappreciated, fundamental mechanism of lysosomal physiology that may have special relevance in tissues with elevated ammonia, such as tumors.

cell biology↗

bioRxiv2023

Development of compact transcriptional effectors using high-throughput measurements in diverse contexts

Human nuclear proteins contain >1000 transcriptional effector domains that can activate or repress transcription of target genes. We lack a systematic understanding of which effector domains regulate transcription robustly across genomic, cell-type, and DNA-binding domain (DBD) contexts. Here, we developed dCas9-mediated high-throughput recruitment (HT-recruit), a pooled screening method for quantifying effector function at endogenous targets, and tested effector function for a library containing 5092 nuclear protein Pfam domains across varied contexts. We find many effectors depend on target and DBD contexts, such as HLH domains that can act as either activators or repressors. We then confirm these findings and further map context dependencies of effectors drawn from unannotated protein regions using a larger library containing 114,288 sequences tiling chromatin regulators and transcription factors. To enable efficient perturbations, we select effectors that are potent in diverse contexts, and engineer (1) improved ZNF705 KRAB CRISPRi tools to silence promoters and enhancers, and (2) a compact human activator combination NFZ for better CRISPRa and inducible circuit delivery. Together, this effector-by-context functional map reveals context-dependence across human effectors and guides effector selection for robustly manipulating transcription.

systems biology↗

bioRxiv2023

Microbiome ssRNA as an environmental cue to activate TLR13-dependent tissue-protective programs in CD5Lhi hepatic macrophages

Hepatic macrophages maintain liver homeostasis, but little is known about the signals that activate the hepatoprotective programs within macrophages. Here, we show that toll-like receptor 13 (TLR13), a sensor of bacterial 23S ribosomal RNA (rRNA), senses microbiome RNAs to drive tissue-protective responses in CD5Lhi hepatic macrophages. Splenomegaly and hepatomegaly developed in the absence of the endosomal RNase, RNaseT2, via TLR13-dependent macrophage proliferation. Furthermore, TLR13 in hepatic Ly6Clo macrophages activated the transcription factors LXR and MafB, leading to expression of tissue-clearance molecules, such as CD5L, C1qb, and Axl. Consequently, Rnaset2-/- mice developed resistance to acute liver injury caused by challenges with acetaminophen and lipopolysaccharide + D-galactosamine. TLR13 responses in Rnaset2-/- mice were impaired by antibiotics, suggesting that TLR13 were activated by microbiome rRNAs, which was detected in the sera and hepatic macrophages. Repeated administration of wild-type mice with the TLR13 ligand, rather than other TLR ligands, selectively increased the number of Kupffer cells, which expressed immunoregulatory and tissue-clearance genes as hepatic macrophages in Rnaset2-/- mice did. Our results suggest that microbiome ssRNA serves as an environmental cue for initiating tissue-protective TLR13 responses in hepatic macrophages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/540294v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@69614eorg.highwire.dtl.DTLVardef@737c69org.highwire.dtl.DTLVardef@1ecd9eforg.highwire.dtl.DTLVardef@d7e10d_HPS_FORMAT_FIGEXP M_FIG In the absence of an endosomal RNase, RNase T2, microbiome RNAs circulating in the vasculature activate TLR13 in hepatic macrophages to drive hepatoprotective responses through expression of immunoregulatory and tissue-clearance molecules. Consequently, mice lacking RNase T2 are resistant against acute liver injuries caused by acetaminophen and LPS + D-galactosamine. C_FIG

immunology↗

bioRxiv2023

Intermediate basal cell population in prostate homeostasis and cancer initiation

Many glandular epithelia are mainly composed of basal cells and luminal cells, including the prostate gland. Adult prostate basal and luminal cells are independently self-sustained by unipotent stem cells that can reactivate multipotency under prostate inflammation and carcinogenesis contexts. However, the defined basal stem cell populations responsible for prostate regeneration and their cell fates in prostate homeostasis, inflammation and carcinogenesis remain unclear. Using a genetic proliferation tracer (ProTracer) system, we found that basal cells exhibited extensive cell loss and proliferation during androgen-mediated prostate regression and regeneration, respectively. A rare intermediate basal cell population that expresses luminal cell markers (Nkx3.1 and Pbsn) (termed Basal-B) and a large basal cell population (termed Basal-A) were identified in mouse prostates by single-cell RNA sequencing. Basal-B cells exhibited a greater capacity for organoid formation and luminal cell differentiation in vitro. Genetic lineage tracing using dual recombinases showed that prostate homeostasis and regeneration are not driven by specific basal cell types. Fate-mapping results showed that Basal-B cells had a greater tendency to generate luminal cells under bacteria-induced prostate inflammation. Deletion of Pten in basal cells resulted in Basal-A-to-Basal-B-to-luminal transition and prostatic intraepithelial neoplasia. Moreover, the human Basal-B-cell population was significantly increased in human benign prostate hyperplasia and prostatic intraepithelial neoplasia samples compared with normal prostate samples. This study identifies intermediate Basal-B cells as a potential stem cell population and provides genetic evidence of prostate basal cell lineage plasticity under physiological and pathological contexts.

developmental biology↗

bioRxiv2023

Single-cell transcriptomics reveals that tumor-infiltrating natural killer cells are activated by localized ablative immunotherapy and share anti-tumor signatures induced by immune checkpoint inhibitors

RationaleNatural killer (NK) cells provide protective anti-cancer immunity. However, the cancer therapy induced activation gene signatures and pathways in NK cells remain unclear. MethodsWe applied a novel localized ablative immunotherapy (LAIT) by synergizing photothermal therapy (PTT) with intra-tumor delivering of the immunostimulant N-dihydrogalactochitosan (GC), to treat breast cancer using a mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) mouse model. We performed single-cell RNA sequencing (scRNAseq) analysis to unveil the cellular heterogeneity and compare the transcriptional alterations induced by PTT, GC, and LAIT in NK cells within the tumor microenvironment (TME). ResultsScRNAseq showed that NK subtypes, including cycling, activated, interferon-stimulated, and cytotoxic NK cells. Trajectory analysis revealed a route toward activation and cytotoxicity following pseudotime progression. Both GC and LAIT elevated gene expression associated with NK cell activation, cytolytic effectors, activating receptors, IFN pathway components, and cytokines/chemokines in NK subtypes. Single-cell transcriptomics analysis using immune checkpoint inhibitor (ICI)-treated animal and human samples revealed that ICI-induced NK activation and cytotoxicity across several cancer types. Furthermore, ICI-induced NK gene signatures were also induced by LAIT treatment. We also discovered that several types of cancer patients had significantly longer overall survival when they had higher expression of genes in NK cells that were also specifically upregulated by LAIT. ConclusionOur findings show for the first time that LAIT activates cytotoxicity in NK cells and the upregulated genes positively correlate with beneficial clinical outcomes for cancer patients. More importantly, our results further establish the correlation between the effects of LAIT and ICI on NK cells, hence expanding our understanding of mechanism of LAIT in remodeling TME and shedding light on the potentials of NK cell activation and anti-tumor cytotoxic functions in clinical applications.

immunology↗

bioRxiv2023

An Ensemble Learning Approach to perform Link Prediction on Large Scale Biomedical Knowledge Graphs for Drug Repurposing and Discovery

Generating knowledge graph embeddings (KGEs) to represent entities (nodes) and relations (edges) in large scale knowledge graph datasets has been a challenging problem in representation learning. This is primarily because the embeddings / vector representations that are required to encode the full scope of data in a large heterogeneous graph needs to have a high dimensionality. The orientation of a large number of vectors requires a lot of space which is achieved by projecting the embeddings to higher dimensions. This is not a scalable solution especially when we expect the knowledge graph to grow in size in order to incorporate more data. Any efforts to constrain the embeddings to lower number of dimensions could be problematic as insufficient space to spatially orient the large number of embeddings / vector representations within limited number of dimensions could lead to poor inferencing on downstream tasks such as link prediction which leverage these embeddings to predict the likelihood of existence of a link between two or more entities in a knowledge graph. This is especially the case with large biomedical knowledge graphs which relate several diverse entities such as genes, diseases, signaling pathways, biological functions etc. that are clinically relevant for the application of KGs to drug discovery. The size of the biomedical knowledge graphs are therefore much larger compared to typical benchmark knowledge graph datasets. This poses a huge challenge in generating embeddings / vector representations of good quality to represent the latent semantic structure of the graph. Attempts to circumvent this challenge by increasing the dimensionality of the embeddings often render hardware limitations as generating high dimensional embeddings is computationally expensive and often times infeasible. To practically deal with representing the latent structure of such large scale knowledge graphs (KGs), our work proposes an ensemble learning model in which the full knowledge graph is sampled into several smaller subgraphs and KGE models generate embeddings for each individual subgraph. The results of link prediction from the KGE models trained on each subgraph are then aggregated to generate a consolidated set of link predictions across the full knowledge graph. The experimental results demonstrated significant improvement in rank-based evaluation metrics on task specific link predictions as well as general link predictions on four open-sourced biomedical knowledge graph datasets.

bioinformatics↗

bioRxiv2023

CHOP drives cells to mutually exclusive cell fates--death and proliferation--during ER stress

Cellular stresses elicit signaling cascades that are capable of either mitigating the inciting dysfunction or initiating cell death. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. However, it is not clear whether CHOP also has a beneficial role during adaptation. Here, we have combined a new, versatile, genetically modified Chop allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we found that CHOP promoted death in some cells, but proliferation--and hence recovery--in others. Strikingly, this function of CHOP conferred to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggested that CHOP maximizes UPR activation, which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. Taken together, these findings suggest that CHOPs function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates--adaptation or death--during stresses of physiological intensity.

cell biology↗

bioRxiv2023

Airway secretory cell-derived p63+ progenitors contribute to alveolar regeneration after sterile lung injury

Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. However, the origin and fate of injury-induced progenitors are poorly defined. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced lung injury. These p63+ progenitors proliferate rapidly and differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells through distinct trajectories. Dual recombinase-mediated sequential genetic lineage tracing reveals that p63+ progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is required for efficient alveolar regeneration from secretory cells. Our study identifies a secretory cell-derived p63+ progenitor that contributes to alveolar repair, indicating a potential therapeutic avenue for lung regeneration after injury.

cell biology↗

bioRxiv2023

Omics Analysis Unveils the Pathway Involved in the Purple Coloration in Tomato Seedling and Fruits

The purple tomato variety Indigo Rose(InR) is favored due to its bright appearance and abundant anthocyanins. SlHY5 is associated with anthocyanin biosynthesis in Indigo Rose plants. However, residual anthocyanins still present in Slhy5 seedlings and fruit peel indicated there was an anthocyanin induction pathway that is independent of HY5 in plants. The molecular mechanism of color formation in Indigo Rose and Slhy5 mutants is unclear. In this study, we performed omics analysis to clarify the regulatory network underlying coloration in seedling and fruit peel of Indigo Rose and Slhy5 mutant. Results showed that the total amount of anthocyanins in both seedling and fruit of InR were significantly higher than those in Slhy5 mutant and most genes associated with anthocyanin biosynthesis exhibited higher expression levels in InR, suggesting that SlHY5 play pivotal roles in flavonoid biosynthesis both in tomato seedlings and fruit. Yeast two-hybrid (Y2H) results revealed that SlBBX24 physically interacts with SlAN2-like and SlAN2, while SlWRKY44 could interact with SlAN11 protein. Unexpectedly, both SlPIF1 and SlPIF3 were found to interact with SlBBX24, SlAN1 and SlJAF13 by yeast two-hybrid assay. Suppression of SlBBX24 by virus-induced gene silencing (VIGS) retarded the purple coloration of the fruit peel, indicating an important role of SlBBX24 in the regulation of anthocyanin accumulation. These results deepen the understanding of purple color formation in tomato seedling and fruits in an HY5-dependent or independent manner via excavating the genes involved in anthocyanin biosynthesis based on omics analysis.

molecular biology↗