Biology subjects

Cai, J.

Publications and source records attributed to Cai, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Biological characteristics of rabbit KLF12 and its regulation of proliferation and apoptosis of ovarian granulosa cells

Granulosa cells (GCs), as the largest somatic cell group in follicles, provide nutrients and microenvironment for oocyte growth and maturation. GC proliferation and apoptosis are influenced by several genes, with the Kruppel Like Factor 12 (KLF12) gene contributing to the modulation of several cellular activities. Nevertheless, the precise modulatory function of this gene within the context of ovarian GCs remains unelucidated. We cloned the KLF12 gene of New Zealand female rabbits, and evaluated its expression and localization in the ovaries of female rabbits of different ages by quantitative real-time PCR (qRT-PCR) and fluorescence in situ hybridization (FISH). In order to determine the role of KLF12 in ovarian GCs, we used qRT-PCR, WB, CCK-8 and Annexin V-FITC/PI to detect the effect of KLF12 on GCs proliferation and apoptosis. The coding sequence of KLF12 gene of New Zealand female rabbit was predicted and cloned for the first time in this study. The coding region was 1209 bp, encoding 402 amino acids. KLF12 overexpression has a negative effect on the proliferation and cell cycle progression of rabbit GCs. KLF12 knockdown partially rescues GCs proliferation, accelerates GCs cycle progression, and promotes Estradiol (E2) and Progesterone (P) secretion. In addition, KLF12 was also proved to be a key regulator of PI3K/Akt signaling pathway in GCs. In conclusion, the study provides evidence that KLF12 plays a pivotal role in the maturation and proliferation of ovarian GCs in female rabbits. This work establishes a conceptual foundation for investigating deeper into the possible regulatory mechanisms underlying follicular development and growth. Author summaryGCs are essential for oocyte growth, not only providing necessary nutritional support for oocyte growth and maturation, but also constructing a key microenvironment. In this study, the biological function of KLF12 gene was systematically elucidated in rabbit for the first time. It was found that KLF12 inhibited follicular development by negatively regulating GCs proliferation and cell cycle. Combined with its effect on E2 and P secretion, the important regulatory role of KLF12 in follicular maturation and hormone balance was revealed. These innovative findings not only deepen the understanding of the regulatory network of ovarian development, but also provide a new theoretical basis for the basic research of reproductive biology. More importantly, it provides a potential molecular target for the development of new technologies to improve the reproductive efficiency of livestock. It also provides a valuable reference model for the study of the mechanism of human reproductive dysfunction related diseases.

genetics↗

bioRxiv2025

Impact of Peptide Initial Configuration and Membrane Composition on Melittin's Pore-Forming Ability under Unbiased All-Atom Molecular Dynamics Simulations

The rising challenge of antimicrobial resistance has accelerated the search for alternative therapeutics. Antimicrobial peptides (AMPs), a class of naturally occurring defense molecules found across diverse species, are promising candidates. Despite their potent membrane-disrupting activity, the atomic details of the pore formation process remain insufficiently understood. In this study, we employed all-atom molecular dynamics (MD) simulations to investigate the pore formation process of melittin under different initial configurations. Simulations were conducted using three different membrane systems: a pure POPC bilayer, a mammalian membrane model (DOPC:Cholesterol, 9:1), and a bacterial membrane model (DOPE:DOPG, 3:1). For each system, we examined four different starting configurations, in which six melittin peptides were arranged in a star-like pattern. Our results demonstrated that the pore formation process strongly depends on the initial peptide configuration. In one specific initial arrangement (termed as Conf.I), pore formation consistently occurred within 100 nanoseconds, regardless of membrane composition. Furthermore, the simulations revealed that pore formation was more challenging in the mammalian membrane model and even more so in the bacterial membrane model, in comparison with the pure POPC bilayer. These findings are in line with previously reported minimum inhibitory concentration (MIC) and the 50% hemolysis concentration (HC50) of melittin in the literature. Additionally, we identified lysine-7 (K7) as the key residue in determining whether a stable pore can form. In configurations where the K7 side chain formed electrostatic interactions with the phosphate group of a lipid, melittin were anchored to the membrane surface, thereby preventing pore formation. In contrast, simulations of melittin mutants K7A and K7Q showed no such anchoring effect, and thus pore formation was possible in multiple initial configurations. Notably, the K7Q mutation showed a preference for pore formation in bacterial membranes over mammalian membranes, suggesting that reducing toxicity while maintaining antimicrobial efficacy is possible.

biochemistry↗

bioRxiv2025

PML1-Mediated Feedforward Loop Through PI3K and MAPK Axes Drives Endocrine Resistance

Treatment of estrogen receptor-positive (ER+) breast cancer is significantly hindered by endocrine resistance. We identified PML1 as a key therapeutic entity that can be targeted to overcome resistance. Endocrine-resistant breast cancer cells share three key characteristics: elevated PML1 protein levels, enhanced activity of PI3K, MAPK, or both signaling pathways, and reduced ER activity. We developed a PML1 gene signature that predicts poor prognosis and correlates strongly with PI3K, MAPK, and endocrine resistance gene signatures, as evident by cellular studies, scRNA-seq analysis, and spatial transcriptomics of endocrine therapy-treated tumors. This signature is present in endocrine-resistant breast cancer cells harboring the Y537S ER mutation. We consistently demonstrate high PML1 protein levels across cells resistant to various treatments, including 4-hydroxytamoxifen, fulvestrant, elacestrant, and CDK4/6 inhibitors. Furthermore, treatments with these therapeutic agents or knockdown of ESR1 mRNA also increase PML1 protein levels. Mechanistically, we show that ER inhibition through fulvestrant treatment activates PI3K and MAPK signaling, which enhance PML1 protein stability and synthesis. PML1 then drives a feedforward loop by stimulating the expression of cytokine and growth factor mRNAs, including CCL5 and HBEGF, further amplifying PI3K and MAPK signaling. Consequently, in endocrine-resistant cells, endocrine therapies, while inactivating ER, paradoxically reinforce this loop through increased PI3K/MAPK activation and PML1 protein accumulation, ultimately compromising therapeutic efficacy. Finally, we demonstrated that arsenic trioxide, an FDA-approved, PML-reducing drug, effectively disrupts this feedforward loop, offering a promising strategy for treating resistant metastatic breast cancer. STATEMENT OF SIGNIFICANCEEndocrine resistance remains a major obstacle in treating estrogen receptor-positive metastatic breast cancer. Our study identifies PML1 as a central mediator of this resistance, revealing how it maintains a self-reinforcing signaling network through PI3K and MAPK pathways by enhancing the production of cytokines and growth factors. The clinical significance of our findings is threefold: we establish PML1 as a biomarker for therapy resistance, demonstrate its mechanistic role in treatment failure, and show that FDA-approved arsenic trioxide can disrupt PML1-driven resistance. These insights provide a direct path to clinical translation, as combining arsenic trioxide with existing therapies could benefit patients with limited treatment options.

cancer biology↗

bioRxiv2025

Dual function of DOT1L suppresses tumor intrinsic immunogenicity in hepatocellular carcinoma

Immune checkpoint inhibitor (ICB) therapy for many cancers remains limited in patients overall response rate. Discovery and development of more effective combinatorial approaches is urgent. Here, through CRISPR/Cas9 genetic screens, we identify DOT1L as a versatile epigenetic factor that functions to suppress tumor-intrinsic immunity through a dual mechanism. Depletion of DOT1L induces the expression of transposable elements and subsequent type I interferon (IFN) response, and meanwhile lowers ZEB1 levels to further unleash the expression of immune-related genes. In turn, we demonstrate that DOT1L loss or treatment with the clinical stage inhibitor EPZ-5676 sensitizes tumors to ICB with increased immune infiltration in mice. More importantly, EPZ-5676 treatment alone is sufficient to enhance antitumor immunity in humanized mice. TCGA data analysis reveals an inverse correlation between DOT1L expression and IFN signatures across multiple cancer types. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance. One Sentence SummaryCRISPR genetic screens identified DOT1L as a potential suppressor of tumor intrinsic immunogenicity

cell biology↗

bioRxiv2025

A molecular circuit regulates fate plasticity in emerging and adult AT2 cells

Alveolar AT1 and AT2 cells are vital for lung gas exchange and become compromised in several diseases. While key differentiation signals are known, their emergence and fate plasticity are unclear. Here we show in the embryonic lung that single AT2s emerge at intermediate zones, extrude, and connect with nearby epithelium via interlumenal junctioning. We observe that AT2s retain fate plasticity until the bZIP transcription factor C/EBP suppresses Notch signaling at a novel Dlk1 enhancer. Both Dlk1 and Cebpa are regulated by the polycomb repressive complex (PRC2), which together form a "pulse generator" circuit that times Dlk1 expression and thus Notch activation, resulting in a "salt and pepper" pattern of AT1 and AT2 fate. In injured adult lungs, C/EBP downregulation is required to re-access AT2 fate plasticity and is mediated by the dominant negative C/EBP family member CHOP. Finally, Cebpa loss also activates a "defender" AT2 state, distinct from its reparative state, and we propose AT2s toggle between either state following infection to protect and repair alveoli.

developmental biology↗

bioRxiv2025

Single-Cell eQTL Mapping Reveals Cell Type-Specific Genetic Regulation in Lung Cancer

Genome-wide association studies (GWAS) have identified over 50 lung cancer risk loci; however, the precise cellular context of these genetic mechanisms remains unclear due to limitations in bulk tissue eQTL analyses. Here, we present the largest single-cell eQTL atlas of human lung tissue to date, profiling 222 donors using multiplexed scRNA-seq. We identified 16,785 eQTLs across 17 cell types, with over 90% of sc-eQTLs and 59% eGene being cell-type-specific, and fewer than 23% were detectable in paired bulk datasets. Integration with GWAS for non-small cell lung cancer highlighted epithelial and immune cells as key contributors to genetic susceptibility, identifying 28 candidate genes within known risk loci and 24 in novel regions. Notably, 47% of established NSCLC susceptibility loci exhibited cell-type-specific pleiotropic genetic regulation. This study provides a valuable resource of lung sc-eQTLs and illuminates how genetic variation modulates gene expression in a cell-type-specific fashion, contributing to lung cancer susceptibility.

genetics↗

bioRxiv2025

Predictive Coding Explains Asymmetric Connectivity in the Brain: A Neural Network Study

Seminal frameworks of predictive coding propose a hierarchy of generative modules, each attempting to infer the neural representation of the module one level below; the predictions are carried by top-down feedback projections, while the predictive error is propagated by reciprocal forward pathways. Such symmetric feedback connections support visual processing of noisy stimuli in computational models. However, neurophysiological studies have yielded evidence of asymmetric cortical feedback connections. We investigated the contribution of neural feedback during sensorimotor processes, in particular visual processing during grasp planning, by utilizing convolutional neural network models that had been augmented with predictive feedback and were trained to compute grasp positions for real-world objects. After establishing an ameliorative effect of symmetric feedback on grasp detection performance when evaluated on noisy stimuli, we characterized the performance effects of asymmetric feedback, similar to that observed in the cortex. Specifically, we tested model variants extended with short-, medium- and long-range feedback connections (i) originating at the same source layer or (ii) terminating at the same target layer. We found that the performance-enhancing effect of predictive coding under adverse conditions was optimal for medium-range asymmetric feedback. Moreover, this effect was most prominent when medium-range feedback originated at a level of representational abstraction that was proximal to the input layer, in contrast to more distal layers. To conclude, our simulations show that introducing biologically realistic asymmetric predictive feedback improves model robustness to noisy visual stimuli in a neural network model optimized for grasp detection. Significance statementIt is commonly held that the brain predicts the causes of its sensorium via top-down neural pathways. While canonical models of predictive coding assume reciprocal feedforward and feedback connections, functional evidence highlights the importance of non-reciprocal asymmetric feedback, whose role remains poorly understood, particularly in sensorimotor functions. Using neural network models of grasp planning, we characterized optimal pathlengths and source regions for asymmetric feedback facilitating visuomotor processing of noisy sensory inputs. Our findings show that medium-range feedback from early layers marks a sweet spot, incorporating optimal distance between the neural representations of source/target layers and representational abstraction of the feedback source. This intimates an uncharted role of intermediate brain areas along the visuomotor stream as a source of predictive signals.

neuroscience↗

bioRxiv2025

China Autism Brain Imaging Consortium: Charting Brain Growth in Chinese Children with Autism

Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental condition characterized by atypical brain growth. While advances in neuroimaging and openly sharing large-sample datasets such as the Autism Brain Imaging Data Exchange (ABIDE) have improved understanding of ASD, most studies focus on adolescents and adults, with early brain development-critical for diagnosis and intervention-remaining underexplored. Existing research predominantly involves Western samples, offering limited insight and generalizability into non-Caucasian populations. We introduce the China Autism Brain Imaging Consortium (CABIC) (https://php.bdnilab.com/resources/), a grassroots effort by researchers across the country to aggregate previously collected multi-site structural MRI datasets and phenotypic information from 1,451 autistic children and 1,119 typically developing children, covering an age range from early childhood to school age (1.0 - 12.92 years). Here, we present this resource and depict brain growth charts to push forward a more comprehensive understanding of the brain development in Chinese autism children. We constructed brain growth charts that reveal a developmental shift in autistic children, transitioning from early overgrowth to delayed maturation. Regional analyses identified distinct atypical trajectories across specific brain regions. Individual deviation scores quantified inter-subject variability, characterizing the heterogeneity of brain development in ASD. Comparative analyses between CABIC and ABIDE highlighted differences potentially attributable to ethnicity and culture, advancing our understanding of cross-population neurodevelopmental diversity. CABIC MRI datasets will be shared publicly to foster investigation of the potential neural mechanisms underlying ASD in non-Western populations and support efforts toward precision medicine for autistic individuals across diverse backgrounds.

neuroscience↗

bioRxiv2025

Coro1a promotes the multivesicular body and plasma membrane fusion by facilitating PKM2-mediated SNAP-23 phosphorylation

During the formation of endosomal pathway-dependent extracellular vesicles (EVs), intraluminal vesicles in multivesicular bodies (MVBs) fuse with the plasma membrane (PM), releasing intraluminal vesicles to produce exosomes. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, membrane fusion effector, is essential in this process. However, which SNARE complex is involved in MVB and PM fusion and how its assembly is regulated remain elusive. We have demonstrated that neddylation of Coro1a inhibits EV secretion by inducing Rab7-mediated degradation of MVBs. Here, we find that Coro1a increases EV biogenesis by promoting the assembly of SNARE complex STX-12-SNAP-23-VAMP-7 in a neddylation-independent manner. Coro1a activates PKM2 to enhance SNAP-23 phosphorylation in the presence of neddylation inhibitor MLN4924, which drives SNAP-23 to recruit more STX-12 and VAMP7, leading to increased formation of the STX-12-SNAP-23-VAMP-7 complex. Correspondingly, Coro1a-induced EV biogenesis is eliminated by PKM2 inhibitor or SNAP-23 silencing independent of neddylation. Reduced EVs from tumors due to Coro1a knockout cannot be observed in MLN4924-treated tumor mice with PKM2 inhibitor treatment either. Furthermore, Coro1a increases in tumor tissues from lung tumor patients with tumor progression, and high Coro1a indicates unfavorable survival of tumor patients, suggesting that increased Coro1a-mediated enhanced EV production from tumors accelerates tumor progression. Altogether, our data demonstrate that Coro1a facilitates EV biogenesis by promoting the assembly of STX-12-SNAP-23-VAMP-7 complex during MVB and PM fusion independent of neddylation, thereby being involved in the progression of EV-related diseases.

cell biology↗

bioRxiv2025

Decoding semantics from natural speech using human intracranial EEG

Brain-computer interfaces (BCIs) hold promise for restoring natural language production capabilities in patients with speech impairments, potentially enabling smooth conversation that conveys meaningful information via synthesized words. While considerable progress has been made in decoding phonetic features of speech, our ability to extract lexical semantic information (i.e. the meaning of individual words) from neural activity remains largely unexplored. Moreover, most existing BCI research has relied on controlled experimental paradigms rather than natural conversation, limiting our understanding of semantic decoding in ecological contexts. Here, we investigated the feasibility of decoding lexical semantic information from stereo-electroencephalography (sEEG) recordings in 14 participants during spontaneous conversation. Using multivariate pattern analysis, we were able to decode word level semantic features during language production with an average accuracy of 21% across all participants compared to a chance level of 10%. This semantic decoding remained robust across different semantic representations while maintaining specificity to semantic features. Further, we identified a distributed left-lateralized network spanning precentral gyrus, pars triangularis, and middle temporal cortex, with low-frequency oscillations showing stronger contributions. Together, our results establish the feasibility of extracting word meanings from neural activity during natural speech production and demonstrate the potential for decoding semantic content from unconstrained speech.

neuroscience↗

bioRxiv2025

Old vs. New Local Ancestry Inference in HCHS/SOL: A Comparative Study

Hispanic/Latino populations are admixed, with genetic contributions from multiple ancestral populations. Studies of genetic association in these admixed populations often use methods such as admixture mapping, which relies on inferred counts of "local" ancestry, i.e., of the source ancestral population at a locus. Local ancestries are inferred using external reference panels that represent ancestral populations, making the choice of inference method and reference panel critical. This study used a dataset of Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) to evaluate the "old" local ancestry inference performed using the state-of-the-art inference method, RFMix, alongside "new" inferences performed using Fast Local Ancestry Estimation (FLARE), which also used an updated reference panel. We compared their performance in terms of global and local ancestry correlations, as well as admixture mapping-based associations. Overall, the old RFMix and new FLARE inferences were highly similar for both global and local ancestries, with FLARE-inferred datasets yielding admixture mapping results consistent with those computed from RFMix. However, in some genomic regions the old and new local ancestries have relatively lower correlations (Pearson R < 0.9). Most of these genomic regions (86.42%) were mapped to either ENCODE blacklist regions, or to gene clusters, compared to 7.67% of randomly-matched regions with high correlations (Pearson R > 0.97) between old and new local ancestries.

genetics↗

bioRxiv2025

Tensor analysis of animal behavior by matricization and feature selection

Contemporary neurobehavior research often collects multi-dimensional tensor (MDT) data, consisting of time-series measurements for multiple features from multiple animals subjected to various perturbations. Proper analysis of the MDT data can facilitate the dissection of the underlying neural circuitry driving the behavior. However, many common approaches for MDT analysis, such as tensor decomposition, often yield results that are difficult to interpret and not directly compatible with standard multivariate analysis (MVA), which is designed for simpler, lower-dimensional data structures. To address this issue, dimensionality reduction techniques, including matricization methods such as Index Construction and Feature Concatenation, are applied to transform all or a subset of the features in the MDT into a lower-dimensional tensor, commonly a 2-dimensional tensor (2DT), that is compatible with MVA. However, the matricization methods may exclude information from the MDT features or create too many 2DT features that introduce spurious noise to the downstream analyses. Their impacts on the downstream MVA performance remain elusive. In this study, we systematically evaluated different approaches for matricization and feature selection and their impacts on MVA performance using an MDT dataset of zebrafish visual- motor response collected from wild-types (WTs) and visually-impaired mutants. We matricized the MDT dataset using various Index Construction and Feature Concatenation methods, then identified informative 2DT features using the filter and embedded methods. To evaluate these feature-selection approaches, we conducted a classification task distinguishing WT and visually-impaired zebrafish by multiple classifiers. We then assessed classification performance with cross-validation and holdout validation. We found that most classifiers performed the best when using all 2DT features matricized by Feature Concatenation and selected by the embedded method. The results also revealed unique behavioral differences between the WTs and visually-impaired mutants that were not identified by standard MVA or MDT analysis. Our results demonstrate the utility of analyzing MDT behavioral data by matricization and feature selection.

animal behavior and cognition↗

bioRxiv2024

TCPGdb: A comprehensive T cell perturbation genomics database for identification of critical T cell regulators

CAR-T therapies utilizing T cells engineered with chimeric antigen receptors (CARs) have revolutionized the treatment of hematologic and immune-related malignancies. However, the anti-tumor capability of engineered CAR-T cells are often not persistent, which greatly dampen its clinical efficacy. To address this limitation, massive parallel genetic screens were widely used to identified novel targets and regulators that enhance T cell anti-tumor capability and persistence in tumor microenvironment. We hypothesized that by combining the pooled screen data from multiple independent genetic screens we could provide a systematic, comprehensive, and robust analysis of the effect of gene perturbation on T-cell based immunotherapies. After collecting data from previously published T cell screens, including CRISPR-based and ORF-based screens, through Gene Expression Omnibus (GEO), we reprocessed the gene hits summary and conducting a pathway enrichment analysis. A T cell screen perturbation score (TPS) was employed to quantifies the impact of the gene on T cell function. Additionally, gene expression data (both bulk RNA level and single-cell RNA level) from autoimmune disease and T cell-derived cancers were analyzed to pick up gene perturbations that potentially augment T cell proliferation. We integrated all data and analysis on 27 T-cells screens into our state-of-the-art T cell perturbation genomics database (TCPGdb), which is made easily accessible through our webserver and allows users to interactively explore the impact of query genes on T cell function based on prior screen data and our TPS scoring module. TCPGdb is publicly accessible at http://tcpgdb.sidichenlab.org/.

bioinformatics↗

bioRxiv2024

Chicken shank color determined by Inhibition of dermal melanin (ID) is mediated by a structural variation regulating CDKN2A expression

It is well established that the color of a chickens shank is primarily determined by four genetic loci. Among these, the Inhibition of dermal melanin (ID) locus, which suppresses black pigmentation in the dermal layer of the shank, is the sole sex-linked mutation and its molecular mechanisms remained elusive. In this study, a resource family with segregating shank colors was constructed. A genome-wide association study utilizing FarmCPU software identified a top-associated SNP located on the Z chromosome. Subsequent linkage mapping further refined the candidate region, enabling the screening of the candidate structural variation. The candidate structural variation is associated with the yellow shank and characterized by a 143 bp deletion accompanied by a 2 bp insertion. Within the same Topologically Associating Domain, only the CDKN2A gene showed differential expression. Functional studies, including CRISPR/Cas9-edited cells, provided evidence that this mutation regulates CDKN2A transcription and is responsible for the ID shank color in chickens. The absence of melanocytes is likely due to their apoptosis. This study completes the puzzle of chicken shank color genetics and paves the way for the application of the ID mutation in the auto-sexing of chicks which is intensively needed in layer and broiler industries.

genetics↗

bioRxiv2024

Retrotransposon LINE1 trans-regulatory differentiation process maintain embryonic stem cell identity

Long Interspersed Nuclear Elements-1s (LINE1s) are one of the >17% most abundant Retrotransposons in mammalian genomes. LINE1 RNA is high expression during early embryonic development, meanwhile is under tight epigenetic control. Some studies have confirmed LINE1 play a critical role in early embryo development and ESC identity. Previous studies focused on the role of LINE1 in cis-regulation, however, the function of L1 RNA in tans-regulation remains largely unknown. In this study, we performed a high-throughput proximity MARGI (pxMARGI) experiment found transposon LINE1 RNA trans-regulated prefer to young LINE1 subfamily, and in hybrid and non-hybrid two different manner repress ESC to dual progress of 2C-like cells and differentiation. In differentiation process, LINE1 RNA as a scaffold recruit polycomb core subunits combine three core pluripotent factors maintain ESC identity. In 2C process, LINE1 RNA in a sequence-specific manner recruit Kap1 to old L1 subfamily, and recruit ELL3 to RE 5 UTR maintain ESC self-renewal. Our data point to LINE1 transcriptions more detail trans-regulation mechanism to orchestrate developmental progression for the self-renewal of embryonic stem cells (ESCs). LINE1 RNA may be potential biomarker for noninvasive embryo selection.

genomics↗

bioRxiv2024

Regulating of Koisio technology-produced fluid on Vascular Adventitial Interstitial Fluid flow and its Effect on heart rate by delivering Esmolol

Acupoint-originated interstitial fluid (ISF) circulatory network along the vasculature has been demonstrated to play a role as an extravascular drug delivery pathway. We aim to reveal the regulation of Koisio technology-produced fluid (KF), which is rich in Ultra-small Particle Size Nanobubbles (UsNBs), on vascular adventitial ISF flow and its Effect on heart rate by delivering Esmolol. In animal experiments, using real-time fluorescent imaging technology, it was found that: when normal saline-fluorescent liquid was given at Kunlun acupoint, the velocity of the adventitial ISF along the femoral vein was measured to be about 600 m/sec, and the width of the tunica ISF channel on the adventitia surface of the femoral vein was about 210m; when KF-fluorescent liquid was injected into the subcutaneous tissue of Kunlun acupoint, the velocity of the adventitia ISF slowed down by about 24% compared with before; the width of the tunica ISF channel on the adventitia surface of the femoral vein increased by about 35% compared with before; When 150L of KF with high-concentration UsNBs was injected into Kunlun acupoint, it was observed that the adventitial ISF flow velocity was decreased by 43%, and recovered after 30 minutes. Administration of normal saline-esmolol solution at Kunlun acupoint caused the heart rate to drop from 410 bpm to 380 bpm, a decrease of 7.3%, which continued for 5 minutes before recovery. Administration of KF-esmolol solution at Kunlun acupoint caused the heart rate to drop from 410 bpm to 371 bpm, a decrease of 9.5%, which continued for 15 minutes before recovery. Thus, acupoint injection of KF can regulate the velocity of the adventitia ISF flow along the femoral vein and increase the width of the tunica ISF channel. These results may reveal a new mechanism of the physiological effect of Koisio drinking water rich in ultra-small particle size nanobubbles. KF may not only regulate the acupoint-originated ISF circulatory system, but also play a role in adventitial drug delivery, nutrient supply, and waste removal.

physiology↗

bioRxiv2024

SPP1+ tumor-associated macrophages induce radioresistance of nasopharyngeal carcinoma through crosstalk with the tumor microenvironment

The function and phenotype of tumor-associated macrophages (TAMs) influence the efficacy of radiotherapy. However, the effect of different subsets of TAMs on the radioresistance in nasopharyngeal carcinoma (NPC) still needs to be further explored. This study utilized single-cell RNA sequencing (scRNA-seq) to analyze 120,579 cells obtained from 15 NPC samples. Cell annotation, cell-cell communication analysis, and functional annotation were used to investigate the impact of TAMs on the effectiveness of radiotherapy in NPC patients. Additionally, we employed RNA-seq data and clinical information from many patients, including 24 NPC samples from Zhujiang Hospital, 3,934 samples from patients with a history of radiotherapy, for further validation. We identified a hub TAM subpopulation, SPP1+ TAMs, that induced radioresistance in NPC based on single-cell RNA sequencing (scRNA-seq) data. We combined many public datasets to confirm their prognostic value in radiotherapy patients. We found that SPP1+ TAMs had stronger protumorigenic and immunosuppressive effects in the postradiotherapy recurrent tumor (PRRT) group. SPI1 transcription factor efficiently regulates the expression level of SPP1 in macrophages. In addition, we validated the underlying mechanisms by molecular docking, multiplex immunofluorescence and cellular experiments. In conclusions, by forming an immunosuppressive microenvironment and promoting tumor cell proliferation, SPP1+ TAMs leading to radioresistance and poor clinical prognosis in NPC patients. Targeting SPP1+ TAMs could provide new insights into improving the efficacy of radiotherapy in NPC patients.

cancer biology↗

bioRxiv2024

Probing Biomass Precursor Synthesis as a Key Factor in Microbial Adaptation to Unadapted Carbon Sources

Industrial microorganisms often face challenges in utilizing renewable substrates such as methanol, formate, and xylose. We present findings that the proportion of biomass precursors that must be synthesized from unadapted carbon sources is a critical determinant of the evolutionary driving force and minimal substrate requirements, using a new computational framework, AdaptUC. We predict metabolic engineering strategies for Adaptive Laboratory Evolution (ALE). These strategies enable microorganisms to co-utilize an adapted co-substrate and an unadapted carbon source or, in some cases, rely exclusively on the unadapted source. AdaptUC was validated through experimental records and literature, confirming its effectiveness in identifying gene knockout strategies. Case studies in Escherichia coli and Corynebacterium glutamicum highlight superior strategies with higher driving forces and reduced substrate requirements. This method has the potential to transform industrial biosynthesis by enabling more efficient use of renewable carbon sources. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/619944v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@36fe02org.highwire.dtl.DTLVardef@5e73fdorg.highwire.dtl.DTLVardef@110ffdaorg.highwire.dtl.DTLVardef@10d45dc_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗