Biology subjects

Gao, F.

Publications and source records attributed to Gao, F..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

DeOri 10.0: An Updated Database of Experimentally Identified Eukaryotic Replication Origins

DNA replication is a complex and crucial biological process in eukaryotes. To facilitate the study of eukaryotic replication events, we present database of eukaryotic DNA replication origins (DeOri), a database that collects scattered data and integrates extensive sequencing data on eukaryotic DNA replication origins. With continuous updates of DeOri, the number of datasets in the new release increased from 10 to 151 and the number of sequences increased from 16,145 to 9,742,396. Besides nucleotide sequences and bed files, corresponding annotation files, such as coding sequences (CDS), mRNA, and other biological elements within replication origins, are also provided. The experimental techniques used for each dataset, as well as other statistical data, are also presented on web page. Differences in experimental methods, cell lines, and sequencing technologies have resulted in distinct replication origins, making it challenging to differentiate between cell-specific and non-specific replication. We combined multiple replication origins at the species level, scored them, and screened them. The screened regions were considered as species-conservative origins. They are integrated and presented as reference replication origins (rORIs), including Homo sapiens, Gallus gallus, Mus musculus, Drosophila melanogaster, and Caenorhabditis elegans. Additionally, we analyzed the distribution of relevant genomic elements associated with replication origins at the genome level, such as CpG island (CGI), transcription start site (TSS), and G-quadruplex (G4). These analysis results allow users to select the required data based on it. DeOri is available at http://tubic.tju.edu.cn/deori10/.

bioinformatics↗

bioRxiv2024

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag- RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

neuroscience↗

bioRxiv2024

FLASH radiotherapy using high-energy X-rays: validation of the FLASH effect triggered by a compact single high-energy X-ray source device

PurposeThis preclinical study aimed to verify the FLASH effect of compact single high-energy X-ray source (CHEXs) and to explore whether three irradiations with single-gantry rotation two 30 s pauses can generate FLASH effect in mice. Materials and methodsThe absolute dose and pulsed beam of the CHEXs were measured using an EBTXD radiochromic film and fast current transformer. Healthy C57BL/6J female mice and a subcutaneous tumor model were irradiated under different conditions: sham (control), FLASH-RT (FLASH1: delivering the total dose in 1 fraction; FLASH3: delivering the total dose with two 30 second pauses to simulate a three-field delivery where the gantry rotation is occurring within 30 seconds), and conventional dose rate radiotherapy (CONV-RT). Various total doses were administered to the corresponding normal tissues (whole thorax, 30 Gy; whole abdomen, 12 Gy; and skin, 36 Gy) and tumors (CT26, 16.5 Gy; and LLC, 18 Gy). Survival status, normal tissue damage, and tumor growth suppression were recorded in each group. ResultsThe average dose rate of the CHEXs exceeded 40 Gy/s. For whole-thorax and skin irradiation, both FLASH1 and FLASH3 demonstrated protective effects. For whole-abdomen irradiation, FLASH1 exhibited a superior protective effect. No significant differences in tumor growth responses were observed between the FLASH1, FLASH3, and CONV-RT groups (P>0.05). ConclusionThis study confirmed that the FLASH effect could be triggered using CHEXs FLASH radiotherapy, and demonstrated that three irradiations with single gantry rotation two 30 s pauses can trigger the FLASH effect, indicating the potential benefit of CHEXs 3D conformal radiotherapy. Our findings indicate that further clinical trials on CHEXs are warranted.

cancer biology↗

bioRxiv2024

Strawberry COP9 signalosome FvCSN5 regulates plant development and fruit ripening by facilitating polyamine oxidase FvPAO5 degradation to control polyamine and H2O2 homeostasis

Polyamines (PAs), mainly including putrescine, spermidine, and spermine, are essential for plant growth and development. However, the post-translational regulation of PA metabolism remains unknown. Here, we report the COP9 signalosome subunit 5A (FvCSN5A)-mediated degradation of the PA oxidase FvPAO5, which catalyzes the conversion of spermidine/spermine to produce H2O2. FvCSN5A is localized in the cytoplasm and nucleus, ubiquitously expressed in strawberry plants, and rapidly increases during fruit ripening. FvCSN5A RNA interference (RNAi) transgenic strawberries exhibit pleiotropic effects on plant development, fertility, and fruit ripening by regulating PA and H2O2 homeostasis, similar to FvPAO5 overexpression transgenic lines. FvCSN5A interacts with FvPAO5 in vitro and in vivo. The ubiquitination and degradation of FvPAO5 are impaired in FvCSN5A RNAi lines. Additionally, FvCSN5A interacts with cullin 1 (FvCUL1), a core component of the E3 ubiquitin-protein ligase complex. Transient genetic analysis in cultivated strawberry fruits showed that inhibiting FaPAO5 expression could partially rescue the ripening phenotype of FaCSN5A RNAi fruits. Collectively, the CSN5A-CUL1-PAO5 signaling pathway responsible for PA and H2O2 homeostasis is crucial to strawberry vegetative and reproductive growth and, final to fruit ripening. Our findings may open a promising avenue for improving crop yield and quality by manipulating the CSN5-PAO5 pair.

plant biology↗

bioRxiv2024

Msh3 and Pms1 Set Neuronal CAG-repeat Migration Rate to Drive Selective Striatal and Cortical Pathogenesis in HD Mice

Modifiers of Huntingtons disease (HD) include mismatch repair (MMR) genes; however, their underlying disease-altering mechanisms remain unresolved. Knockout (KO) alleles for 9 HD GWAS modifiers/MMR genes were crossed to the Q140 Huntingtin (mHtt) knock-in mice to probe such mechanisms. Four KO mice strongly (Msh3 and Pms1) or moderately (Msh2 and Mlh1) rescue a triad of adult-onset, striatal medium-spiny-neuron (MSN)-selective phenotypes: somatic Htt DNA CAG-repeat expansion, transcriptionopathy, and mHtt protein aggregation. Comparatively, Q140 cortex also exhibits an analogous, but later-onset, pathogenic triad that is Msh3-dependent. Remarkably, Q140/homozygous Msh3-KO lacks visible mHtt aggregates in the brain, even at advanced ages (20-months). Moreover, Msh3-deficiency prevents striatal synaptic marker loss, astrogliosis, and locomotor impairment in HD mice. Purified Q140 MSN nuclei exhibit highly linear age-dependent mHtt DNA repeat expansion (i.e. repeat migration), with modal-CAG increasing at +8.8 repeats/month (R2=0.98). This linear rate is reduced to 2.3 and 0.3 repeats/month in Q140 with Msh3 heterozygous and homozygous alleles, respectively. Our study defines somatic Htt CAG-repeat thresholds below which there are no detectable mHtt nuclear or neuropil aggregates. Mild transcriptionopathy can still occur in Q140 mice with stabilized Htt 140-CAG repeats, but the majority of transcriptomic changes are due to somatic repeat expansion. Our analysis reveals 479 genes with expression levels highly correlated with modal-CAG length in MSNs. Thus, our study mechanistically connects HD GWAS genes to selective neuronal vulnerability in HD, in which Msh3 and Pms1 set the linear rate of neuronal mHtt CAG-repeat migration to drive repeat-length dependent pathogenesis; and provides a preclinical platform for targeting these genes for HD suppression across brain regions. One Sentence SummaryMsh3 and Pms1 are genetic drivers of sequential striatal and cortical pathogenesis in Q140 mice by mediating selective CAG-repeat migration in HD vulnerable neurons.

neuroscience↗

bioRxiv2024

Synergically enhanced anti-tumor immunity of in vivo CAR by circRNA vaccine boosting

Chimeric Antigen Receptor (CAR) T cell therapy has shown promise in treating hematologic malignancies. However, it is limited to individualized cell therapy and faces challenges, including high costs, extended preparation time, and limited efficacy against solid tumors. Here, we generated circular RNAs (circRNAs) encoding Chimeric Antigen Receptor (CAR) transmembrane proteins, referred to as circRNACAR, which mediated remarkable tumor killing in both T cells and macrophages. In addition, macrophages exhibited efficient phagocytosis of tumor cells and pro-inflammatory polarization induced by circRNACAR in vitro. We demonstrated that circRNACAR, delivered with immunocyte-tropic lipid nanoparticles (LNPs), significantly inhibited tumor growth, improved survival rates and induced a pro-inflammatory tumor microenvironment in mice. Importantly, the combination of circRNAAnti-HER2-CAR and circRNA-based cancer vaccines encoding the corresponding transmembrane HER2 antigen, termed circRNAHER2, exhibited synergistically enhanced anti-tumor activity. This proof-of-concept study demonstrated that the combination of circRNA-based in vivo CAR and vaccines, termed in vivo CAR-VAC, holds the potential to become an upgraded off-the-shelf immunotherapy.

immunology↗

bioRxiv2024

Polyunsaturated Fatty Acid - mediated Cellular Rejuvenation for Reversing Age-related Vision Decline

The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), which are primarily localized in cell membranes, where they govern membrane biophysical properties such as diffusion, permeability, domain formation, and curvature generation. During aging, alterations in lipid metabolism lead to reduced content of very long-chain PUFAs (VLC-PUFAs) in the retina, and this decline is associated with normal age-related visual decline and pathological age-related macular degeneration (AMD). ELOVL2 (Elongation of very-long-chain fatty acids-like 2) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs, and methylation level of its promoter is currently the best predictor of chronological age. Here, we show that mice lacking ELOVL2-specific enzymatic activity (Elovl2C234W) have impaired contrast sensitivity and slower rod response recovery following bright light exposure. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals significantly improved visual function and reduced accumulation of ApoE, HTRA1 and complement proteins in sub-RPE deposits. At the molecular level, the gene expression pattern observed in retinas supplemented with 24:5n-3 exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature of younger retina. Finally, we present the first human genetic data showing significant association of several variants in the human ELOVL2 locus with the onset of intermediate AMD, underlying the translational significance of our findings. In sum, our study identifies novel therapeutic opportunities and defines ELOVL2 as a promising target for interventions aimed at preventing age-related vision loss.

molecular biology↗

bioRxiv2024

Myocardial infarction creates a critical time window for AAV gene therapy

Recombinant adeno-associated virus (AAV) is a major gene delivery vector for cardiac gene therapy. The factors that influence AAV-based cardiac gene transfer remain incompletely understood. This study showed that myocardial infarction (MI) enhanced cardiac AAV transduction and gene expression in mice after systemic administration, peaking at the third day post MI. These additional AAV vectors enriched at the infarcted region, correlated with the pathological permeabilization of the coronary vessels. The outcome of AAV-base gene therapy for MI, via Camk2d base editing, was significantly improved when AAV was injected at the third day post MI. Together, our findings uncovered a critical therapeutic time window after MI that facilitated AAV-based cardiac gene transfer, which could be harnessed to boost both basic and translational cardiology. MethodsAdult C57BL/6 mice were subjected to left anterior descending (LAD) coronary artery ligation. Permanent LAD ligation created the MI model while 30min ligation followed by reperfusion established the ischemia/reperfusion (I/R) model. 2x1011 AAV vectors were injected into the mice via tail vein. The AAV vectors carried transgenes that were activated by the cardiomyocyte-specific Tnnt2 promoter or the constitutively active CMV promoter. AAV expressed luciferase with the hemagglutinin (HA) tag. The amount of AAV vectors were quantified by real-time quantitative PCR (RT-qPCR) analysis of genomic DNA. Transgene expression was measured by RT-qPCR at the mRNA level or HA tag immunofluorescence imaging and western blot at the protein level. Luciferase activity was measured via bioluminescence imaging.

physiology↗

bioRxiv2024

An orphan viral genome with controversial evolutionary status sheds light on a distinct lineage of flavi-like virus infecting plants

Advancements in high-throughput sequencing and associated bioinformatics methods have significantly expanded the RNA virus repertoire, including novel viruses with highly divergent genomes encoding orphan proteins that apparently lack homologous sequences. This absence of homologs in routine sequence similarity search complicates their taxonomic classification and raises a fundamental question: Do these orphan viral genomes represent bona fide viruses? In 2022, an orphan viral genome encoding a large polyprotein was identified in alfalfa (Medicago sativa) and named Snake River alfalfa virus (SRAV). Initially, SRAV was proposed to be within the flavi-like lineage of the family Flaviviridae. Subsequently, another research group showed its common occurrence in alfalfa but challenged its taxonomic position, suggesting it belongs to the family Endornaviridae rather than Flaviviridae. In this study, a large-scale analysis of 77 publicly available small RNA datasets indicated that SRAV could be detected across various tissues and cultivars of alfalfa, and has a broad geographical distribution. Moreover, profiles of the SRAV-derived small interfering RNAs (vsiRNAs) exhibited typical characteristics of virus in plant hosts. Through comprehensive evolutionary analysis, we demonstrated that SRAV should be a positive single-stranded RNA (ssRNA) flavi-like virus that infects alfalfa, rather than a member of the double-stranded RNA (dsRNA) of the family Endornaviridae. Our findings suggest that SRAV represents a unique class of plant-hosted flavi-like viruses with unusual genome organization and evolutionary status, differing from previously identified flavi-like viruses documented to infect plants. The latter shows a close evolutionary relationship to flavi-like viruses primarily found in plant-feeding invertebrates and lacks evidence of triggering host RNA interference (RNAi) responses so far. In summary, our study resolves the taxonomic controversy surrounding SRAV and suggests the potential existence of two distinct clades of plant-hosted flavi-like viruses with independent evolutionary origins. Furthermore, our research provides the first evidence of plant-hosted flavi-like viruses triggering the hosts RNAi antiviral response. The widespread occurrence of SRAV underscores its potential ecological significance in alfalfa, a crop of substantial economic importance.

evolutionary biology↗

bioRxiv2024

The phylogenetic position of the Yunxian cranium elucidates the origin of Dragon Man and the Denisovans

Diverse Middle Pleistocene forms of Homo coexisted in Africa, Europe, and Asia, and its controversial whether these fossil humans represent different species or clades. The [~]1 Ma old Yunxian 2 fossil from China is crucial for understanding the cladogenesis of Homo and the origin of Homo sapiens. Here, we restored and reconstructed the distorted Yunxian 2 cranium using new technology. The results show that this cranium displays mosaic features of plesiomorphy and apomorphy. Geometric-morphometric, phylogenetic and Bayesian tip-dating analyses including the reconstructed Yunxian 2 suggest that it is an early member of the Asian Homo longi clade, which probably includes the Denisovans, and is the sister group to the Homo sapiens clade. Both the H. sapiens and H. longi clades had deep roots extending beyond the Middle Pleistocene, and the basal position of the Yunxian fossil cranium suggests that it represents a population lying close to the last common ancestor of the two clades. One-Sentence SummaryThe newly-reconstructed Yunxian 2 cranium represents a basal member of the Homo longi and Denisovan clade, and probably lies close to the last common ancestor of that clade and the clade of H. sapiens.

evolutionary biology↗

bioRxiv2024

Structural insights into transcription regulation of the global virulence factor PhoP from Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), remaining as the leading cause of the worldwide threat Tuberculosis, relies heavily on its transcriptional reprogramming of diverse stress genes to swiftly adapt to adverse environments and ensure infections. The global virulence factor PhoP plays a pivotal role in coordinating transcription activation or repression of the essential phosphate-nitrogen metabolic remodeling genes. However, what defines PhoP to deferentially act as an activator or a repressor remains largely unexplored. Here, we determine one cryo-EM structure of Mtb RNAP-promoter open complex, three cryo-EM structures of PhoP-dependent transcription activation complexes (PhoP-TACs) consisting of Mtb RNA polymerase (RNAP), different number of PhoP molecules binding to different types of well-characterized consensus promoters, and one cryo-EM structure of Mtb PhoP-dependent transcription repression complex (PhoP-TRC) comprising of Mtb RNAP, PhoP, the nitrogen metabolism regulator GlnR and their co-regulated promoter. Structural comparisons reveal phosphorylation of PhoP is required for stabilization of PhoP-TACs, PhoP specifically recognizes promoters as novel tandem dimers and recruits RNAP through extensively interacting with its conserved {beta} flap and {sigma}AR4 domains. Strikingly, the distinct promoter spacer length and PhoP-GlnR interactions in PhoP-TRC constrain the upstream DNA into a distinct topology and retain PhoP in a novel dragging repression mode. Collectively, these data highlight the dual regulatory mechanisms of PhoP-dependent transcription regulation in governing stress adaptation. These findings provide structural basis for developing potential anti-tuberculosis drugs and/or interventions.

microbiology↗

bioRxiv2024

Regional Glymphatic Dysfunction is linked to Spinocerebellar Ataxia Type 3 pathophysiology

Spinocerebellar ataxia type 3 (SCA3) involves neuroinflammation and imbalance between production and clearance of proteins which affects the glymphatic system, the lymphatic-like, fluid-transport system in the brain. However, it is unclear whether SCA3 is related to impairments in glymphatic function. Using multimodal imaging data, 34 SCA3 patients and 36 age-, sex- and educational matched healthy controls (HCs) were compared using multiple glymphatic measurements, including choroid plexus (CP) and cerebrospinal fluid (CSF) volume, diffusion tensor imaging along the perivascular (DTI-ALPS) index, and coupling relationship between blood-oxygen-level-dependent signals and CSF flow (BOLD-CSF coupling). Then, we evaluated regional glymphatic function by dividing DTI-ALPS and BOLD-CSF coupling into anterior, middle, posterior, and cerebellum regions, thereby identifying the spatial variation of glymphatic function in the two groups. We demonstrated that compared with HCs, larger CP and CSF volumes were found in SCA3 patients. More importantly, for DTI-ALPS index and BOLD-CSF coupling, these surrogate markers for glymphatic clearance were weaker in SCA3 patients. Furthermore, altered regional glymphatic functions were most prominent in midbrain, cerebellum and middle regions. Crucially, the altered midbrain, cerebellum, middle and global glymphatic functions were accompanied by the severity of ataxia and other SCA3 symptoms. Similar to other neurodegenerative disorders, the association between multiple glymphatic indexes and SCA3 symptoms suggested that waste clearance is disrupted in SCA3 patients, which shed light on the pathogenesis of this disease from a glymphatic lens. Our findings highlighted the dysregulated glymphatic function as a novel diagnostic marker for SCA3.

neuroscience↗

bioRxiv2024

SHOOTMERISTEMLESS autoactivation: A prerequisite for fruit metamorphosis

In animals and plants, organ shape is primarily determined during primordium development by carefully coordinated growth and cell division1-3. Rare examples of post-primordial change in morphology (reshaping) exist that offer tractable systems to study mechanisms required for organ-shape determination and diversification. One such example is the heart-shape formation of Capsella fruits that occurs by reshaping the ovate spheroid gynoecium upon fertilization4. Here we use whole-organ live-imaging to show that dynamic changes in growth and cell division coupled with local maintenance of meristematic identity drives Capsella fruit-shape formation. At the molecular level, we reveal an auxin-induced mechanism ultimately descending on a single cis regulatory element to mediate morphological alteration. This element resides in the promoter of the Capsella rubella SHOOTMERISTEMLESS5 (CrSTM) gene. The CrSTM meristem identity factor positively regulates its own expression through binding to this element thereby providing a feed-forward loop at the position and time when protrusions emerge to form the heart. Independent evolution of the STM-binding element in STM promoters across Brassicaceae species correlates with those undergoing a gynoecium-to-fruit metamorphosis. Accordingly, genetic and phenotypic studies showed that the STM-binding element is required to facilitate the shape transition and reveals a conserved molecular mechanism for organ morphogenesis.

plant biology↗

bioRxiv2024

Tmc7 deficiency causes acrosome biogenesis defects and male infertility in mice

Transmembrane channel-like (TMC) proteins are a highly conserved ion channel family consisting of eight members (TMC1-TMC8) in mammals. TMC1/2 are components of the mechanotransduction channel in hair cells, and mutations of TMC1/2 cause deafness in humans and mice. However, the physiological roles of other TMC proteins remain largely unknown. Here, we show that Tmc7 is specifically expressed in the testis and that it is required for acrosome biogenesis during spermatogenesis. Tmc7-/- mice exhibited abnormal sperm head, disorganized mitochondrial sheaths, and reduced number of elongating spermatids, similar to human oligo-astheno-teratozoospermia. We further demonstrate that TMC7 is colocalized with GM130 at the cis-Golgi region in round spermatids. TMC7 deficiency leads to aberrant Golgi morphology and impaired fusion of Golgi-derived vesicles to the developing acrosome. Moreover, upon loss of TMC7 intracellular ion homeostasis is impaired and ROS levels are increased, which in turn causes Golgi and endoplasmic reticulum (ER) stress. Taken together, these results suggest that TMC7 is required to maintain pH and ion homeostasis, which is needed for acrosome biogenesis. Our findings unveil a novel role for TMC7 in acrosome biogenesis during spermiogenesis.

developmental biology↗

bioRxiv2023

Camel milk affects serum metabolites by modulating the intestinal microflora

Gut microbes play a vital role in human health and are influenced by numerous factors including diet, genetics, and environment. (Fermented) Camel milk, which is abundant in nutrients and lacks allergenic proteins, has been consumed for its edible and medicinal properties for centuries. Research on camel milks impact on gut microbiota and host metabolism is still limited. The results found that sour camel milk contained various beneficial bacteria such as Lactobacillus helveticus, Acinetobacter lwoffii, Eubacterium coprostanoligenes group, Lachnospiraceae, which could be transported to the recipients intestines by diet. This study specified that the transportation of microbiome happened both intra- and inter-species and played a principal role in the formation of progeny gut microflora. An investigation on type 2 diabetic rats revealed that the composition of gut microflora and serum metabolites of those fed with high-dose camel whey was closer to that of the normal. Eubacterium limnetica, which can reduce the risk of diseases by producing MtcB protein, was found in the gut microflora of the ones taking camel milk. These results evidenced the high potential of camel milk as a functional food.

microbiology↗

bioRxiv2023

Cardiac afferent signals can facilitate visual dominance in binocular rivalry

Sensory signals from the bodys visceral organs (e.g. the heart) can robustly influence the perception of exteroceptive sensations. This interoceptive-exteroceptive interaction has been argued to underlie self-awareness by situating ones perceptual awareness of exteroceptive stimuli in the context of ones internal state, but studies probing cardiac influences on visual awareness have yielded conflicting findings. In this study, we presented separate grating stimuli to each of subjects eyes as in a classic binocular rivalry paradigm - measuring the duration for which each stimulus dominates in perception. However, we caused the gratings to "pulse" at specific times relative to subjects real-time electrocardiogram, manipulating whether pulses occurred during cardiac systole, when baroreceptors signal to the brain that the heart has contracted, or in diastole when baroreceptors are silent. The influential "Baroreceptor Hypothesis" predicts the effect of baroreceptive input on visual perception should be uniformly suppressive. In contrast, we observed that dominance durations increased for systole-entrained stimuli, inconsistent with the Baroreceptor Hypothesis. Further, we show that this cardiac-dependent rivalry effect is preserved in subjects who are at-chance discriminating between systole-entrained and diastole-presented stimuli in a separate interoceptive awareness task, suggesting that our results are not dependent on conscious access to heartbeat sensations.

neuroscience↗

bioRxiv2023

Cognitive and neural mechanisms underlying sequential risk-taking behaviors among individuals with internet gaming disorder

Internet gaming disorder (IGD) raises questions on how feedback from the previous gaming round affects the risk-taking behavior in the subsequent round. Forty-two participants underwent a sequential risk-taking task, which was measured be behavioral modeling. Concurrent electroencephalogram and functional near-infrared spectroscopy (EEG-fNIRS) recordings were performed to demonstrate when, where and how the previous-round feedback affects the decision making to the next round. We discovered that the IGD illustrated heightened risk-taking propensity as compared to the HCs, indicating by the computational modeling (p = 0.028). EEG results also showed significant time window differences in univariate and multivariate pattern analysis between the IGD and HCs after the loss of the game. Further, reduced brain activation in the prefrontal cortex during the task was detected in IGD as compared to that of the control group. Risky decision-making in IGD might be due to the complex interplay between emotional response and other cognitive factors.

neuroscience↗

bioRxiv2023

Patient-derived tumor organoids from resected non-small cell lung cancers for high-throughput response testing with approved and repurposed drugs

BackgroundThe five-year survival for non-metastatic non-small cell lung cancer (NSCLC) patients undergoing curative surgery remains poor at [~]50% that is due to locoregional and/or distant metastatic recurrences. Patient-derived tumor organoids (PDTOs) have high potential as clinically relevant high-throughput drug testing platforms to personalize and improve treatment of NSCLC patients. We aimed to develop PDTOs from non-metastatic NSCLC patients to assess their suitability to study tumor heterogeneities and personalized drug responses. MethodsTen non-metastatic (stage I-IIIA) NSCLC patients undergoing curative surgical resection were prospectively enrolled. PDTOs were established from resected lung tumor tissues and were compared with matched primary tumors by histopathology, immunohistochemistry, whole exome and whole transcriptome sequencing analysis. PDTO responses to standard of care carboplatin/paclitaxel chemotherapy were determined by measuring organoid growth using bright-field 3D imaging. Transcriptomic differential gene expression analysis identified molecular targets for drug repurposing to overcome chemoresistance. ResultsNSCLC PDTOs were successfully generated from all 10 (100%) primary tumors with a median time of 12 days (range 4-16 days). All 10 PDTOs could be grown from cryopreserved tumor tissues or reconstituted from frozen PDTOs (living biobank). PDTOs retained histopathological, immunohistochemical protein expression and mutational landscape of the matched primary tumors. Microenvironment cell population analysis revealed epithelial cell signatures of the PDTOs that matched the patients lung tumor tissues. Treatment responses of PDTOs to carboplatin/paclitaxel were determined by growth differences versus vehicle control group. 5/10 (50%) PDTOs were chemo-sensitive, whereas 5/10 (50%) were chemo-resistant. Upregulation of aldo-keto reductases (AKR1B10/15) was observed in chemoresistant PDTOs by differential gene expression analysis and confirmed by real-time PCR and immunohistochemistry in PDTOs and tumor tissues. Epalrestat, an anti-diabetic AKR1B10 inhibitory drug, was repurposed to effectively sensitize PDTOs to carboplatin/paclitaxel. ConclusionsPDTOs can be established from resected NSCLC primary tumor tissues with high success rates and conserve cellular, molecular and genomic characteristics of the matched NSCLC tumors. PDTOs can serve as clinically applicable and relevant personalized drug screening platforms to evaluate the therapeutic efficacy of drugs, including repurposed drugs, to overcome chemoresistance.

cancer biology↗