Search

Tumor microenvironment (TME) is closely associated with the progression and prognosis of head and neck squamous cell carcinoma (HNSCC). To investigate potential biomarkers for predicting therapeutic outcomes in HNSCC, we analyzed the immune and stromal status of HNSCC based on the genes associated with TME using the ESTIMATE algorithm. Immune and stromal genes were identified with differential gene expression and weighted gene co-expression network analysis (WGCNA). From these genes, 118 were initially selected through Cox univariate regression and then further input into least absolute shrinkage and selection operator (LASSO) regression analysis. As a result, 11 genes were screened out for the TME-related risk (TMErisk) score model which presented promising overall survival predictive potential. The TMErisk score was negatively associated with immune and stromal scores but positively associated with tumor purity. Individuals with high TMErisk scores exhibited decreased expression of most immune checkpoints and all human leukocyte antigen family genes, and reduced abundance of infiltrating immune cells. Divergent genes were mutated in HNSCC. In both high and low TMErisk score groups, the tumor protein P53 exhibited the highest mutation frequency. A higher TMErisk score was found to be associated with reduced overall survival probability and worse outcomes of immunotherapy. Therefore, the TMErisk score could serve as a valuable model for the outcome prediction of HNSCC in clinic.

Summary: We previously reported that loss of function of TYW1 led to cerebral palsy with severe intellectual disability through reduced neural proliferation. However, whether TYW1 loss affects neural differentiation is unknown. In this study, we first demonstrated that TYW1 loss blocked the formation of OHyW in tRNAphe and therefore affected the translation efficiency of UUU codon. Using the brain organoid model, we showed impaired neuron differentiation when TYW1 was depleted. Interestingly, retrotransposons were differentially regulated in TYW1−/− hESCs (human embryonic stem cells). In particular, one kind of human-specific endogenous retrovirus-K (HERVK/HML2), whose reactivation impaired human neurodevelopment, was significantly up-regulated in TYW1−/− hESCs. Consistently, a UUU codon-enriched protein, SMARCAD1, which was a key factor in controlling endogenous retroviruses, was reduced. Taken together, TYW1 loss leads to up-regulation of HERVK in hESCs by down-regulated SMARCAD1, thus impairing neuron differentiation.

Abstract Background Changes in gene expression levels during brain development are thought to have played an important role in the evolution of human cognition. With the advent of high-throughput sequencing technologies, changes in brain developmental expression patterns, as well as human-specific brain gene expression, have been characterized. However, interpreting the origin of evolutionarily advanced cognition in human brains requires a deeper understanding of the regulation of gene expression, including the epigenomic context, along the primate genome. Here, we used chromatin immunoprecipitation sequencing (ChIP-seq) to measure the genome-wide profiles of histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac), both of which are associated with transcriptional activation in the prefrontal cortex of humans, chimpanzees, and rhesus macaques. Results We found a discrete functional association, in which H3K4me3HP gain was significantly associated with myelination assembly and signaling transmission, while H3K4me3HP loss played a vital role in synaptic activity. Moreover, H3K27acHP gain was enriched in interneuron and oligodendrocyte markers, and H3K27acHP loss was enriched in CA1 pyramidal neuron markers. Using strand-specific RNA sequencing (ssRNA-seq), we first demonstrated that approximately 7 and 2% of human-specific expressed genes were epigenetically marked by H3K4me3HP and H3K27acHP, respectively, providing robust support for causal involvement of histones in gene expression. We also revealed the co-activation role of epigenetic modification and transcription factors in human-specific transcriptome evolution. Mechanistically, histone-modifying enzymes at least partially contribute to an epigenetic disturbance among primates, especially for the H3K27ac epigenomic marker. In line with this, peaks enriched in the macaque lineage were found to be driven by upregulated acetyl enzymes. Conclusions Our results comprehensively elucidated a causal species-specific gene-histone-enzyme landscape in the prefrontal cortex and highlighted the regulatory interaction that drove transcriptional activation.

IntroductionAdenoid hypertrophy (AH) is a common upper respiratory disorder in children. Disturbances of gut microbiota have been implicated in AH. However, the interplay of alteration of gut microbiome and enlarged adenoids remains elusive.Methods119 AH children and 100 healthy controls were recruited, and microbiome profiling of fecal samples in participants was performed using 16S rRNA gene sequencing. Fecal microbiome transplantation (FMT) was conducted to verify the effects of gut microbiota on immune response in mice.ResultsIn AH individuals, only a slight decrease of diversity in bacterial community was found, while significant changes of microbial composition were observed between these two groups. Compared with HCs, decreased abundances of Akkermansia, Oscillospiraceae and Eubacterium coprostanoligenes genera and increased abundances of Bacteroides, Faecalibacterium, Ruminococcus gnavus genera were revealed in AH patients. The abundance of Bacteroides remained stable with age in AH children. Notably, a microbial marker panel of 8 OTUs were identified, which discriminated AH from HC individuals with an area under the curve (AUC) of 0.9851 in the discovery set, and verified in the geographically different validation set, achieving an AUC of 0.9782. Furthermore, transfer of mice with fecal microbiota from AH patients dramatically reduced the proportion of Treg subsets within peripheral blood and nasal-associated lymphoid tissue (NALT) and promoted the expansion of Th2 cells in NALT.ConclusionThese findings highlight the effect of the altered gut microbiota in the AH pathogenesis.

In the realm of online social networks, the spreading of information is influenced by a complex interplay of factors. To explore the dynamics of one-time retweet information spreading, we propose a Susceptible–Infected–Completed (SIC) multi-information spreading model. This model captures how multiple pieces of information interact in online social networks by introducing inhibiting and enhancement factors. The SIC model considers the completed state, where nodes cease to spread a particular piece of information after transmitting it. It also takes into account the impact of past and present information received from neighboring nodes, dynamically calculating the probability of nodes spreading each piece of information at any given moment. To analyze the dynamics of multiple information pieces in various scenarios, such as mutual enhancement, partial competition, complete competition, and coexistence of competition and enhancement, we conduct experiments on BA scale-free networks and the Twitter network. Our findings reveal that competing information decreases the likelihood of its spread while cooperating information amplifies the spreading of mutually beneficial content. Furthermore, the strength of the enhancement factor between different information pieces determines their spread when competition and cooperation coexist. These insights offer a fresh perspective for understanding the patterns of information propagation in multiple contexts.

To assess the medium-term performance of porous asphalt pavement during service and its influence on tire/pavement noise level, a seven-year continuous observation and data analysis study was conducted. Key performance indicators were measured and calculated by using automated pavement technology testing equipment. The noise levels were tested by using the on-board sound intensity (OBSI) method on three types of porous asphalt pavements (PUC-10, PAC-13, and PUC-10 + PAC-13) and one dense thin layer course (DTC) for comparison. The findings indicated that the Damage Rate (DR) and Surface Friction Coefficient (SFC) of porous asphalt pavements diminished greatly over time, while the International Roughness Index (IRI) and Rut Depth (RD) remained relatively stable. The two-layer porous asphalt pavement showed the largest noise reduction over the medium-term. Compared to DTC, the OBSI noise levels of these structures were lower by 2.09 dB, 1.53 dB, and 2.88 dB, respectively. The OBSI was found to be closely correlated with the SFC, IRI, test speed, lane, and pavement type. The RD had a notable effect on the OBSI in PUC-10 pavements. In PUC-10 + PAC-13 pavements, a significant linear relationship was observed between the OBSI and SFC. This is mainly because of the polishing of the coarse aggregates, which leads to micro-texture reduction, high frequency noise increase, and SFC decrease. This study makes a valuable contribution to understanding the laws of porous asphalt pavement performance changes and the relationship between tire/pavement noise and pavement characteristics.

The recurrence of bacterial infectious diseases is closely associated with bacterial persisters. This subpopulation of bacteria can escape antibiotic treatment by entering a metabolic status of low activity through various mechanisms, for example, biofilm, toxin–antitoxin modules, the stringent response, and the SOS response. Correspondingly, multiple new treatments are being developed. However, due to their spontaneous low abundance in populations and the lack of research on in vivo interactions between persisters and the host’s immune system, microfluidics, high-throughput sequencing, and microscopy techniques are combined innovatively to explore the mechanisms of persister formation and maintenance at the single-cell level. Here, we outline the main mechanisms of persister formation, and describe the cutting-edge technology for further research. Despite the significant progress regarding study techniques, some challenges remain to be tackled.

Immune cell changes are associated with Kawasaki disease (KD) pathogenesis. Here, using single cell RNA sequencing of PBMC, the authors show monocyte inflammatory genes are over-expressed in KD and TCR and BCR clonotype sequences show oligoclonal expansions after intravenous immunoglobulin therapy.

Networks of identical coupled oscillators display a remarkable spatiotemporal pattern, the chimera state, where coherent oscillations coexist with incoherent ones. In this paper we show quantitatively in terms of basin stability that stable and breathing chimera states in the original two coupled networks typically have very small basins of attraction. In fact, the original system is dominated by periodic and quasi-periodic chimera states, in strong contrast to the model after reduction, which can not be uncovered by the Ott-Antonsen ansatz. Moreover, we demonstrate that the curve of the basin stability behaves bimodally after the system being subjected to even large perturbations. Finally, we investigate the emergence of chimera states in brain network, through inducing perturbations by stimulating brain regions. The emerged chimera states are quantified by Kuramoto order parameter and chimera index, and results show a weak and negative correlation between these two metrics.

ObjectivesAlthough hypervirulent Klebsiella pneumoniae (hvKp) is an increasing public health problem, there remains limited epidemiological information regarding hvKp infections in children. Here, we conducted a clinical, molecular and phenotypic surveillance of hvKp strains in a pediatric population.MethodsNon-repetitive K. pneumoniae (Kp) strains consecutively collected during 2019-2020 were screened for hypervirulence genes (prmpA, prmpA2, iucA, iroB, and peg344) using PCR. Positive strains were further characterized by four phenotypic assays (string test, serum killing assay, siderophore production, Galleria mellonella lethality assay), followed by murine sepsis model to determine virulence in vitro and in vivo. Also, capsular types, sequence types, plasmid replicon types, antimicrobial resistance determinants and susceptibility were analyzed.ResultsA total of 352 isolates were collected, wherein 83 (23.6%) were hypervirulence genes-positive Kp (hgKp). A significant increase in KPC-2-producing KL47-ST11 among hgKp strains was observed, from 5.3% (1/19) in 2019 to 67.6% (25/37) in 2020 (P

Convective transport of drug solutes in biological tissues is regulated by the interstitial fluid pressure, which plays a crucial role in drug absorption into the lymphatic system through the subcutaneous (SC) injection. In this paper, an approximate continuum poroelasticity model is developed to simulate the pressure evolution in the soft porous tissue during an SC injection. This poroelastic model mimics the deformation of the tissue by introducing the time variation of the interstitial fluid pressure. The advantage of this method lies in its computational time efficiency and simplicity, and it can accurately model the relaxation of pressure. The interstitial fluid pressure obtained using the proposed model is validated against both the analytical and the numerical solution of the poroelastic tissue model. The decreasing elasticity elongates the relaxation time of pressure, and the sensitivity of pressure relaxation to elasticity decreases with the hydraulic permeability, while the increasing porosity and permeability due to deformation alleviate the high pressure. An improved Kedem–Katchalsky model is developed to study solute transport across the lymphatic vessel network, including convection and diffusion in the multi-layered poroelastic tissue with a hybrid discrete-continuum vessel network embedded inside. At last, the effect of different structures of the lymphatic vessel network, such as fractal trees and Voronoi structure, on the lymphatic uptake is investigated. In this paper, we provide a novel and time-efficient computational model for solute transport across the lymphatic vasculature connecting the microscopic properties of the lymphatic vessel membrane to the macroscopic drug absorption.

Droplet digital PCR (ddPCR) recently has been shown to be a potential diagnostic tool for adults with bloodstream infections (BSIs); however, its application in children remains obscure. In this study, 76 blood samples of children with suspected BSIs were synchronously detected by traditional blood cultures (BCs) and ddPCRs. Our team validated the diagnostic performance of ddPCR including sensitivity, specificity, and positive and negative predictive values. The 76 pediatric patients from the hematology department (67.1%), the pediatric intensive care unit (PICU, 27.6%), and other departments (5.2%) were enrolled. The positive rate of ddPCR results was 47.9%, whereas that for BC was 6.6%. In addition, the time consumption of ddPCR was shorter, only for 4.7 ± 0.9 h, in comparison with the detection timing of BC (76.7 ± 10.4 h, p < 0.01). The levels of agreement and disagreement between BC and ddPCR were 96.1% and 4.2%, and the negative agreement reached 95.6%. The sensitivity of ddPCR was 100%, with corresponding specificities ranging from 95.3 to 100.0%. In addition, a total of nine viruses were identified by ddPCR. In China, the multiplexed ddPCR first could be a tool for the rapid and accurate diagnosis of children with suspected BSIs and can be an early indicator of the possibility of viraemia in children with immunosuppression.

Abstract Background Analysis of lymphocyte cell lines revealed substantial differences in the expression of mRNA and microRNA (miRNA) among human populations. The extent of such population-associated differences in actual human tissues remains largely unexplored. The placenta is one of the few solid human tissues that can be collected in substantial numbers in a controlled manner, enabling quantitative analysis of transient biomolecules such as RNA transcripts. Here, we analyzed microRNA (miRNA) expression in human placental samples derived from 36 individuals representing four genetically distinct human populations: African Americans, European Americans, South Asians, and East Asians. All samples were collected at the same hospital following a unified protocol, thus minimizing potential biases that might influence the results. Results Sequence analysis of the miRNA fraction yielded 938 annotated and 70 novel miRNA transcripts expressed in the placenta. Of them, 82 (9%) of annotated and 11 (16%) of novel miRNAs displayed quantitative expression differences among populations, generally reflecting reported genetic and mRNA-expression-based distances. Several co-expressed miRNA clusters stood out from the rest of the population-associated differences in terms of miRNA evolutionary age, tissue-specificity, and disease-association characteristics. Among three non-environmental influenced demographic parameters, the second largest contributor to miRNA expression variation after population was the sex of the newborn, with 32 miRNAs (3% of detected) exhibiting significant expression differences depending on whether the newborn was male or female. Male-associated miRNAs were evolutionarily younger and correlated inversely with the expression of target mRNA involved in neuron-related functions. In contrast, both male and female-associated miRNAs appeared to mediate different types of hormonal responses. Demographic factors further affected reported imprinted expression of 66 placental miRNAs: the imprinting strength correlated with the mother’s weight, but not height. Conclusions Our results showed that among 12 assessed demographic variables, population affiliation and fetal sex had a substantial influence on miRNA expression variation among human placental samples. The effect of newborn-sex-associated miRNA differences further led to expression inhibition of the target genes clustering in specific functional pathways. By contrast, population-driven miRNA differences might mainly represent neutral changes with minimal functional impacts.

The increasing urban traffic problems have made the transportation system require a large amount of data. Aiming at the current problems of data types redundancy and low coordination rate of intelligent transportation systems (ITS), this paper proposes an improved digital twin architecture applicable to ITS. Based on the improved digital twin architecture, a framework for dynamic and static data collaboration in ITS is constructed. For various collaboration methods, this paper specifically describes the collaboration methods and scopes, and designs the framework and interfaces for data mapping. Finally, the effectiveness of the framework is verified by case studies to mine the spatiotemporal distribution characteristics of data, capture human travel characteristics, and visualize intersections using digital twins. This paper provides a new data fusion idea for digital twin systems in ITS, and the framework covers all data types in digital twin systems for cross-integration analysis.

ABSTRACT We report here a hypermucoviscous, New Delhi metallo-β-lactamase 1 (NDM-1) and imipenemase 4 (IMP-4) carbapenemases-coproducing Klebsiella variicola isolate obtained from a pediatric patient. This strain was resistant to carbapenems and most other β-lactams. Although hypermucoviscous, this strain possessed attenuated virulence according to serum killing assay and Galleria mellonella infection model. Notably, two copies of blaNDM-1 were contained on two tandem ISCR1 elements and coexisted with blaIMP-4 in a novel hybrid multidrug resistance plasmid. This is the first description of the coexistence of blaNDM-1 and blaIMP-4 in a single plasmid of hypermucoviscous K. variicola. IMPORTANCE As an important member of the Klebsiella pneumoniae complex, Klebsiella variicola is poorly studied as an emerging human pathogen. We, for the first time, report a unique K. variicola isolated from a pediatric patient in China. This isolate exhibited hypermucoviscosity, a classic hypervirulence characteristic of K. pneumoniae, and contained multiple carbapenem-resistant genes, including blaIMP-1 and blaNDM-1. Interestingly, these antimicrobial resistance genes were located on a novel hybrid plasmid, and our results suggested that this plasmid might have been introduced from K. pneumoniae and undergone a series of integration and recombination evolutionary events. Overall, our study provides more insight into K. variicola and highlights its superior capability to acquire and maintain foreign resistance genes.

Developmental trajectories of gene expression may reverse in their direction during ageing, a phenomenon previously linked to cellular identity loss. Our analysis of cerebral cortex, lung, liver, and muscle transcriptomes of 16 mice, covering development and ageing intervals, revealed widespread but tissue-specific ageing-associated expression reversals. Cumulatively, these reversals create a unique phenomenon: mammalian tissue transcriptomes diverge from each other during postnatal development, but during ageing, they tend to converge towards similar expression levels, a process we term Divergence followed by Convergence (DiCo). We found that DiCo was most prevalent among tissue-specific genes and associated with loss of tissue identity, which is confirmed using data from independent mouse and human datasets. Further, using publicly available single-cell transcriptome data, we showed that DiCo could be driven both by alterations in tissue cell-type composition and also by cell-autonomous expression changes within particular cell types.

Summary: N6-methyladenosine (m6A) is emerging as a vital factor regulating neural differentiation. Here, we report that deficiency of Arhgef2, a novel cause of a neurodevelopmental disorder we identified recently, impairs neurogenesis, neurite outgrowth, and synaptic formation by regulating m6A methylation. Arhgef2 knockout decreases expression of Mettl14 and total m6A level significantly in the cerebral cortex. m6A sequencing reveals that loss of Arhgef2 reduces m6A methylation of 1,622 mRNAs, including Npdc1 and Cend1, which are both strongly associated with cell cycle exit and terminal neural differentiation. Arhgef2 deficiency decreases m6A methylations of the Npdc1 and Cend1 mRNAs via down-regulation of Mettl14, and thereby inhibits the translation of Npdc1 and nuclear export of Cend1 mRNAs. Overexpression of Mettl14, Npdc1, and Cend1 rescue the abnormal phenotypes in Arhgef2 knockout mice, respectively. Our study provides a critical insight into a mechanism by which defective Arhgef2 mediates m6A-tagged target mRNAs to impair neural differentiation.

Tumor angiogenesis is one of the hallmarks of cancer as well as an attractive target for cancer therapy. Characterization of novel pathways that act in parallel with the VEGF/VEGFR axis to promote tumor angiogenesis may provide insights into novel anti‐angiogenic therapeutic targets. We found that the expression level of Nogo‐B is positively correlated with tumor vessel density in hepatocellular carcinoma (HCC). While Nogo‐B depletion inhibited tumor angiogenesis, Nogo‐B overexpression promoted tumor angiogenesis in a tumor xenograft subcutaneous model of the human HCC cell line. Mechanically, Nogo‐B regulates tumor angiogenesis based on its association with integrin αvβ3 and activation of focal adhesion kinase. Moreover, Nogo‐B antibody successfully abolished the function of Nogo‐B in tumor angiogenesis in vitro and in vivo. Collectively, our results strongly suggest that Nogo‐B is an important tumor angiogenic factor and blocking Nogo‐B selectively inhibits tumor angiogenesis.

The models of time-varying network have a profound impact on the study of virus spreading on the networks. On the basis of an activity-driven memory evolution model, a time-varying spatial memory model (TSM) is proposed. In the TSM model, the cumulative number of connections between nodes is recorded, and the spatiality of nodes is considered at the same time. Therefore, the active nodes tend to connect the nodes with high intimacy and close proximity. Then, the TSM model is applied to epidemic spreading, and the epidemic spreading on different models is compared. To verify the universality of the TSM model, this model is also applied to rumor spreading, and it is proved that it can also play a good inhibiting effect. We find that, in the TSM network, the introduction of spatiality and memory can slow down the propagation speed and narrow the propagation scope of disease or rumor, and memory is more important. We then explore the impact of different prevention and control methods on pandemic spreading to provide reference for COVID-19 management control and find when the activity of node is restricted, the spreading will be controlled. As floating population has been acknowledged as a key parameter that affects the situation of COVID-19 after work resumption, the factor of population mobility is introduced to calculate the interregional population interaction rate, and the time-varying interregional epidemic model is established. Finally, our results of infectious disease parameters based on daily cases are in good agreement with the real data, and the effectiveness of different control measures is evaluated.

We generated an induced human pluripotent stem cell line from a child with microcephaly carrying compound heterozygous mutations of TYW1 inherited from healthy parents. This iPS cell line showed typical embryonic stem cell-like morphology, expressed pluripotent markers that comparable to human embryonic stem cells. Moreover, these cells have the ability to differentiate into three germ layers and maintain a normal karyotype.

Cognitive defects in autism spectrum disorder (ASD) include socialization and communication: key behavioral capacities that separate humans from other species. Here, we analyze gene expression in the prefrontal cortex of 63 autism patients and control individuals, as well as 62 chimpanzees and macaques, from natal to adult age. We show that among all aberrant expression changes seen in ASD brains, a single aberrant expression pattern overrepresented in genes involved synaptic-related pathways is enriched in nucleotide variants linked to autism. Furthermore, only this pattern contains an excess of developmental expression features unique to humans, thus resulting in the disruption of human-specific developmental programs in autism. Several members of the early growth response (EGR) transcription factor family can be implicated in regulation of this aberrant developmental change. Our study draws a connection between the genetic risk architecture of autism and molecular features of cortical development unique to humans.

Hypoxia has been reported to cause the significant enhancement of hemoglobin (Hb) and hematocrit (Hct), which stabilizes at relatively high levels after an individual ascends to a high altitude. However, the quality of the suspended red blood cells (SRBCs) obtained from individuals at high altitudes such as Tibetan plateau migrants after storage has not been studied. In this study, we compared the storage quality of SRBCs prepared from Tibetan plateau and Deyang lowland populations by adding a normal volume of mannitol-adenine-phosphate (MAP), which is a common additive solution used in blood storage in Asian countries. The storage cell characteristics were examined on days 1, 7, 14 and 35.We found higher Hct and Hb levels and viscosity in the high altitude samples. The metabolic rates, including those for electrolytes and lactate, were higher in plateau SRBCs than in lowland SRBCs; these findings were consistent with the higher osmotic fragility and hemolysis of plateau SRBCs throughout the entire storage period. In addition, the reduction rates of 2,3-diphosphoglycerate (2,3-DPG) and oxygen tension to attain 50% oxygen saturation of Hb (P50) in plateau SRBCs were higher than those in lowland SRBCs, and the oxygen delivering capacity in plateau SRBCs was weaker than that in lowland SRBCs. We concluded that the storage quality of plateau SRBCs was inferior to that of lowland SRBCs when using the same concentration of MAP. We suggested that the optimal formula, including the MAP concentration or even a new additive solution, to store the plateau SRBCs must be assessed and regulated.

RLIM acts as a negative regulator of LIM-Homeodomain proteins either by recruiting Sin3A/Histone Deacetylase (HDAC) co-repressor complex or through degradation of CLIM coactivator, thus playing an important role in embryonic development. Recent studies by different research groups have shown that RLIM acts as an X-encoded, dose-dependent inducer of X chromosome inactivation in mouse embryonic stem cells. However, until now, very little is known about the expression regulation of RLIM gene, and we tried to study the transcriptional regulation of RLIM gene. In the present study, we identified RLIM as a novel target of p53 and demonstrated that p53 repressed both mRNA and protein levels of RLIM. Expression of wild type p53, but not p53 mutants, led to repression of the RLIM promoter activity. We further identified four putative Sp1 elements (S1 to S4) on the RLIM promoter that are essential for p53-mediated repression of RLIM. Although p53 does not directly bind to the RLIM promoter, it physically interacts with and prevents the binding of Sp1 to the RLIM promoter. Thus, RLIM is a novel target of p53, and p53 exerts its inhibitory effect on RLIM expression by interfering with Sp1-mediated transcriptional activation on RLIM. Our results provided data to enlarge the knowledge of transcriptional regulation of RLIM and suggested a new pathway by which physiological and pathological activators of p53 may affect development.