YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner.

RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.

Refining 2SVCA Method for Measuring Telehealth Accessibility of Primary Care Physicians in Baton Rouge, Louisiana.

Equity in health care delivery is a longstanding concern of public health policy. Telehealth is considered an important way to level the playing field by broadening health services access and improving quality of care and health outcomes. This study refines the recently developed "2-Step Virtual Catchment Area (2SVCA) method" to assess the telehealth accessibility of primary care in the Baton Rouge Metropolitan Statistical Area, Louisiana. The result is compared to that of spatial accessibility via physical visits to care providers based on the popular 2-Step Floating Catchment Area (2SFCA) method. The study shows that both spatial and telehealth accessibilities decline from urban to low-density and then rural areas. Moreover, disproportionally higher percentages of African Americans are in areas with higher spatial accessibility scores; but such an advantage is not realized in telehealth accessibility. In the study area, absence of broadband availability is mainly a rural problem and leads to a lower average telehealth accessibility than physical accessibility in rural areas. On the other side, lack of broadband affordability is a challenge across the rural-urban continuum and is disproportionally associated with high concentrations of disadvantaged population groups such as households under the poverty level and Blacks.

Nosocomial outbreak of COVID-19 pneumonia in Wuhan, China.

BACKGROUND: The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infected over 3300 healthcare workers in early 2020 in China. Little information is known about nosocomial infections of healthcare workers in the initial period. We analysed data from healthcare workers with nosocomial infections in Wuhan Union Hospital (Wuhan, China) and their family members. METHODS: We collected and analysed data on exposure history, illness timelines and epidemiological characteristics from 25 healthcare workers with laboratory-confirmed coronavirus disease 2019 (COVID-19) and two healthcare workers in whom COVID-19 was highly suspected, as well as 10 of their family members with COVID-19, between 5 January and 12 February 2020. The demographics and clinical features of the 35 laboratory-confirmed cases were investigated and viral RNA of 12 cases was sequenced and analysed. RESULTS: Nine clusters were found among the patients. All patients showed mild to moderate clinical manifestation and recovered without deterioration. The mean period of incubation was 4.5 days, the mean±sd clinical onset serial interval (COSI) was 5.2±3.2 days, and the median virus shedding time was 18.5 days. Complete genomic sequences of 12 different coronavirus strains demonstrated that the viral structure, with small irrelevant mutations, was stable in the transmission chains and showed remarkable traits of infectious traceability. CONCLUSIONS: SARS-CoV-2 can be rapidly transmitted from person to person, regardless of whether they have symptoms, in both hospital settings and social activities, based on the short period of incubation and COSI. The public health service should take practical measures to curb the spread, including isolation of cases, tracing close contacts, and containment of severe epidemic areas. Besides this, healthcare workers should be alert during the epidemic and self-quarantine if self-suspected of infection.

Delimitating the Natural City with Points of Interests Based on Service Area and Maximum Entropy Method.

The natural city, which is essential to understand urban physical scale and identify urban sprawling in urban studies, represents the urban functional boundaries of the city defined by human activities rather than the administrative boundaries. Most studies tend to utilize physical environment data such as street networks and remote sensing data to delimitate the natural city, however, such data may not match the real distribution of human activity density in the new cities or even ghost cities in China. This paper suggests aggregating the natural city boundary from the service area polygons of points of interest based on Reilly's Law of Retail Gravitation and the maximum entropy method, since most points of interests provide services for surrounding communities, reflecting the vitality in a bottom-up way. The results indicate that the natural city defined by points of interests shows a high resolution and accuracy, providing a method to define the natural city with POIs.

Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner.

Exposure to total body irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term or residual bone marrow (BM) injury. This residual BM injury is mainly attributed to permanent damage to hematopoietic stem cells (HSCs), including impaired self-renewal, decreased long-term repopulating capacity, and myeloid skewing. These HSC defects were associated with significant increases in production of reactive oxygen species (ROS), expression of p16(Ink4a) (p16) and Arf mRNA, and senescence-associated ß-galacotosidase (SA-ß-gal) activity, but not with telomere shortening or increased apoptosis, suggesting that TBI induces residual BM injury via induction of HSC premature senescence. This suggestion is supported by the finding that SA-ß-gal(+) HSC-enriched LSK cells showed more pronounced defects in clonogenic activity in vitro and long-term engraftment after transplantation than SA-ß-gal(-) LSK cells isolated from irradiated mice. However, genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression and HSC senescence, because HSCs from irradiated p16 and/or Arf knockout (KO) mice exhibited changes similar to those seen in HSCs from wild-type mice after exposure to TBI. These findings provide important new insights into the mechanism by which TBI causes long-term BM suppression (eg, via induction of premature senescence of HSCs in a p16-Arf-independent manner).

Senescence Promotes the Recovery of Stemness among Cancer Cells via Reprograming.

Both the senescence of cancer cells and the maintenance of cancer stem cells seem to be mutually exclusive because senescence is considered a physiological mechanism that effectively suppresses tumor growth. Recent studies have revealed common signaling pathways between cellular senescence and the maintenance of stemness in cancer cells, thus challenging the conventional understanding of this process. Although the links between these processes have not yet been fully elucidated, emerging evidence indicates that senescent cancer cells can undergo reprograming to recover stemness. Herein, we provide a comprehensive overview of the close correlation between senescence and stemness reprograming in cancer cells, with a particular focus on the mechanisms by which senescent cancer cells recover their stemness in various tumor systems.

MIFAM-DTI: a drug-target interactions predicting model based on multi-source information fusion and attention mechanism.

Accurate identification of potential drug-target pairs is a crucial step in drug development and drug repositioning, which is characterized by the ability of the drug to bind to and modulate the activity of the target molecule, resulting in the desired therapeutic effect. As machine learning and deep learning technologies advance, an increasing number of models are being engaged for the prediction of drug-target interactions. However, there is still a great challenge to improve the accuracy and efficiency of predicting. In this study, we proposed a deep learning method called Multi-source Information Fusion and Attention Mechanism for Drug-Target Interaction (MIFAM-DTI) to predict drug-target interactions. Firstly, the physicochemical property feature vector and the Molecular ACCess System molecular fingerprint feature vector of a drug were extracted based on its SMILES sequence. The dipeptide composition feature vector and the Evolutionary Scale Modeling -1b feature vector of a target were constructed based on its amino acid sequence information. Secondly, the PCA method was employed to reduce the dimensionality of the four feature vectors, and the adjacency matrices were constructed by calculating the cosine similarity. Thirdly, the two feature vectors of each drug were concatenated and the two adjacency matrices were subjected to a logical OR operation. And then they were fed into a model composed of graph attention network and multi-head self-attention to obtain the final drug feature vectors. With the same method, the final target feature vectors were obtained. Finally, these final feature vectors were concatenated, which served as the input to a fully connected layer, resulting in the prediction output. MIFAM-DTI not only integrated multi-source information to capture the drug and target features more comprehensively, but also utilized the graph attention network and multi-head self-attention to autonomously learn attention weights and more comprehensively capture information in sequence data. Experimental results demonstrated that MIFAM-DTI outperformed state-of-the-art methods in terms of AUC and AUPR. Case study results of coenzymes involved in cellular energy metabolism also demonstrated the effectiveness and practicality of MIFAM-DTI. The source code and experimental data for MIFAM-DTI are available at https://github.com/Search-AB/MIFAM-DTI.

Electrochemical detection of nitrofurazone using laser-engraved three-electrode graphene array.

BACKGROUND: Nitrofurazone (NFZ) is a widely-used antimicrobial agent in aquaculture. The NFZ residue can be transmitted to humans through the food chain, and cause adverse health effects including carcinogenesis and teratogenesis. Until now, a number of modified electrodes have been developed for NFZ detection, however, there are some issues that need to be improved. For example, the reported detection sensitivity is relatively low, the modification procedure is complicated, and conventional three-electrode system is used. Therefore, it is quite important to develop new NFZ detection method with higher sensitivity, simplicity and practicality. RESULTS: Herein, a kind of integrated three-electrode array consisted with porous graphene is easily prepared through laser engraving of commercial polyimide tape. Five kinds of graphene arrays were prepared at different laser power percentage (i.e. 30 %, 40 %, 50 %, 60 % and 70 %). It is found that their structure, morphology, fluffiness and porosity show great difference, consequently affecting the electrochemical performance of graphene arrays such as conductivity, active area and electron transfer ability. The engraved graphene array at 50 % laser power percentage (LIG-50 array) is superior owing to uniform 3D structure, abundant pores and high stability. More importantly, LIG-50 array is more active for NFZ oxidation, and significantly enhances the detection sensitivity. The linear range of LIG-50 sensor is from 0.2 to 8 µM, and the detection limit is 0.035 µM, which is successfully used in fish meat samples. SIGNIFICANCE: A sensitive, portable and practical electrochemical sensor has been successfully developed for NFZ using laser-engraved graphene array. The demonstration using fish meat samples manifests this new sensor has good accuracy and great potential in application. This study could provide a new possibility for the design and fabrication of other high-performance electrochemical sensor for various applications in the future.

RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment.

The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.

Factors and Methods for the Detection of Gene Expression Regulation.

Gene-expression regulation involves multiple processes and a range of regulatory factors. In this review, we describe the key factors that regulate gene expression, including transcription factors (TFs), chromatin accessibility, histone modifications, DNA methylation, and RNA modifications. In addition, we also describe methods that can be used to detect these regulatory factors.

The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy of myeloid hematopoietic cells, which is characterized by the aberrant clonal proliferation of immature myeloblasts and compromised hematopoiesis. The leukemic cell population is strongly heterogeneous. Leukemic stem cells (LSCs) are an important leukemic cell subset with stemness characteristics and self-renewal ability, which contribute to the development of refractory or relapsed AML. It is now acknowledged that LSCs develop from hematopoietic stem cells (HSCs) or phenotypically directed cell populations with transcriptional stemness characteristics under selective pressure from the bone marrow (BM) niche. Exosomes are extracellular vesicles containing bioactive substances involved in intercellular communication and material exchange under steady state and pathological conditions. Several studies have reported that exosomes mediate molecular crosstalk between LSCs, leukemic blasts, and stromal cells in the BM niche, promoting LSC maintenance and AML progression. This review briefly describes the process of LSC transformation and the biogenesis of exosomes, highlighting the role of leukemic-cell- and BM-niche-derived exosomes in the maintenance of LSCs and AML progression. In addition, we discuss the potential application of exosomes in the clinic as biomarkers, therapeutic targets, and carriers for targeted drug delivery.

Disparities in spatial accessibility of primary care in Louisiana: From physical to virtual accessibility.

Telehealth has been widely employed and has transformed how healthcare is delivered in the United States as a result of COVID-19 pandemic. While telehealth is utilized and encouraged to reduce the cost and travel burden for access to healthcare, there are debates on whether telehealth can promote equity in healthcare services by narrowing the gap among diverse groups. Using the Two-Step Floating Catchment Area (2SFCA) and Two-Step Virtual Catchment Area (2SVCA) methods, this study compares the disparities of physical and virtual access to primary care physicians (PCPs) in Louisiana. Both physical and virtual access to PCPs exhibit similar spatial patterns with higher scores concentrated in urban areas, followed by low-density and rural areas. However, the two accessibility measures diverge where broadband availability and affordability come to play an important role. Residents in rural areas experience additive disadvantage of even more limited telehealth accessibility than physical accessibility due to lack of broadband service provision. Areas with greater Black population proportions tend to have better physical accessibility, but such an advantage is eradicated for telehealth accessibility because of lower broadband subscription rates in these neighborhoods. Both physical and virtual accessibility scores decline in neighborhoods with higher Area Deprivation Index (ADI) values, and the disparity is further widened for in virtual accessibility compared to than physical accessibility. The study also examines how factors such as urbanicity, Black population proportion, and ADI interact in their effects on disparities of the two accessibility measures.

Aerial Images Meet Crowdsourced Trajectories: A New Approach to Robust Road Extraction.

Land remote-sensing analysis is a crucial research in earth science. In this work, we focus on a challenging task of land analysis, i.e., automatic extraction of traffic roads from remote-sensing data, which has widespread applications in urban development and expansion estimation. Nevertheless, conventional methods either only utilized the limited information of aerial images, or simply fused multimodal information (e.g., vehicle trajectories), thus cannot well recognize unconstrained roads. To facilitate this problem, we introduce a novel neural network framework termed cross-modal message propagation network (CMMPNet), which fully benefits the complementary different modal data (i.e., aerial images and crowdsourced trajectories). Specifically, CMMPNet is composed of two deep autoencoders for modality-specific representation learning and a tailor-designed dual enhancement module for cross-modal representation refinement. In particular, the complementary information of each modality is comprehensively extracted and dynamically propagated to enhance the representation of another modality. Extensive experiments on three real-world benchmarks demonstrate the effectiveness of our CMMPNet for robust road extraction benefiting from blending different modal data, either using image and trajectory data or image and light detection and ranging (LiDAR) data. From the experimental results, we observe that the proposed approach outperforms current state-of-the-art methods by large margins. Our source code is resealed on the project page http://lingboliu.com/multimodal_road_extraction.html.

Online Metro Origin-Destination Prediction via Heterogeneous Information Aggregation.

Metro origin-destination prediction is a crucial yet challenging time-series analysis task in intelligent transportation systems, which aims to accurately forecast two specific types of cross-station ridership, i.e., Origin-Destination (OD) one and Destination-Origin (DO) one. However, complete OD matrices of previous time intervals can not be obtained immediately in online metro systems, and conventional methods only used limited information to forecast the future OD and DO ridership separately. In this work, we proposed a novel neural network module termed Heterogeneous Information Aggregation Machine (HIAM), which fully exploits heterogeneous information of historical data (e.g., incomplete OD matrices, unfinished order vectors, and DO matrices) to jointly learn the evolutionary patterns of OD and DO ridership. Specifically, an OD modeling branch estimates the potential destinations of unfinished orders explicitly to complement the information of incomplete OD matrices, while a DO modeling branch takes DO matrices as input to capture the spatial-temporal distribution of DO ridership. Moreover, a Dual Information Transformer is introduced to propagate the mutual information among OD features and DO features for modeling the OD-DO causality and correlation. Based on the proposed HIAM, we develop a unified Seq2Seq network to forecast the future OD and DO ridership simultaneously. Extensive experiments conducted on two large-scale benchmarks demonstrate the effectiveness of our method for online metro origin-destination prediction. Our code is resealed at https://github.com/HCPLab-SYSU/HIAM.

Development of Nafion/single-walled carbon nanotube integrated arrays for the rapid detection of salbutamol doping.

Salbutamol (SAL), a drug originally intended for the treatment of bronchial and pulmonary diseases, has repeatedly been used for doping in competitive sports. Herein, an integrated array (NFCNT array) that prepared by template-assisted scalable filtration using Nafion-coated single-walled carbon nanotube (SWCNT) is presented for the rapid field detection of SAL. Spectroscopic and microscopic measurements were used to confirm the introduction of Nafion onto the surface of the array and to analyze the resulting morphological changes. The effects of Nafion addition on the resistance and electrochemical properties of the arrays (e.g., the electrochemically active area, charge-transfer resistance, and adsorption charge) are also discussed in depth. With an electrolyte/Nafion/SWCNT interface and moderate resistance, the NFCNT-4 array prepared containing 0.04 wt% Nafion suspension exhibits the greatest voltammetric response to SAL. Subsequently, a possible mechanism for the oxidation of SAL was proposed, and a calibration curve in the range of 0.1-15 µM was established. Finally, the NFCNT-4 arrays were applied to the detection of SAL in human urine samples with satisfactory recoveries.

Road Network-Guided Fine-Grained Urban Traffic Flow Inference.

Accurate inference of fine-grained traffic flow from coarse-grained one is an emerging yet crucial problem, which can help greatly reduce the number of the required traffic monitoring sensors for cost savings. In this work, we note that traffic flow has a high correlation with road network, which was either completely ignored or simply treated as an external factor in previous works. To facilitate this problem, we propose a novel road-aware traffic flow magnifier (RATFM) that explicitly exploits the prior knowledge of road networks to fully learn the road-aware spatial distribution of fine-grained traffic flow. Specifically, a multidirectional 1-D convolutional layer is first introduced to extract the semantic feature of the road network. Subsequently, we incorporate the road network feature and coarse-grained flow feature to regularize the short-range spatial distribution modeling of road-relative traffic flow. Furthermore, we take the road network feature as a query to capture the long-range spatial distribution of traffic flow with a transformer architecture. Benefiting from the road-aware inference mechanism, our method can generate high-quality fine-grained traffic flow maps. Extensive experiments on three real-world datasets show that the proposed RATFM outperforms state-of-the-art models under various scenarios. Our code and datasets are released at https://github.com/luimoli/RATFM.

Engineered mesenchymal stem cell exosomes loaded with miR-34c-5p selectively promote eradication of acute myeloid leukemia stem cells.

Most patients with acute myeloid leukemia (AML) relapse eventually because of the inability to effectively eliminate leukemia stem cells (LSCs), prompting the search of new therapies to eradicate LSCs. Our previous study demonstrated that miR-34c-5p promotes the clearance of LSCs in an AML mouse model, highlighting its potential as a therapeutic target for eradicating LSCs, but the effective delivery of miR-34c-5p to LSCs remains a great challenge. Here, we employed simultaneous two-step modifications to engineer mesenchymal stem cells (MSCs) and MSC-derived exosomes to create exosomes overexpressing the fused protein lysosome-associated membrane protein 2-interleukin 3 (Lamp2b-IL3) and hematopoietic cell E-selectin/L-selectin ligand (HCELL), and demonstrated that the engineered exosomes exhibited an enhanced ability for bone marrow homing and selective targeting of LSCs. Additionally, using a humanized AML mouse model, we confirmed that the engineered exosomes, loaded with miR-34c-5p, could selectively promote eradication of LSCs and impede the AML development in vivo. In summary, we successfully designed an effective delivery system and provided new insights into the development of novel therapies for delivering miRNA or other molecules to LSCs with greater cellular targeting specificity.

Inhibition of p38 MAPK activity promotes ex vivo expansion of human cord blood hematopoietic stem cells.

Ex vivo expansion of hematopoietic stem cells (HSCs) depends on HSC self-renewing proliferation and functional maintenance, which can be negatively affected by HSC differentiation, apoptosis, and senescence. Therefore, inhibition of HSC senescence may promote HSC expansion. To test this hypothesis, we examined the effect of inhibition of p38 mitogen-activated protein kinase (p38) on the expansion of human umbilical cord blood (hUCB) CD133(+) cells because activation of p38 has been implicated in the induction of HSC senescence under various physiological and pathological conditions. Our results showed that ex vivo expansion of hUCB CD133(+) cells activated p38, which was abrogated by the p38 specific inhibitor SB203580 (SB). Inhibition of p38 activity with SB promoted the expansion of CD133(+) cells and CD133(+)CD38(-) cells. In addition, hUCB CD133(+) cells expanded in the presence of SB for 7 days showed about threefold increase in the clonogenic function of HSCs and engraftment in non-obese diabetic/severe combined immunodeficient mice after transplantation compared to the input cells. In contrast, the cells expanded without SB exhibited a significant reduction in these HSC functions. The enhancement of ex vivo expansion of hUCB HSCs is primarily attributable to SB-mediated inhibition of HSC senescence. In addition, inhibition of HSC apoptosis and upregulation of CXCR4 may also contribute to the enhancement. However, p38 inhibition had no significant effect on HSC differentiation and proliferation. These findings suggest that inhibition of p38 activation may represent a novel strategy to promote ex vivo expansion of hUCB HSCs.

Lower phosphorylation of p38 MAPK blocks the oxidative stress-induced senescence in myeloid leukemic CD34(+)CD38 (-) cells.

Leukemia seems to depend on a small population of "leukemia stem cells (LSCs)" for its growth and metastasis. However, the precise surviving mechanisms of LSCs remain obscure. Cellular senescence is an important obstacle for production and surviving of tumor cells. In this study we investigated the activated state of a pathway, in which reactive oxygen species (ROS) induces cellular senescence through DNA damage and phophorylation of p38 MAPK (p38), in myeloid leukemic CD34(+)CD38(-) cells. Bone marrow samples were obtained from patients with acute myeloid leukemia (AML, n=11) and chronic myeloid leukemia (CML, n=9). CD34(+)CD38(-) cells were isolated from mononuclear cells from these bone marrow samples, and K562 and KG1a cells (two kinds of myeloid leukemia cell lines) by mini-magnetic activated cell sorting. Hematopoietic stem cells (HSCs) from human cord blood served as controls. Intracellular ROS level was detected by flow cytometry. DNA damage defined as the γH2AX level was measured by immunofluorescence staining. Real-time RT-PCR was used to detect the expression of p21, a senescence-associated gene. Western blotting and immunofluorescence staining were employed to determine the p38 expression and activation. The proliferation and apoptosis of CD34(+)CD38(-) cells were detected by MTT assay and flow cytometry. Our results showed that ROS and DNA damage were substantially accumulated and p38 was less phosphorated in myeloid leukemic CD34(+)CD38(-) cells as compared with HSCs and H(2)O(2)-induced senescent HSCs. Furthermore, over-phosphorylation of p38 by anisomycin, a selective activator of p38, induced both the senescence-like growth arrest and apoptosis of CD34(+)CD38(-) cells from K562 and KG1a cell lines. These findings suggested that, although excessive accumulation of oxidative DNA damage was present in LSCs, the relatively decreased phosphorylation of p38 might help leukemic cells escape senescence and apoptosis.