Cytokine immunotherapy represents an attractive strategy to stimulate robust immune responses for renal injury repair in ischemic acute kidney injury (AKI). However, its clinical application is ...hindered by its nonspecificity to kidney, short circulation half-life, and severe side effects. An ideal cytokine immunotherapy for AKI requires preferential delivery of cytokines with accurate dosage to the kidney and sustained-release of cytokines to stimulate the immune responses. Herein, we developed a DNA nanoraft cytokine by precisely arranging interleukin-33 (IL-33) nanoarray on rectangle DNA origami, through which IL-33 can be preferentially delivered to the kidney for alleviation of AKI. A nanoraft carrying precisely quantified IL-33 predominantly accumulated in the kidney for up to 48 h. Long-term sustained-release of IL-33 from nanoraft induced rapid expansion of type 2 innate lymphoid cells (ILC 2s) and regulatory T cells (Tregs) and achieved better treatment efficiency compared to free IL-33 treatment. Thus, our study demonstrates that a nanoraft can serve as a structurally well-defined delivery platform for cytokine immunotherapy in ischemic AKI and other renal diseases.
Leukemia stem cells (LSCs) are believed to have more distinct vulnerabilities than the bulk acute myeloid leukemia (AML) cells, but their rarity and the lack of universal markers for their ...prospective isolation hamper their study. We report that genetically clonal induced pluripotent stem cells (iPSCs) derived from an AML patient and characterized by exceptionally high engraftment potential give rise, upon hematopoietic differentiation, to a phenotypic hierarchy. Through fate-tracking experiments, xenotransplantation, and single-cell transcriptomics, we identify a cell fraction (iLSC) that can be isolated prospectively by means of adherent in vitro growth that resides on the apex of this hierarchy and fulfills the hallmark features of LSCs. Through integrative genomic studies of the iLSC transcriptome and chromatin landscape, we derive an LSC gene signature that predicts patient survival and uncovers a dependency of LSCs, across AML genotypes, on the RUNX1 transcription factor. These findings can empower efforts to therapeutically target AML LSCs.
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•AML-iPSC-derived hematopoietic cells recapitulate a LSC hierarchy•iLSCs can be easily prospectively isolated•A LSC 16-gene set correlates with AML patient survival•The RUNX1 TF is critical for the maintenance of LSCs across AML genetic subgroups
Wesely et al. report that AML-iPSC-derived hematopoietic cells are hierarchically organized and contain cells with hallmark features of LSCs (iLSCs). Through integrative genomic studies of bulk and single-cell transcriptomes and chromatin accessibility, they derive a LSC gene signature and identify RUNX1 as an AML LSC dependency with therapeutic implications.
Prion diseases are caused by the misfolding of prion protein (PrP). Misfolded PrP forms protease-resistant aggregates in vivo (PrP
) that are able to template the conversion of the native form of the ...protein (PrP
), a property shared by in vitro-produced PrP fibrils. Here we produced amyloid fibrils in vitro from recombinant, full-length human PrP
(residues 23-231) and determined their structure using cryo-EM, building a model for the fibril core comprising residues 170-229. The PrP fibril consists of two protofibrils intertwined in a left-handed helix. Lys194 and Glu196 from opposing subunits form salt bridges, creating a hydrophilic cavity at the interface of the two protofibrils. By comparison with the structure of PrP
, we propose that two α-helices in the C-terminal domain of PrP
are converted into β-strands stabilized by a disulfide bond in the PrP fibril. Our data suggest that different PrP mutations may play distinct roles in modulating the conformational conversion.
Neuroimaging research suggests that the resting cerebral physiology is characterized by complex patterns of neuronal activity in widely distributed functional networks. As studied using functional ...magnetic resonance imaging (fMRI) of the blood-oxygenation-level dependent (BOLD) signal, the resting brain activity is associated with slowly fluctuating hemodynamic signals (~10s). More recently, multimodal functional imaging studies involving simultaneous acquisition of BOLD-fMRI and electroencephalography (EEG) data have suggested that the relatively slow hemodynamic fluctuations of some resting state networks (RSNs) evinced in the BOLD data are related to much faster (~100ms) transient brain states reflected in EEG signals, that are referred to as “microstates”.
To further elucidate the relationship between microstates and RSNs, we developed a fully data-driven approach that combines information from simultaneously recorded, high-density EEG and BOLD-fMRI data. Using independent component analysis (ICA) of the combined EEG and fMRI data, we identified thirteen microstates and ten RSNs that are organized independently in their temporal and spatial characteristics, respectively. We hypothesized that the intrinsic brain networks that are active at rest would be reflected in both the EEG data and the fMRI data. To test this hypothesis, the rapid fluctuations associated with each microstate were correlated with the BOLD-fMRI signal associated with each RSN.
We found that each RSN was characterized further by a specific electrophysiological signature involving from one to a combination of several microstates. Moreover, by comparing the time course of EEG microstates to that of the whole-brain BOLD signal, on a multi-subject group level, we unraveled for the first time a set of microstate-associated networks that correspond to a range of previously described RSNs, including visual, sensorimotor, auditory, attention, frontal, visceromotor and default mode networks. These results extend our understanding of the electrophysiological signature of BOLD RSNs and demonstrate the intrinsic connection between the fast neuronal activity and slow hemodynamic fluctuations.
► A novel, data-driven approach to the analysis of EEG microstates is introduced. ► 13 EEG microstates and 10 BOLD RSNs were identified from simultaneous recordings. ► Microstates as specific electrophysiological correlates for a wide range of RSNs. ► Each microstate correlated to one, two, or a combination of several RSNs.
Accurate survival prediction is a critical goal in the prognosis of breast cancer patients because it can help physicians make more patient-friendly decisions and further guide appropriate treatment. ...Breast cancer is often caused by genetic abnormalities, which prompts researchers to consider information such as gene expression and copy number variation in addition to clinical data in their studies. The integration of these multi-modal data can improve the predictive power of models. However, with the highly unbalanced information of breast cancer patient data, it becomes a new challenge for breast cancer patient survival prediction to fully extract the characteristic information of these multi-modal data and to consider the complementarity of this information. To this end, we propose a deep multi-modal fusion network (DMMFN) to predict the five-year survival of breast cancer patients by integrating clinical data, copy number variation data, and gene expression data. The imbalanced dataset is first processed using the oversampling method SMOTE-NC. Then the abstract modal features of the multi-modal data are extracted by the two-layer one-dimensional convolutional neural network and the bi-directional long short-term memory network. Next, the weight coefficients of each modal data are dynamically adjusted using gated multimodal units to obtain fusion features. Finally, the fusion features are fed into the MaxoutMLP classifier to obtain the final prediction results. We conducted experiments on the METABRIC dataset to verify the validity of the multi-modal data and compared it with other methods. The comprehensive performance evaluation shows that DMMFN has better prediction performance.
Host-guest complex solid state molecular motion is a critical but underexplored phenomenon. In principle, it can be used to control molecular machines that function in the solid state. Here we ...describe a solid state system that operates on the basis of complexation between an all-hydrocarbon macrocycle, D
-CDMB-8, and perylene. Molecular motion in this solid state machine is induced by exposure to organic solvents or grinding and gives rise to different co-crystalline, mixed crystalline, or amorphous forms. Distinct time-dependent emissive responses are seen for different organic solvents as their respective vapours or when the solid forms are subject to grinding. This temporal feature allows the present D
-CDMB-8⊃perylene-based system to be used as a time-dependent, colour-based 4th dimension response element in pattern-based information codes. This work highlights how dynamic control over solid-state host-guest molecular motion may be used to induce a tuneable temporal response and provide materials with information storage capability.
Neutrophil extracellular traps (NETs) have been found to play a role in the development of autoimmune diseases. In the past two years, studies have demonstrated a significantly increase of NETs in ...skin tissues during the early stages of IgAV, indicating their involvement in disease activity among children with IgAV. However, the presence of NETs in IgAV animal models has not yet been reported. The objective of this study is to investigate whether NETs are involved in the pathogenesis of IgA vasculitis (IgAV) rats.
Twenty-four SD rats were randomly divided into three groups: the ovalbumin group, the gliadin group, and the control group. The IgAV rat models were established administering Indian ink with ovalbumin (ovalbumin group) or gliadin (gliadin group) with Freund's complete adjuvant. The cell-free DNA (cf-DNA) was quantified by using dsDNA quantification kit, while the levels of Immunoglobulins, complement C3 and myeloperoxidase-DNA (MPO-DNA) in serum were tested using enzyme linked immunosorbent assay (ELISA). The IgA, complement C3 and NETs in tissues were detected through multiple immunofluorescences.
Both the ovalbumin group and gliadin group showed IgA and C3 deposition in various tissues, including the glomerular mesangial region, skin, and digestive tract, while the control group showed no such deposition. The levels of circulatory cf-DNA and MPO-DNA, which are components of NETs, were significantly elevated in both ovalbumin and gliadin groups compared with the control group. Furthermore, the presence of NETs were found in gastrointestinal and renal tissues of the ovalbumin and gliadin groups, but not in the control group.
IgAV model rat can be established through the combination of ovalbumin and gliadin with Indian ink and Freund's complete adjuvant. This study provides the first confirmation that NETs are involved in the pathogenesis of IgAV rat.
Grasping unstructured objects and sensing the contact force are two vital issues for grippers. However, it is still difficult for most existing grippers to realize these two functions simultaneously. ...In this article, we revise the traditional fin-ray finger by inserting a series of rigid nodes into the compliant structure and develop an adaptive two-finger gripper. This design linearizes the gripper's deformation-force relationship and enables an intrinsic force sensing ability without any tactile sensor. Experimental results show that the finger has high accuracy in sensing the external force applied at its middle part (average error less than 3%) but much larger errors appear near its two ends. Further experiments indicate that the gripper functions well in sensing the total grasping force (average error less than 8%). Although larger errors are observed in estimating the force distribution at each node, the variation tendency of the sensed force coincides well with the ground truth. Experiments are also carried out on grasping free-form objects and performing pick-and-place operations to further prove the gripper's adaptive grasping and intrinsic force sensing abilities.
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