Bekwhite7899

More than 1050 clinical trials are registered at FDA.gov that explore multipotent mesenchymal stromal cells (MSCs) for nearly every clinical application imaginable, including neurodegenerative and cardiac disorders, perianal fistulas, graft-versus-host disease, COVID-19, and cancer. Several companies have or are in the process of commercializing MSC-based therapies. However, most of the clinical-stage MSC therapies have been unable to meet primary efficacy end points. The innate therapeutic functions of MSCs administered to humans are not as robust as demonstrated in preclinical studies, and in general, the translation of cell-based therapy is impaired by a myriad of steps that introduce heterogeneity. In this review, we discuss the major clinical challenges with MSC therapies, the details of these challenges, and the potential bioengineering approaches that leverage the unique biology of MSCs to overcome the challenges and achieve more potent and versatile therapies.Engineered heterostructures formed by complex oxide materials are a rich source of emergent phenomena and technological applications. In the quest for new functionality, a vastly unexplored avenue is interfacing oxide perovskites with materials having dissimilar crystallochemical properties. Here, we propose a unique class of heterointerfaces based on nitride antiperovskite and oxide perovskite materials as a previously unidentified direction for materials design. We demonstrate the fabrication of atomically sharp interfaces between nitride antiperovskite Mn3GaN and oxide perovskites (La0.3Sr0.7)(Al0.65Ta0.35)O3 and SrTiO3. Using atomic-resolution imaging/spectroscopic techniques and first-principles calculations, we determine the atomic-scale structure, composition, and bonding at the interface. The epitaxial antiperovskite/perovskite heterointerface is mediated by a coherent interfacial monolayer that interpolates between the two antistructures. We anticipate our results to be an important step for the development of functional antiperovskite/perovskite heterostructures, combining their unique characteristics such as topological properties for ultralow-power applications.Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20S proteasome. Decline in 20S activity characterizes neurodegenerative diseases. Here, we examine 20S degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer's disease. We show that cleavage of tau by the 20S proteasome is most efficient within the aggregation-prone repeat region of tau and generates both short, aggregation-deficient peptides and two long fragments containing residues 1 to 251 and 1 to 218. Phosphorylation of tau by the non-proline-directed Ca2+/calmodulin-dependent protein kinase II inhibits degradation by the 20S proteasome. Phosphorylation of tau by GSK3β, a major proline-directed tau kinase, modulates tau degradation kinetics in a residue-specific manner. The study provides detailed insights into the degradation products of tau generated by the 20S proteasome, the residue specificity of degradation, single-residue degradation kinetics, and their regulation by posttranslational modification.Interpreting the function of noncoding mutations in cancer genomes remains a major challenge. Here, we developed a computational framework to identify putative causal noncoding mutations of all classes by joint analysis of mutation and gene expression data. We identified thousands of SNVs/small indels and structural variants as putative causal mutations in five major pediatric cancers. We experimentally validated the oncogenic role of CHD4 overexpression via enhancer hijacking in B-ALL. We observed a general exclusivity of coding and noncoding mutations affecting the same genes and pathways. We showed that integrated mutation profiles can help define novel patient subtypes with different clinical outcomes. Our study introduces a general strategy to systematically identify and characterize the full spectrum of noncoding mutations in cancers.Engineered extracellular vesicles (EVs) carrying therapeutic molecules are promising candidates for disease therapies. Yet, engineering EVs with optimal functions is a challenge that requires careful selection of functionally specific vesicles and a proper engineering strategy. Here, we constructed chimeric apoptotic bodies (cABs) for on-demand inflammation modulation by combining pure membrane from apoptotic bodies (ABs) as a bioconjugation/regulation module and mesoporous silica nanoparticles (MSNs) as a carrier module. MSNs were preloaded with anti-inflammatory agents (microRNA-21 or curcumin) and modified with stimuli-responsive molecules to achieve accurate cargo release at designated locations. The resulting cABs actively target macrophages in the inflammatory region and effectively promote M2 polarization of these macrophages to modulate inflammation due to the synergistic regulatory effects of AB membranes and the intracellular release of preloaded cargos. This work provides strategies to arbitrarily engineer modular EVs that integrate the advantages of natural EVs and synthetic materials for various applications.We present Scaden, a deep neural network for cell deconvolution that uses gene expression information to infer the cellular composition of tissues. Vorapaxar Scaden is trained on single-cell RNA sequencing (RNA-seq) data to engineer discriminative features that confer robustness to bias and noise, making complex data preprocessing and feature selection unnecessary. We demonstrate that Scaden outperforms existing deconvolution algorithms in both precision and robustness. A single trained network reliably deconvolves bulk RNA-seq and microarray, human and mouse tissue expression data and leverages the combined information of multiple datasets. Because of this stability and flexibility, we surmise that deep learning will become an algorithmic mainstay for cell deconvolution of various data types. Scaden's software package and web application are easy to use on new as well as diverse existing expression datasets available in public resources, deepening the molecular and cellular understanding of developmental and disease processes.The progression in the hair follicle cycle from the telogen to the anagen phase is the key to regulating hair regrowth. Dermal papilla (DP) cells support hair growth and regulate the hair cycle. However, they gradually lose key inductive properties upon culture. DP cells can partially restore their capacity to promote hair regrowth after being subjected to spheroid culture. In this study, results revealed that DP spheroids are effective at inducing the progression of the hair follicle cycle from telogen to anagen compared with just DP cell or minoxidil treatment. Because of the importance of paracrine signaling in this process, secretome and exosomes were isolated from DP cell culture, and their therapeutic efficacies were investigated. We demonstrated that miR-218-5p was notably up-regulated in DP spheroid-derived exosomes. Western blot and immunofluorescence imaging were used to demonstrate that DP spheroid-derived exosomes up-regulated β-catenin, promoting the development of hair follicles.Human skin perceives external mechanical stimuli by sensing the variation in the membrane potential of skin sensory cells. Many scientists have attempted to recreate skin functions and develop electronic skins (e-skins) based on active and passive sensing mechanisms. Inspired by the skin sensory behavior, we investigated materials and electronic devices that allow us to encode mechanical stimuli into potential differences measured between two electrodes, resulting in a potentiometric mechanotransduction mechanism. We present here a potentiometric mechanotransducer that is fabricated through an all-solution processing approach. This mechanotransducer shows ultralow-power consumption, highly tunable sensing behavior, and capability to detect both static and low-frequency dynamic mechanical stimuli. Furthermore, we developed two novel classes of sensing devices, including strain-insensitive sensors and single-electrode-mode e-skins, which are challenging to achieve using the existing methods. This mechanotransduction mechanism has broad impact on robotics, prosthetics, and health care by providing a much improved human-machine interface.Knowledge of the occurrences of water films on minerals is critical for global biogeochemical and atmospheric processes, including element cycling and ice nucleation. The underlying mechanisms controlling water film growth are, however, misunderstood. Using infrared nanospectroscopy, amplitude-modulated atomic force microscopy, and molecular simulations, we show how water films grow from water vapor on hydrophilic mineral nanoparticles. We imaged films with up to four water layers that grow anisotropically over a single face. Growth usually begins from the near edges of a face where defects preferentially capture water vapor. Thicker films produced by condensation cooling completely engulf nanoparticles and form thicker menisci over defects. The high surface tension of water smooths film surfaces and produces films of inhomogeneous thickness. Nanoscale topography and film surface energy thereby control anisotropic distributions and thicknesses of water films on hydrophilic mineral nanoparticles.Tumor heterogeneity drives disease progression, treatment resistance, and patient relapse, yet remains largely underexplored in invasion and metastasis. Here, we investigated heterogeneity within collective cancer invasion by integrating DNA methylation and gene expression analysis in rare purified lung cancer leader and follower cells. Our results showed global DNA methylation rewiring in leader cells and revealed the filopodial motor MYO10 as a critical gene at the intersection of epigenetic heterogeneity and three-dimensional (3D) collective invasion. We further identified JAG1 signaling as a previously unknown upstream activator of MYO10 expression in leader cells. Using live-cell imaging, we found that MYO10 drives filopodial persistence necessary for micropatterning extracellular fibronectin into linear tracks at the edge of 3D collective invasion exclusively in leaders. Our data fit a model where epigenetic heterogeneity and JAG1 signaling jointly drive collective cancer invasion through MYO10 up-regulation in epigenetically permissive leader cells, which induces filopodia dynamics necessary for linearized fibronectin micropatterning.Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono-adenosine 5'-diphosphate (ADP)-ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.