Cellular Therapy for Fanconi Anemia: The Past, Present, and Future

Allogeneic hematopoietic cell transplantation (HCT) remains the only proven curative therapy for the hematologic manifestation of Fanconi anemia (FA). Over the past 2 decades, major advances have been made such that transplant outcomes have markedly improved. With the development of in vitro fertilization and preimplantation genetic diagnosis, HLA-matched sibling donor umbilical blood transplantation may be an option for more patients with FA. Recently, the use of pluripotent stem cells has been explored as a novel approach to model the hematopoietic developmental defects in FA, and to provide a potential source of autologous stem cells that can be genetically manipulated and used to generate corrected hematopoietic progenitors

Eight pruning deep learning models for low storage and high-speed COVID-19 computed tomography lung segmentation and heatmap-based lesion localization: A multicenter study using COVLIAS 2.0.

COVLIAS 1.0: an automated lung segmentation was designed for COVID-19 diagnosis. It has issues related to storage space and speed. This study shows that COVLIAS 2.0 uses pruned AI (PAI) networks for improving both storage and speed, wiliest high performance on lung segmentation and lesion localization.ology: The proposed study uses multicenter ∼9,000 CT slices from two different nations, namely, CroMed from Croatia (80 patients, experimental data), and NovMed from Italy (72 patients, validation data). We hypothesize that by using pruning and evolutionary optimization algorithms, the size of the AI models can be reduced significantly, ensuring optimal performance. Eight different pruning techniques (i) differential evolution (DE), (ii) genetic algorithm (GA), (iii) particle swarm optimization algorithm (PSO), and (iv) whale optimization algorithm (WO) in two deep learning frameworks (i) Fully connected network (FCN) and (ii) SegNet were designed. COVLIAS 2.0 was validated using "Unseen NovMed" and benchmarked against MedSeg. Statistical tests for stability and reliability were also conducted.Pruning algorithms (i) FCN-DE, (ii) FCN-GA, (iii) FCN-PSO, and (iv) FCN-WO showed improvement in storage by 92.4%, 95.3%, 98.7%, and 99.8% respectively when compared against solo FCN, and (v) SegNet-DE, (vi) SegNet-GA, (vii) SegNet-PSO, and (viii) SegNet-WO showed improvement by 97.1%, 97.9%, 98.8%, and 99.2% respectively when compared against solo SegNet. AUC > 0.94 (p 0.86 (p < 0.0001) on NovMed data set for all eight EA model. PAI <0.25 s per image. DenseNet-121-based Grad-CAM heatmaps showed validation on glass ground opacity lesions.Eight PAI networks that were successfully validated are five times faster, storage efficient, and could be used in clinical settings

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant R24-DK092760)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant R24-DK49216)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant U54DK110805)National Heart, Lung, and Blood Institute (Grant UO1-HL100001)National Heart, Lung, and Blood Institute (Grant U01HL134812)National Heart, Lung, and Blood Institute (Grant R01HL04880)National Institutes of Health (U.S.) (Grant R24OD017870-01

Simultaneous sequencing of oxidized methylcytosines produced by TET/JBP dioxygenases in Coprinopsis cinerea

A prominent epigenetic mechanism for gene regulation is methylation of cytosine bases in DNA. TET enzymes facilitate DNA demethylation by converting 5-methylcytosine (5mC) to oxidized methylcytosines (oxi-mCs). We show that oxi-mCs are generated by conserved TET/JBP enzymes encoded in the genome of the model organism Coprinopsis cinerea and present a method for simultaneous mapping of the three different species of oxi-mCs at near–base-pair resolution. We observe that centromeres and transposable elements exhibit distinctive patterns of 5mC and oxi-mC, and show that gene body 5mC and oxi-mC mark silent paralogous multicopy genes. Our study describes a method to map three species of oxi-mC simultaneously and reveals the colocation of 5mC and oxi-mC at functional elements throughout the C. cinerea genome

Somatic coding mutations in human induced pluripotent stem cells

Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein coding point mutations per exome). The majority of these mutations were non-synonymous, nonsense, or splice variants, and were enriched in genes mutated or having causative effects in cancers. At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, while the rest were newly occurring during or after reprogramming. Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications. Extensive genetic screening should become a standard procedure to ensure hiPS safety before clinical use

Large intergenic non-coding RNA-RoR modulates reprogramming of human induced pluripotent stem cells

February 17, 2011The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome[superscript 1, 2, 3, 4, 5], resulting in altered patterns of gene expression[superscript 2, 6, 7, 8, 9]. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs)[superscript 10, 11] that occurs upon derivation of human iPSCs and identify numerous lincRNAs whose expression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression was elevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote the emergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of key pluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found that one such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration for critical functions of lincRNAs in the derivation of pluripotent stem cells

A Chirality-Based Quantum Leap

There is increasing interest in the study of chiral degrees of freedom occurring in matter and in electromagnetic fields. Opportunities in quantum sciences will likely exploit two main areas that are the focus of this Review: (1) recent observations of the chiral-induced spin selectivity (CISS) effect in chiral molecules and engineered nanomaterials and (2) rapidly evolving nanophotonic strategies designed to amplify chiral light-matter interactions. On the one hand, the CISS effect underpins the observation that charge transport through nanoscopic chiral structures favors a particular electronic spin orientation, resulting in large room-temperature spin polarizations. Observations of the CISS effect suggest opportunities for spin control and for the design and fabrication of room-temperature quantum devices from the bottom up, with atomic-scale precision and molecular modularity. On the other hand, chiral-optical effects that depend on both spin- and orbital-angular momentum of photons could offer key advantages in all-optical and quantum information technologies. In particular, amplification of these chiral light-matter interactions using rationally designed plasmonic and dielectric nanomaterials provide approaches to manipulate light intensity, polarization, and phase in confined nanoscale geometries. Any technology that relies on optimal charge transport, or optical control and readout, including quantum devices for logic, sensing, and storage, may benefit from chiral quantum properties. These properties can be theoretically and experimentally investigated from a quantum information perspective, which has not yet been fully developed. There are uncharted implications for the quantum sciences once chiral couplings can be engineered to control the storage, transduction, and manipulation of quantum information. This forward-looking Review provides a survey of the experimental and theoretical fundamentals of chiral-influenced quantum effects and presents a vision for their possible future roles in enabling room-temperature quantum technologies.ISSN:1936-0851ISSN:1936-086