Suppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion

Transplantation of hematopoietic stem cells (HSCs) from human umbilical cord blood (hUCB) holds great promise for treating a broad spectrum of hematological disorders including cancer, but the limited number of HSCs in a single hUCB unit restricts its widespread use. Although extensive efforts have developed multiple methods for ex vivo expansion of human HSCs by targeting single molecules or pathways, it remains unknown whether simultaneously manipulating a large number of targets essential for stem cell self-renewal could be achievable. Recent studies have emerged that N6-methyladenosine (m6A) modulates expression of a group of mRNAs critical for stem cell fate determination by influencing their stability. Among several m6A readers, Ythdf2 is well recognized to promote the targeted mRNA decay. However, the physiological functions of Ythdf2 on adult stem cells are still elusive. Here we show that conditional knockout (KO) mouse Ythdf2 increased phenotypic and functional HSC numbers, but neither skewed lineage differentiation nor led to hematopoietic malignancies. Furthermore, knockdown (KD) of human YTHDF2 led to over 10-fold increase in ex vivo expansion of hUCB HSCs, 5-fold increase in colony-forming units (CFUs), and more than 8-fold increase in functional hUCB HSCs in the secondary serial of limiting dilution transplantation assay. Mechanistically, m6A mapping of RNAs from mouse hematopoietic stem and progenitor cells (HSPCs) as well as from hUCB HSCs revealed m6A enrichment on mRNAs encoding transcription factors critical for stem cell self-renewal. These m6A-marked mRNAs were recognized by Ythdf2 and underwent mRNA decay. In Ythdf2 KO HSPCs and YTHDF2 KD hUCB HSCs, these mRNAs were stabilized, leading to an increase in protein levels and facilitating HSC expansion. Knockdown one of the Ythdf2 key targets, Tal1 mRNA, partially rescued the phenotype. Therefore, our study for the first time shows the function of Ythdf2 in adult stem cell maintenance and identifies an important role of Ythdf2 in regulating HSC ex vivo expansion via the mechanism of controlling the stability of multiple mRNAs critical for HSC self-renewal, thus having a strong potential for future clinical applications

Coulombic Efficiency for Practical Zinc Metal Batteries: Critical Analysis and Perspectives

Climate change and energy depletion are common worries of this century. During the global clean energy transition, aqueous zinc metal batteries (AZMBs) are expected to meet societal needs due to their large-scale energy storage capability with earth-abundant, non-flammable, and economical chemistries. However, the poor reversibility of Zn poses a severe challenge to AZMB implementation. Coulombic efficiency (CE) is a quantitative index of electrode reversibility in rechargeable batteries but is not well understood in AZMBs. Thus, in this work, the state-of-art CE to present the status quo of AZMB development is summarized. A fictional 120 Wh kg-1 AZMB pouch cell is also proposed and evaluated revealing the improvement room and technical goal of AZMB chemistry. Despite some shared mechanisms between AZMBs and lithium metal batteries, misconceptions prevalent in AZMBs are clarified. Essentially, AZMB has its own niche in the market with unique merits and demerits. By incorporating academic and industrial insights, the development pathways of AZMB are suggested. This work comprehensively explores recent advancements in the Coulombic efficiency of aqueous zinc ion batteries, illuminating overlooked test details. Setting a target of 99.9% efficiency, the researchers propose a hypothetical 120 Wh kg-1 MnO2/Zn pouch cell and delineate a three-stage plan to enhance energy density in future developments. Additionally, this work provides valuable insights for improving Coulombic efficiency and refining battery testing methodologies.imag

Efficient 2075-nm Laser Emission From Ho3+-Doped Fluorotellurite Glass in a Compact All-Fiber Structure

In this Letter, we report an Ho3+-doped fluorotellurite glass all-fiber laser at 2075 nm. The gain fiber is pumped in-band with a 1976-nm fiber laser and connected by fusion splicing. A high-quality fusion splicing point with a loss of \u3c 0.1 dB was obtained by finely adjusting the splicing power and offset. In addition, by optimizing the writing parameters, a third-order fiber Bragg grating (FBG) with a reflectivity of 98% was achieved at 2075 nm using the femtosecond laser direct-writing method. Using the FBG as the laser cavity mirror and a relatively short 28-cm-long home-made Ho3+-doped fluorotellurite fiber as the laser medium, a laser with a maximum unsaturated output power of 7.33 W was obtained, and the corresponding slope efficiency was as high as 93.4%. The first, to the best of our knowledge, demonstration of the fluorotellurite glass all-fiber ∼2.1-µm laser presented in this work may pave the way for a high-power 2.1-µm fiber laser with a compact structure

MetaBox: A Benchmark Platform for Meta-Black-Box Optimization with Reinforcement Learning

Recently, Meta-Black-Box Optimization with Reinforcement Learning (MetaBBO-RL) has showcased the power of leveraging RL at the meta-level to mitigate manual fine-tuning of low-level black-box optimizers. However, this field is hindered by the lack of a unified benchmark. To fill this gap, we introduce MetaBox, the first benchmark platform expressly tailored for developing and evaluating MetaBBO-RL methods. MetaBox offers a flexible algorithmic template that allows users to effortlessly implement their unique designs within the platform. Moreover, it provides a broad spectrum of over 300 problem instances, collected from synthetic to realistic scenarios, and an extensive library of 19 baseline methods, including both traditional black-box optimizers and recent MetaBBO-RL methods. Besides, MetaBox introduces three standardized performance metrics, enabling a more thorough assessment of the methods. In a bid to illustrate the utility of MetaBox for facilitating rigorous evaluation and in-depth analysis, we carry out a wide-ranging benchmarking study on existing MetaBBO-RL methods. Our MetaBox is open-source and accessible at: https://github.com/GMC-DRL/MetaBox.Comment: Accepted at NuerIPS 202

Direct Femtosecond Laser Inscription of High-Order Bragg Gratings in Fluoroaluminate Glass Fiber

This letter reports the fabrication of fiber Bragg gratings (FBGs) within in-house fabricated fluoroaluminate (AlF3) glass fibers using femtosecond (fs) laser inscription at 800 nm. The grating strength of the FBGs was investigated for different pulse energies and different orders, and a 3rd-order FBG with Bragg wavelength at 1557 nm was found to have the highest reflectivity of 99.5%. In addition, the reflectivity of the mid-IR grating peaks for different orders was also studied, and a 2nd-order FBG with a reflectivity of 98.8% was obtained at 2864 nm. Finally, the temperature characteristics of a mid-IR FBG were studied between 30 °C and 150 °C, showing a linear wavelength dependence and an excellent stability for the refractive index modulation. Such highly reflectivity FBGs in AlF3 fiber have significant potential for applications in the development of compact all-fiber mid-IR fiber lasers

Photocatalytic Activity Enhancement of Anatase TiO 2

We employed high-energy ball-milling technique to fabricate TiO/TiO2 heterogeneous nanostructures. XRD proved the existence of TiO/TiO2 heterogeneous structures. SEM and HRTEM investigation evidenced that the mean particle size and mean grain size of the as-prepared samples are 23 nm and 13 nm, respectively. UV-Vis spectra exhibited that TiO has enhanced the visible light absorption of TiO2 and has changed the Eg of TiO2. UPS examination indicated that the electron work function (EWF) of TiO is higher than that of TiO2. Photocatalytic degradation experiments revealed that an appropriate TiO content can enhance the photocatalytic activity of pure anatase TiO2. The best photocatalytic activity of TiO/TiO2 heterogeneous nanostructures is even better than that of Au-deposited TiO2 by keeping high degradation efficiency of 93%. The internal electrical field producing in TiO/TiO2 heterogeneous nanostructures was considered to be dominantly responsible for the enhanced photocatalytic activity. Therefore, the substitution of TiO with noble metal in TiO2 will be widely used in the future due to its low cost. This study also provides a clear direction of enhancing photocatalytic activity of TiO2: incorporating a guest compound into TiO2 with an appropriate content if the compound has much higher electron work function than that of TiO2

The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism

The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions in some types of stem cell, but its role in hematopoietic stem cells (HSCs) is unknown. Here, we show that the Dlk1-Gtl2 locus plays a critical role in preserving long-term repopulating HSCs (LT-HSCs). Through transcriptome profiling in 17 hematopoietic cell types, we found that ncRNAs expressed from the Dlk1-Gtl2 locus are predominantly enriched in fetal liver HSCs and the adult LT-HSC population and sustain long-term HSC functionality. Mechanistically, the miRNA mega-cluster within the Dlk1-Gtl2 locus suppresses the entire PI3K-mTOR pathway. This regulation in turn inhibits mitochondrial biogenesis and metabolic activity and protects LT-HSCs from excessive reactive oxygen species (ROS) production. Our data therefore show that the imprinted Dlk1-Gtl2 locus preserves LT-HSC function by restricting mitochondrial metabolism

Performance Characteristics of the NeuroEXPLORER, a Next-Generation Human Brain PET/CT Imager.

The collaboration of Yale, the University of California, Davis, and United Imaging Healthcare has successfully developed the NeuroEXPLORER, a dedicated human brain PET imager with high spatial resolution, high sensitivity, and a built-in 3-dimensional camera for markerless continuous motion tracking. It has high depth-of-interaction and time-of-flight resolutions, along with a 52.4-cm transverse field of view (FOV) and an extended axial FOV (49.5 cm) to enhance sensitivity. Here, we present the physical characterization, performance evaluation, and first human images of the NeuroEXPLORER. Methods: Measurements of spatial resolution, sensitivity, count rate performance, energy and timing resolution, and image quality were performed adhering to the National Electrical Manufacturers Association (NEMA) NU 2-2018 standard. The systems performance was demonstrated through imaging studies of the Hoffman 3-dimensional brain phantom and the mini-Derenzo phantom. Initial 18F-FDG images from a healthy volunteer are presented. Results: With filtered backprojection reconstruction, the radial and tangential spatial resolutions (full width at half maximum) averaged 1.64, 2.06, and 2.51 mm, with axial resolutions of 2.73, 2.89, and 2.93 mm for radial offsets of 1, 10, and 20 cm, respectively. The average time-of-flight resolution was 236 ps, and the energy resolution was 10.5%. NEMA sensitivities were 46.0 and 47.6 kcps/MBq at the center and 10-cm offset, respectively. A sensitivity of 11.8% was achieved at the FOV center. The peak noise-equivalent count rate was 1.31 Mcps at 58.0 kBq/mL, and the scatter fraction at 5.3 kBq/mL was 36.5%. The maximum count rate error at the peak noise-equivalent count rate was less than 5%. At 3 iterations, the NEMA image-quality contrast recovery coefficients varied from 74.5% (10-mm sphere) to 92.6% (37-mm sphere), and background variability ranged from 3.1% to 1.4% at a contrast of 4.0:1. An example human brain 18F-FDG image exhibited very high resolution, capturing intricate details in the cortex and subcortical structures. Conclusion: The NeuroEXPLORER offers high sensitivity and high spatial resolution. With its long axial length, it also enables high-quality spinal cord imaging and image-derived input functions from the carotid arteries. These performance enhancements will substantially broaden the range of human brain PET paradigms, protocols, and thereby clinical research applications

Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations

Article suggests that common standards for recording, detection, and reporting for intracranial recordings in humans that suggest their role in episodic and semantic memory does not exist. Authors of the article outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations, and argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery