The ATF4-RPS19BP1 axis modulates ribosome biogenesis to promote erythropoiesis.

ABSTRACT: Hematopoietic differentiation is controlled by intrinsic regulators and the extrinsic hematopoietic niche. Activating transcription factor 4 (ATF4) plays a crucial role in the function of fetal and adult hematopoietic stem cell maintenance. However, the precise function of ATF4 in the bone marrow (BM) niche and the mechanism by which ATF4 regulates adult hematopoiesis remain largely unknown. Here, we used 4 cell-type-specific mouse Cre lines to achieve conditional knockout of Atf4 in Cdh5+ endothelial cells, Prx1+ BM stromal cells, Osx+ osteoprogenitor cells, and Mx1+ hematopoietic cells and uncovered the role of Atf4 in niche cells and hematopoiesis. Intriguingly, depletion of Atf4 in niche cells did not affect hematopoiesis; however, Atf4-deficient hematopoietic cells exhibited erythroid differentiation defects, leading to hypoplastic anemia. Mechanistically, ATF4 mediated direct regulation of Rps19bp1 transcription, which is, in turn, involved in 40 S ribosomal subunit assembly to coordinate ribosome biogenesis and promote erythropoiesis. Finally, we demonstrate that under conditions of 5-fluorouracil-induced stress, Atf4 depletion impedes the recovery of hematopoietic lineages, which requires efficient ribosome biogenesis. Taken together, our findings highlight the indispensable role of the ATF4-RPS19BP1 axis in the regulation of erythropoiesis.

Performance and Solution Structures of Side-Chain-Bridged Oligo (Ethylene Glycol) Polymer Photocatalysts for Enhanced Hydrogen Evolution under Natural Light Illumination.

Converting solar energy into hydrogen energy using conjugated polymers (CP) is a promising solution to the energy crisis. Improving water solubility plays one of the critical factors in enhancing the hydrogen evolution rate (HER) of CP photocatalysts. In this study, a novel concept of incorporating hydrophilic side chains to connect the backbones of CPs to improve their HER is proposed. This concept is realized through the polymerization of carbazole units bridged with octane, ethylene glycol, and penta-(ethylene glycol) to form three new side-chain-braided (SCB) CPs: PCz2S-OCt, PCz2S-EG, and PCz2S-PEG. Verified through transient absorption spectra, the enhanced capability of PCz2S-PEG for ultrafast electron transfer and reduced recombination effects has been demonstrated. Small- and wide-angle X-ray scattering (SAXS/WAXS) analyses reveal that these three SCB-CPs form cross-linking networks with different mass fractal dimensions (f) in aqueous solution. With the lowest f value of 2.64 and improved water/polymer interfaces, PCz2S-PEG demonstrates the best HER, reaching up to 126.9 µmol h-1 in pure water-based photocatalytic solution. Moreover, PCz2S-PEG exhibits comparable performance in seawater-based photocatalytic solution under natural sunlight. In situ SAXS analysis further reveals nucleation-dominated generation of hydrogen nanoclusters with a size of ≈1.5 nm in the HER of PCz2S-PEG under light illumination.

Small extracellular vesicles derived from acute myeloid leukemia cells promote leukemogenesis by transferring miR-221-3p.

Small extracellular vesicles (sEVs) transfer cargos between cells and participate in various physiological and pathological processes through their autocrine and paracrine effects. However, the pathological mechanisms employed by sEV-encapsulated microRNAs (miRNAs) in acute myeloid leukemia (AML) are still obscure. In this study, we aimed to investigate the effects of AML cells-derived sEVs (AML-sEVs) on AML cells and delineate the underlying mechanisms. We initially used high-throughput sequencing to identify miR-221-3p as the miRNA prominently enriched in AML-sEVs. Our findings revealed that miR-221-3p promoted AML cell proliferation and leukemogenesis by accelerating cell cycle entry and inhibiting apoptosis. Furthermore, Gbp2 was confirmed as a target gene of miR-221-3p by dual luciferase reporter assays and rescue experiments. Additionally, AML-sEVs impaired the clonogenicity, particularly the erythroid differentiation ability, of hematopoietic stem and progenitor cells. Taken together, our findings reveal how sEVs-delivered miRNAs contribute to AML pathogenesis, which can be exploited as a potential therapeutic target to attenuate AML progression.

Overcrowded 14,14'-Bidibenzo[a,j]anthracenes: Challenges in Syntheses and Atypical Property of Lacking Symmetry-Breaking Charge Transfer (SBCT).

14,14'-Bidibenzo[a,j]anthracenes (BDBAs) were prepared by iridium-catalyzed annulation of 5,5'-biterphenylene with alkynes. The molecular geometries of overcrowded BDBAs were verified by X-ray crystallography. The two dibenzo[a,j]anthryl moieties are connected through the sterically hindered 14 positions, resulting in highly distorted molecular halves. The conformation with a small twist angle between two molecular halves can minimize steric conflicts between the substituents at 1 and 13 positions and the carbon atoms of the central axis, as well as steric clashes between those substituents. One such example is octafluoro-substituted BDBA, where the interplanar angle between two anthryl moieties is approximately 31° (currently the lowest reported value, cf. 81° in 9,9'-bianthracene). The intramolecular interactions and electronic couplings between two molecular halves resulted in upfield 1H NMR signals, redshifted absorption and emission bands, and a reduced HOMO-LUMO gap. Photodynamic investigations on BDBAs indicated that the formation of the conventional symmetry-breaking charge transfer (SBCT) state was suspended by restricted rocking around the central C-C bond. Such a mechanism associated with this highly constrained conformation was examined for the first time.

A New Series of Sandwich-Type 5,5'-Biterphenylenes: Synthetic Challenge, Structural Uniqueness and Photodynamics.

A new series of biaryls, bi-linear-terphenylenes (BLTPs), were prepared using the tert-butyllithium-mediated cyclization as the key synthetic step. The three-dimensional structures of the studied compounds were verified using X-ray crystallography and DFT calculations. Tetraaryl(ethynyl)-substituted BLTPs are highly crowded molecules, and the internal rotation around the central C-C bond is restricted due to a high barrier (>50 kcal/mol). These structures contain several aryl/terphenylenyl/aryl sandwiches, where the through-space π-π (TSPP) interactions are strongly reflected in the shielding of 1 H NMR chemical shifts, reduction of oxidation potentials, increasing aromaticity of the central six-membered ring and decreasing antiaromaticity of the four-membered rings in a terphenylenyl moiety based on NICS(0) and iso-chemical shielding surfaces. Despite the restricted C-C bond associated intramolecular TSPP interactions for BLTPs in the ground state, to our surprise, the electronic coupling between two linear terphenylenes (LTPs) in BLTPs in the excited state is weak, so that the excited-state behavior is dominated by the corresponding monomeric LTPs. In other words, all BLTPs undergo ultrafast relaxation dynamics via strong exciton-vibration coupling, acting as a blue-light absorber with essentially no emission.

Singlet Fission in a New Series of Systematically Designed Through-space Coupled Tetracene Oligomers.

Singlet fission (SF) holds great promise for current photovoltaic technologies, where tetracenes, with their relatively high triplet energies, play a major role for application in silicon-based solar cells. However, the SF efficiencies in tetracene dimers are low due to the unfavorable energetics of their singlet and triplet energy levels. In the solid state, tetracene exhibits high yields of triplet formation through SF, raising great interest about the underlying mechanisms. To address this discrepancy, we designed and prepared a novel molecular system based on a hexaphenylbenzene core decorated with 2 to 6 tetracene chromophores. The spatial arrangement of tetracene units, induced by steric hindrance in the central part, dictates through-space coupling, making it a relevant model for solid-state chromophore organization. We then revealed a remarkable increase in SF quantum yield with the number of tetracenes, reaching quantitative (196 %) triplet pair formation in hexamer. We observed a short-lived correlated triplet pair and limited magnetic effects, indicating ineffective triplet dissociation in these through-space coupled systems. These findings emphasize the crucial role of the number of chromophores involved and the interchromophore arrangement for the SF efficiency. The insights gained from this study will aid designing more efficient and technology-compatible SF systems for applications in photovoltaics.

Symmetry-breaking of Dibenzo[b,d]thiophene Sulfone Enhancing Polaron Generation for Boosted Photocatalytic Hydrogen Evolution.

The current bottleneck in the development of efficient photocatalysts for hydrogen evolution is the limited availability of high-performance acceptor units. Over the past nine years, dibenzo[b,d]thiophene sulfone (DBS) has been the preferred choice for the acceptor unit. Despite extensive exploration of alternative structures as potential replacements for DBS, a superior substitute remains elusive. In this study, a symmetry-breaking strategy was employed on DBS to develop a novel acceptor unit, BBTT-1SO. The asymmetric structure of BBTT-1SO proved beneficial for increasing multiple moment and polarizability. BBTT-1SO-containing polymers showed higher efficiencies for hydrogen evolution than their DBS-containing counterparts by up to 166 %. PBBTT-1SO exhibited an excellent hydrogen evolution rate (HER) of 222.03 mmol g-1 h-1 and an apparent quantum yield of 27.5 % at 500 nm. Transient spectroscopic studies indicated that the BBTT-1SO-based polymers facilitated electron polaron formation, which explains their superior HERs. PBBTT-1SO also showed 14 % higher HER in natural seawater splitting than that in deionized water splitting. Molecular dynamics simulations highlighted the enhanced water-PBBTT-1SO polymer interactions in salt-containing solutions. This study presents a pioneering example of a substitute acceptor unit for DBS in the construction of high-performance photocatalysts for hydrogen evolution.

Highly Efficient MAPbI3 -Based Quantum Dots Exhibiting Unusual Nonblinking Single Photon Emission at Room Temperature.

Highly emissive semiconductor nanocrystals, or so-called quantum dots (QDs) possess a variety of applications from displays and biology labeling, to quantum communication and modern security. Though ensembles of QDs have already shown very high photoluminescent quantum yields (PLQYs) and have been widely utilized in current optoelectronic products, QDs that exhibit high absorption cross-section, high emission intensity, and, most important, nonblinking behavior at single-dot level have long been desired and not yet realized at room temperature. In this work, infrared-emissive MAPbI3 -based halide perovskite QDs is demonstrated. These QDs not only show a ≈100% PLQY at the ensemble level but also, surprisingly, at the single-dot level, display an extra-large absorption cross-section up to 1.80 × 10-12 cm2 and non-blinking single photon emission with a high single photon purity of 95.3%, a unique property that is extremely rare among all types of quantum emitters operated at room temperature. An in-depth analysis indicates that neither trion formation nor band-edge carrier trapping is observed in MAPbI3 QDs, resulting in the suppression of intensity blinking and lifetime blinking. Fluence-dependent transient absorption measurements reveal that the coexistence of non-blinking behavior and high single photon purity in these perovskite QDs results from a significant repulsive exciton-exciton interaction, which suppresses the formation of biexciton, and thus greatly reduces photocharging. The robustness of these QDs is confirmed by their excellent stability under continuous 1 h electron irradiation in high-resolution transmission electron microscope inspection. It is believed that these results mark an important milestone in realizing nonblinking single photon emission in semiconductor QDs.

TWIST1 preserves hematopoietic stem cell function via the CACNA1B/Ca2+/mitochondria axis.

Mitochondria of hematopoietic stem cells (HSCs) play crucial roles in regulating cell fate and preserving HSC functionality and survival. However, the mechanism underlying HSC regulation remains poorly understood. Here, we identify transcription factor TWIST1 as a novel regulator of HSC maintenance through modulation of mitochondrial function. We demonstrate that Twist1 deletion results in significantly decreased lymphoid-biased HSC frequency, markedly reduced HSC dormancy and self-renewal capacity, and skewed myeloid differentiation in steady-state hematopoiesis. Twist1-deficient HSCs are more compromised in tolerance of irradiation- and 5-fluorouracil-induced stresses and exhibit typical phenotypes of senescence. Mechanistically, Twist1 deletion induces transactivation of voltage-gated calcium channel (VGCC) Cacna1b, which exhausts lymphoid-biased HSCs, impairs genotoxic hematopoietic recovery, and enhances mitochondrial calcium levels, metabolic activity, and reactive oxygen species production. Suppression of VGCC by a calcium channel blocker largely rescues the phenotypic and functional defects in Twist1-deleted HSCs under both steady-state and stress conditions. Collectively, our data, for the first time, characterize TWIST1 as a critical regulator of HSC function acting through the CACNA1B/Ca2+/mitochondria axis and highlight the importance of Ca2+ in HSC maintenance. These observations provide new insights into the mechanisms for the control of HSC fate.

Radiation-induced bystander effects impair transplanted human hematopoietic stem cells via oxidative DNA damage.

Total body irradiation (TBI) is commonly used in host conditioning regimens for human hematopoietic stem cell (HSC) transplantation to treat various hematological disorders. Exposure to TBI not only induces acute myelosuppression and immunosuppression, but also injures the various components of the HSC niche in recipients. Our previous study demonstrated that radiation-induced bystander effects (RIBE) of irradiated recipients decreased the long-term repopulating ability of transplanted mouse HSCs. However, RIBE on transplanted human HSCs have not been studied. Here, we report that RIBE impaired the long-term hematopoietic reconstitution of human HSCs as well as the colony-forming ability of human hematopoietic progenitor cells (HPCs). Our further analyses revealed that the RIBE-affected human hematopoietic cells showed enhanced DNA damage responses, cell-cycle arrest, and p53-dependent apoptosis, mainly because of oxidative stress. Moreover, multiple antioxidants could mitigate these bystander effects, though at different efficacies in vitro and in vivo. Taken together, these findings suggest that RIBE impair human HSCs and HPCs by oxidative DNA damage. This study provides definitive evidence for RIBE on transplanted human HSCs and further justifies the necessity of conducting clinical trials to evaluate different antioxidants to improve the efficacy of HSC transplantation for the patients with hematological or nonhematological disorders.

Self-Assembled Monolayers of Bi-Functionalized Porphyrins: A Novel Class of Hole-Layer-Coordinating Perovskites and Indium Tin Oxide in Inverted Solar Cells.

Self-assembled monolayers (SAMs) offer the advantage of facile interfacial modification, leading to significant improvements in device performance. In this study, we report the design and synthesis of a new series of carboxylic acid-functionalized porphyrin derivatives, namely AC-1, AC-3, and AC-5, and present, for the first time, a strategy to exploit the large π-moiety of porphyrins as a backbone for interfacing the indium tin oxide (ITO) electrode and perovskite active layer in an inverted perovskite solar cell (PSC) configuration. The electron-rich nature of porphyrins facilitates hole transfer and the formation of SAMs, resulting in a dense surface that minimizes defects. Comprehensive spectroscopic and dynamic studies demonstrate that the double-anchored AC-3 and AC-5 enhance SAMs on ITO, passivate the perovskite layer, and function as conduits to facilitate hole transfer, thus significantly boosting the performance of PSCs. The champion inverted PSC employing AC-5 SAM achieves an impressive solar efficiency of 23.19 % with a high fill factor of 84.05 %. This work presents a novel molecular engineering strategy for functionalizing SAMs to tune the energy levels, molecular dipoles, packing orientations to achieve stable and efficient solar performance. Importantly, our comprehensive investigation has unraveled the associated mechanisms, offering valuable insights for future advancements in PSCs.

Excited-State THz Vibrations in Aggregates of PtII Complexes Contribute to the Enhancement of Near-Infrared Emission Efficiencies.

The exploration of deactivation mechanisms for near-infrared(NIR)-emissive organic molecules has been a key issue in chemistry, materials science and molecular biology. In this study, based on transient absorption spectroscopy and transient grating photoluminescence spectroscopy, we demonstrate that the aggregated PtII complex 4H (efficient NIR emitter) exhibits collective out-of-plane motions with a frequency of 32 cm-1 (0.96 THz) in the excited states. Importantly, similar THz characteristics were also observed in analogous PtII complexes with prominent NIR emission efficiency. The conservation of THz motions enables excited-state deactivation to proceed along low-frequency vibrational coordinates, contributing to the suppression of nonradiative decay and remarkable NIR emission. These novel results highlight the significance of excited-state vibrations in nonradiative processes, which serve as a benchmark for improving device performance.

Towards stimulated Raman scattering spectro-microscopy across the entire Raman active region using a multiple-plate continuum.

Stimulated Raman scattering (SRS) has attracted increasing attention in bio-imaging because of the ability toward background-free molecular-specific acquisitions without fluorescence labeling. Nevertheless, the corresponding sensitivity and specificity remain far behind those of fluorescence techniques. Here, we demonstrate SRS spectro-microscopy driven by a multiple-plate continuum (MPC), whose octave-spanning bandwidth (600-1300 nm) and high spectral energy density (∼1 nJ/cm-1) enable spectroscopic interrogation across the entire Raman active region (0-4000 cm-1), SRS imaging of a Drosophila brain, and electronic pre-resonance (EPR) detection of a fluorescent dye. We envision that utilizing MPC light source will substantially enhance the sensitivity and specificity of SRS by implementing EPR mode and spectral multiplexing via accessing three or more coherent wavelengths.

Vortex beam assisted energy up-scaling for multiple-plate compression with a single spiral phase plate.

The vortex beam (Laguerre-Gaussian, LG10 mode) is employed to alleviate crystal damage in multiple-plate continuum generation. We successfully compressed 190-fs, 1030-nm pulses to 42 fs with 590 µJ input pulse energy, which is 5.5 times higher than that obtained by a Gaussian beam setup of the same footprint. High throughput (86%) and high intensity-weighted beam homogeneity (>98%) have also been achieved. This experiment confirms the great potential of beam shaping in energy up-scaling of nonlinear pulse compression.

USP9X-mediated deubiquitination of B-cell CLL/lymphoma 9 potentiates Wnt signaling and promotes breast carcinogenesis.

Hyperactivation of the canonical Wnt-signaling pathway is a prominent feature of a number of human malignancies. Transcriptional activation of this signaling cascade depends on the formation of the ß-catenin-B-cell CLL/lymphoma 9 (BCL9)-pygopus (PYGO) family plant homeodomain finger 1 complex, yet how the assembly of this complex is regulated remains to be investigated. Here, using MCF-7, HeLa, HEK293T, MDA-MB-231, and Sf9 cells, along with immunoblotting and immunofluorescence, nano-HPLC-MS/MS, deubiquitination, immunoprecipitation, and chromatin immunoprecipitation (ChIP) assays, we report that BCL9 physically associates with a protein deubiquitinase, ubiquitin-specific peptidase 9, X-linked (USP9X), and that USP9X removes Lys-63-linked polyubiquitin on Lys-212 of BCL9. Importantly, the USP9X-mediated BCL9 deubiquitination facilitated the formation of the ß-catenin-BCL9-PYGO complex, thereby potentiating the transcriptional activation of Wnt/ß-catenin target genes. We also show that USP9X-mediated BCL9 deubiquitination promotes the proliferation and invasion of breast cancer cells. Together, these results uncover USP9X as a deubiquitinase of BCL9, implicating USP9X in Wnt/ß-catenin signaling and breast carcinogenesis.

Greater than 50 times compression of 1030 nm Yb:KGW laser pulses to single-cycle duration.

Generation of octave-spanning spectrum that spans from 570 nm to 1300 nm utilizing 1030 nm 170 fs pulses from a Yb:KGW laser and a two-stage multiple-plate arrangement is demonstrated. 3.21 fs sub-single-cycle pulses are obtained after dispersion compensation. The high compression ratio of more than 50 times is achieved for two scenarios with widely different parameters including high input peak power at 1 kHz repetition rate and modest peak power at a high repetition rate of 100 kHz. The output pulses have good spatial mode quality and exhibit long-term stability. The achieved compression ratio and flexibility are unprecedented in ultrafast pulse compression to single-cycle regime. The experiments demonstrate that the technique of multiple-plate pulse compression is versatile and applicable for a wide range of laser pulse parameters.

Efficient nonlinear compression of a mode-locked thin-disk oscillator to 27 fs at 98 W average power.

We demonstrate efficient pulse compression of a 13.4 MHz, 534 fs, 123 W, Yb:YAG thin-disk oscillator down to 27 fs at 98 W average power, resulting in a record-high 166 MW peak power from an amplifier-free oscillator-driven setup. Our compressor is based on two stages: one multipass cell allowing us to reduce the pulse duration to sub-90 fs and, subsequently, a multiple-plate compressor, allowing us to reach 27 fs. The overall average power compression efficiency is 80%, and the beam has excellent beam quality and homogeneity. In addition, we demonstrate further spectral broadening that supports a transform limit of 5 fs in a second multiple-plate stage, demonstrating the potential for reaching a 100 W class, amplifier-free, few-cycle source in the near future. The performance of this unique source is very promising for applications previously restricted to amplified sources, such as efficient generation of extreme ultraviolet light at high repetition rate, and the generation of high-power broadband THz radiation.

Selective variable optical attenuator for visible and mid-Infrared wavelengths.

This work demonstrates a variable optical attenuator (VOA) using dynamic scattering mode (DSM) in ion-doped liquid crystals with negative dielectric anisotropy. The mechanism of attenuation comes from optical scattering, which is generated by the electrically induced instability of undulation of LC textures. Electric fields are applied to switch the initial transparent state of the designed VOA to scattering states, varying the transmittance. The electric field also changes the size of the scattering domain from the LC texture and causes the designed device to exhibit an ultra-broadband selective operation in a visible to mid-IR spectral range. Furthermore, the VOA can selectively block one visible or mid-IR wavelength of light while letting other light pass. Such a VOA has many superior optical switching properties, such as high on/off contrast, insensitivity to polarization, and spectral selectivity; therefore, it has the potential to be used in practical optical systems.

Broadband mid-infrared polarization rotator based on optically addressable LCs.

This work proposes a mid-infrared polarization rotator that incorporates a twisted nematic liquid crystal (TNLC) cell with a photo-controllable alignment layer. The TNLC device with a sufficient phase retardation can act as an achromic polarization rotation device over a wide wavelengths range and thus can rotate the polarization of a mid-IR laser beam. The photo-alignment technique enables TNLCs with arbitrary twisting angles to be generated by the use of visible polarized addressing light to control the directors of the photo-alignment layer. Therefore, arbitrary rotation angles of the polarization axis of a linearly polarized mid-IR laser beam can be realized. Moreover, the rewritable property and reliability of this polarization rotator are experimentally verified. The flexibility of polarization control for broadband mid-IR opens up a large range of potential mid-IR applications.