Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

Effects of phosphorous and antimony doping on thin Ge layers grown on Si.

Suppression of threading dislocations (TDs) in thin germanium (Ge) layers grown on silicon (Si) substrates has been critical for realizing high-performance Si-based optoelectronic and electronic devices. An advanced growth strategy is desired to minimize the TD density within a thin Ge buffer layer in Ge-on-Si systems. In this work, we investigate the impact of P dopants in 500-nm thin Ge layers, with doping concentrations from 1 to 50 × 1018 cm-3. The introduction of P dopants has efficiently promoted TD reduction, whose potential mechanism has been explored by comparing it to the well-established Sb-doped Ge-on-Si system. P and Sb dopants reveal different defect-suppression mechanisms in Ge-on-Si samples, inspiring a novel co-doping technique by exploiting the advantages of both dopants. The surface TDD of the Ge buffer has been further reduced by the co-doping technique to the order of 107 cm-2 with a thin Ge layer (of only 500 nm), which could provide a high-quality platform for high-performance Si-based semiconductor devices.

High-power, electrically-driven continuous-wave 1.55-µm Si-based multi-quantum well lasers with a wide operating temperature range grown on wafer-scale InP-on-Si (100) heterogeneous substrate.

A reliable, efficient and electrically-pumped Si-based laser is considered as the main challenge to achieve the integration of all key building blocks with silicon photonics. Despite the impressive advances that have been made in developing 1.3-µm Si-based quantum dot (QD) lasers, extending the wavelength window to the widely used 1.55-µm telecommunication region remains difficult. In this study, we develop a novel photonic integration method of epitaxial growth of III-V on a wafer-scale InP-on-Si (100) (InPOS) heterogeneous substrate fabricated by the ion-cutting technique to realize integrated lasers on Si substrate. This ion-cutting plus epitaxial growth approach decouples the correlated root causes of many detrimental dislocations during heteroepitaxial growth, namely lattice and domain mismatches. Using this approach, we achieved state-of-the-art performance of the electrically-pumped, continuous-wave (CW) 1.55-µm Si-based laser with a room-temperature threshold current density of 0.65 kA/cm-2, and output power exceeding 155 mW per facet without facet coating in CW mode. CW lasing at 120 °C and pulsed lasing at over 130 °C were achieved. This generic approach is also applied to other material systems to provide better performance and more functionalities for photonics and microelectronics.

CRISPR/CasΦ2-mediated gene editing in wheat and rye.

The compact CRISPR/CasΦ2 system provides a complementary genome engineering tool for efficient gene editing including cytosine and adenosine base editing in wheat and rye with high specificity, efficient use of the protospacer-adjacent motif TTN, and an alternative base-editing window.

Mesenchymal Stem Cells Accelerate Recovery of Acetic Acid-Induced Chronic Gastric Ulcer by Regulating Ekt/Akt/TRIM29 Axis.

Chronic gastric ulcer (CGU), a prevalent digestive disease, has a high incidence and is seriously harmful to human health. Mesenchymal stem cells (MSCs) have been proven to have beneficial therapeutic effects in many human diseases. Here, a CGU model induced by acetic acid in mice was used to evaluate the repair effects and potential mechanism of human umbilical cord-derived MSCs (hUC-MSCs) and hUC-MSCs derived conditioned medium (hUC-MSC-CM). We found that hUC-MSCs and hUC-MSC-CM treatment significantly repaired morphological characteristics of CGU, improved proliferation and decreased apoptosis of gastric cells, and promoted the generation of new blood vessels in granulation tissues. In addition, we could detect the homing of MSCs in gastric tissue, and MSCs may differentiate into Lgr5-positive cells. As well as this, in vitro experiments showed that hUC-MSC-CM could promote cell proliferation, stimulate cell cycle progression, and reduce the incidence of apoptosis. The transcriptome of cells and the iTRAQ proteome of gastric tissues suggest that MSCs may play a therapeutic role by increasing the expression of TRIM29. Additionally, it was found that knocking down TRIM29 significantly decreased the ameliorative effects of hUC-MSC-CM on cell apoptosis. As a result of further molecular experiments, it was found that TRIM29 is capable of phosphorylating Erk/Akt in specific cell type. As a whole, it appears that hUC-MSCs can be an effective therapeutic approach for promoting gastric ulcer healing and may exert therapeutic effects in the form of paracrine and differentiation into gastric cells.

Mutations in yeast Pcf11, a conserved protein essential for mRNA 3' end processing and transcription termination, elicit the Environmental Stress Response.

The Pcf11 protein is an essential subunit of the large complex that cleaves and polyadenylates eukaryotic mRNA precursor. It has also been functionally linked to gene-looping, termination of RNA Polymerase II (Pol II) transcripts, and mRNA export. We have examined a poorly characterized but conserved domain (amino acids 142-225) of the Saccharomyces cerevisiae  Pcf11 and found that while it is not needed for mRNA 3' end processing or termination downstream of the poly(A) sites of protein-coding genes, its presence improves the interaction with Pol II and the use of transcription terminators near gene promoters. Analysis of genome-wide Pol II occupancy in cells with Pcf11 missing this region, as well as Pcf11 mutated in the Pol II CTD Interacting Domain, indicates that systematic changes in mRNA expression are mediated primarily at the level of transcription. Global expression analysis also shows that a general stress response, involving both activation and suppression of specific gene sets known to be regulated in response to a wide variety of stresses, is induced in the two pcf11 mutants, even though cells are grown in optimal conditions. The mutants also cause an unbalanced expression of cell wall-related genes that does not activate the Cell Wall Integrity pathway but is associated with strong caffeine sensitivity. Based on these findings, we propose that Pcf11 can modulate the expression level of specific functional groups of genes in ways that do not involve its well-characterized role in mRNA 3' end processing.

Room-temperature continuous-wave topological Dirac-vortex microcavity lasers on silicon.

Robust laser sources are a fundamental building block for contemporary information technologies. Originating from condensed-matter physics, the concept of topology has recently entered the realm of optics, offering fundamentally new design principles for lasers with enhanced robustness. In analogy to the well-known Majorana fermions in topological superconductors, Dirac-vortex states have recently been investigated in passive photonic systems and are now considered as a promising candidate for robust lasers. Here, we experimentally realize the topological Dirac-vortex microcavity lasers in InAs/InGaAs quantum-dot materials monolithically grown on a silicon substrate. We observe room-temperature continuous-wave linearly polarized vertical laser emission at a telecom wavelength. We confirm that the wavelength of the Dirac-vortex laser is topologically robust against variations in the cavity size, and its free spectral range defies the universal inverse scaling law with the cavity size. These lasers will play an important role in CMOS-compatible photonic and optoelectronic systems on a chip.

TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)-histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63-rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Controlling amorphous silicon in scratching for fabricating high-performance micromixers.

As core parts of microfluidic chip analysis systems, micromixers show robust applications in wide fields. However, restricted by the fabrication technology, it remains challenging to achieve high-quality micromixers with both delicately designed structure and efficient mixing. In this study, based on the theory of chaotic mixing, sinusoidal structures with variable phases were designed and then fabricated through scanning probe lithography (SPL) and post-selective etching. It was found that scratches with phase differences can lead to the periodic formation of amorphous silicon (a-Si), which can resist etching. Consequentially, misaligned sine channels with thick-thin alternating 3D shapes can be generated in situ from the scratched traces after the etching. Further analysis showed that a thicker a-Si layer can be obtained by reducing the line spacing in the scratching, confirmed by Raman detections and simulations. With the proposed method, the misaligned sine micromixer was achieved with higher mixing efficiency than ever. The duplicating process was also investigated for high-precision production of micromixers. The study provided strategies for the miniaturization of high-performance microfluidic chips.

Distortion-free amplification of 100†GHz mode-locked optical frequency comb using quantum dot technology.

Semiconductor mode-locked optical frequency comb (ML-OFC) sources with extremely high repetition rates are central to many high-frequency applications, such as dense wavelength-division multiplexing. Dealing with distortion-free amplification of ultra-fast pulse trains from such ML-OFC sources in high-speed data transmission networks requires the deployment of semiconductor optical amplifiers (SOAs) with ultrafast gain recovery dynamics. Quantum dot (QD) technology now lies at the heart of many photonic devices/systems owing to their unique properties at the O-band, including low alpha factor, broad gain spectrum, ultrafast gain dynamics, and pattern-effect free amplification. In this swork, we report on ultrafast and pattern-free amplification of ∼100 GHz pulsed trains from a passively ML-OFC and up to 80 Gbaud/s non-return-to-zero (NRZ) data transmission using an SOA. Most significantly, both key photonic devices presented in this work are fabricated from identical InAs/GaAs QD materials operating at O-band, which paves the way for future advanced photonic chips, where ML-OFCs could be monolithically integrated with SOAs and other photonic components, all originated from the same QD-based epi-wafer.

Monolithically integrated photonic crystal surface emitters on silicon with a vortex beam by using bound states in the continuum.

Optical resonant cavities with high quality factor (Q-factor) are widely used in science and technology for their capabilities of strong confinement of light and enhanced light-matter interaction. The 2D photonic crystal structure with bound states in the continuum (BICs) is a novel concept for resonators with ultra-compact device size, which can be used to generate surface emitting vortex beams based on symmetry-protected BICs at the Γ point. Here, to the best of our knowledge, we demonstrate the first photonic crystal surface emitter with a vortex beam by using BICs monolithically grown on CMOS-compatible silicon substrate. The fabricated quantum-dot BICs-based surface emitter operates at 1.3 µm under room temperature (RT) with a low continuous wave (CW) optically pumped condition. We also reveal the BIC's amplified spontaneous emission with the property of a polarization vortex beam, which is promising to provide a novel degree of freedom in classical and quantum realms.

Lateral Bending of Ag Nanowires toward Controllable Manipulation.

Nanowires (NWs) provide opportunities for building high-performance sensors and devices at micro-/nanoscales. Directional movement and assembly of NWs have attracted extensive attention; however, controllable manipulation remains challenging partly due to the lack of understanding on interfacial interactions between NWs and substrates (or contacting probes). In the present study, lateral bending of Ag NWs was investigated under various bending angles and pushing velocities, and the mechanical performance corresponding to microstructures was clarified based on high-resolution transmission electron microscope (HRTRM) detections. The bending-angle-dependent fractures of Ag NWs were detected by an atomic force microscope (AFM) and a scanning electron microscope (SEM), and the fractures occurred when the bending angle was larger than 80°. Compared with an Ag substrate, Ag NWs exhibited a lower system stiffness according to the nanoindentation with an AFM probe. HRTRM observations indicated that there were grain boundaries inside Ag NWs, which would be contributors to the generation of fractures and cracks on Ag NWs during lateral bending and nanoindentation. This study provides a guide to controllably manipulate NWs and fabricate high-performance micro-/nanodevices.

Initialization of Nanowire or Cluster Growth Critically Controlled by the Effective V/III Ratio at the Early Nucleation Stage.

For self-catalyzed nanowires (NWs), reports on how the catalytic droplet initiates successful NW growth are still lacking, making it difficult to control the yield and often accompanying a high density of clusters. Here, we have performed a systematic study on this issue, which reveals that the effective V/III ratio at the initial growth stage is a critical factor that governs the NW growth yield. To initiate NW growth, the ratio should be high enough to allow the nucleation to extend to the entire contact area between the droplet and substrate, which can elevate the droplet off of the substrate, but it should not be too high in order to keep the droplet. This study also reveals that the cluster growth between NWs is also initiated from large droplets. This study provides a new angle from the growth condition to explain the cluster formation mechanism, which can guide high-yield NW growth.

Highly diastereo- and enantioselective C2 addition of 5H-oxazol-4-ones to γ-keto-α,ß-unsaturated esters.

The direct C2-addition of 5H-oxazol-4-ones to γ-keto-α,ß-unsaturated esters catalyzed by a chiral squaramide has been achieved. Diverse highly functionalized γ-keto esters bearing a C2-oxazolone at the α-position were afforded in high yields with excellent stereoselectivities (d.r. > 20 : 1 and up to 98% ee).

Improving Quantum Well Tube Homogeneity Using Strained Nanowire Heterostructures.

Bottom-up grown nanostructures often suffer from significant dimensional inhomogeneity, and for quantum confined heterostructures, this can lead to a corresponding large variation in electronic properties. A high-throughput characterization methodology is applied to >15,000 nanoskived sections of highly strained GaAsP/GaAs radial core/shell quantum well heterostructures revealing high emission uniformity. While scanning electron microscopy shows a wide nanowire diameter spread of 540-60+60 nm, photoluminescence reveals a tightly bounded band-to-band transition energy of 1546-3+4 meV. A highly strained core/shell nanowire design is shown to reduce the dependence of emission on the quantum well width variation significantly more than in the unstrained case.

From past to future: on-chip laser sources for photonic integrated circuits.

The realisation of on-chip light sources paves the way towards the full integration of Si-based photonic integrated circuits (PICs).

Appropriate oxygen vacancies and Mo-N bond synergistically modulate charge transfer dynamics of MoO3-x/S-CN for superior photocatalytic disinfection: Unveiling synergistic effects and disinfection mechanism.

Highly efficient charge transfer is a critical factor to modulate the photocatalytic activity. However, the conscious modulation of charge transfer efficiency is still a great challenge. Herein, a novel interfacial Mo-N bond and appropriate oxygen vacancies (OVs) modulated S-scheme MoO3-x/S-CN heterojunction was rationally fabricated for efficient photocatalytic disinfection. The results of characterizations and density functional theory (DFT) calculations suggested that the enhanced charge transfer dynamics is ascribed to the optimizing oxygen vacancies density and forming interfacial Mo-N bond. It can improve charge transfer efficiency from 36.4% (MoO3-x) to 52.5% (MoO3-x/S-CN) and produce more reactive oxygen species (ROS), achieving entirely inactivate of 7.60-log E. coli and S. aureus within 50 min and 75 min. Besides, MoO3-x/S-CN can well resist the disturbance from the coexisting substances, and can be applied in a wide pH range, and even authentic water bodies. Monitoring of bacterial antioxidant systems and membrane integrity revealed that bacterial inactivation begins with the oxidation of cell membrane and dies from leakage of intracellular substances and destruction of cell structure. This work provides an inspiration on consciously modulating S-scheme charge transfer efficiency by optimizing oxygen vacancies density and atomic-level interface control for promoting the photocatalytic antibacterial activity.

UBE3D Regulates mRNA 3'-End Processing and Maintains Adipogenic Potential in 3T3-L1 Cells.

We have previously described the role of an essential Saccharomyces cerevisiae gene, important for cleavage and polyadenylation 1 (IPA1), in the regulation of gene expression through its interaction with Ysh1, the endonuclease subunit of the mRNA 3'-end processing complex. Through a similar mechanism, the mammalian homolog ubiquitin protein ligase E3D (UBE3D) promotes the migratory and invasive potential of breast cancer cells, but its role in the regulation of gene expression during normal cellular differentiation has not previously been described. In this study, we show that CRISPR/Cas9-mediated knockout of Ube3d in 3T3-L1 cells blocks their ability to differentiate into mature adipocytes. Consistent with previous studies in other cell types, Ube3d knockout leads to decreased levels of CPSF73 and global changes in cellular mRNAs indicative of a loss of 3'-end processing capacity. Ube3d knockout cells also display decreased expression of known preadipogenic markers. Overexpression of either UBE3D or CPSF73 rescues the differentiation defect and partially restores protein levels of these markers. These results support a model in which UBE3D is necessary for the maintenance of the adipocyte-committed state via its regulation of the mRNA 3'-end processing machinery.

Low threading dislocation density and antiphase boundary free GaAs epitaxially grown on on-axis Si (001) substrates.

Epitaxial growth of III-V materials on a CMOS-compatible Si (001) substrate enables the feasibility of mass production of low-cost and high-yield Si-based III-V optoelectronic devices. However, the material dissimilarities between III-V and group-IV materials induce several types of defects, especially threading dislocations (TDs) and antiphase boundaries (APBs). The presence of these defects is detrimental to the optoelectronic device performance and thus needs to be eliminated. In this paper, the mechanism of APB annihilation during the growth of GaAs on on-axis Si (001) is clarified, along with a detailed investigation of the interaction between TDs and the periodic {110} APBs. A significant reduction in the TD density ascribed to the presence of periodic APBs is discussed. This new observation opens the possibility of reducing both APBs and TDs simultaneously by utilising optimised GaAs growth methods in the future. Hence, a thin APB-free GaAs/Si (001) platform with a low TD density (TDD) was obtained. Based on this platform, a high-performance high-yield III-V optoelectronic device grown on CMOS-compatible Si (001) substrates with an overall thickness below the cracking threshold is feasible, enabling the mass production of Si-based photonic integrated circuits (PICs).

Measurement of the quantum-confined Stark effect in InAs/In(Ga)As quantum dots with p-doped quantum dot barriers.

The quantum-confined Stark effect in InAs/In(Ga)As quantum dots (QDs) using non-intentionally doped and p-doped QD barriers was investigated to compare their performance for use in optical modulators. The measurements indicate that the doped QD barriers lead to a better figure of merit (FoM), defined as the ratio of the change in absorption Δα for a reverse bias voltage swing to the loss at 1 V α(1 V), FoM=Δα/α (1 V). The improved performance is due to the absence of the ground-state absorption peak and an additional component to the Stark shift. Measurements indicate that p-doping the QD barriers can lead to more than a 3x increase in FoM modulator performance between temperatures of -73 °C to 100 °C when compared with the stack with NIDQD barriers.