A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver.

Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent "switch" from corepressor to activator binding to thyroid hormone receptors (TRs), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRß1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR and defined high-confidence binding sites where TRs functioned at enhancers regulated in the same direction as the nearest gene in a TRß-dependent manner. Remarkably, although positive and negative regulation by THs have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical "all or none" coregulator switch model, THs regulate gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.

Transcriptional control of cone photoreceptor diversity by a thyroid hormone receptor.

Cone photoreceptor diversity allows detection of wavelength information in light, the first step in color (chromatic) vision. In most mammals, cones express opsin photopigments for sensitivity to medium/long (M, "green") or short (S, "blue") wavelengths and are differentially arrayed over the retina. Cones appear early in retinal neurogenesis but little is understood of the subsequent control of diversity of these postmitotic neurons, because cone populations are sparse and, apart from opsins, poorly defined. It is also a challenge to distinguish potentially subtle differences between cell subtypes within a lineage. Therefore, we derived a Cre driver to isolate individual M and S opsin-enriched cones, which are distributed in counter-gradients over the mouse retina. Fine resolution transcriptome analyses identified expression gradients for groups of genes. The postnatal emergence of gradients indicated divergent differentiation of cone precursors during maturation. Using genetic tagging, we demonstrated a role for thyroid hormone receptor ß2 (TRß2) in control of gradient genes, many of which are enriched for TRß2 binding sites and TRß2-regulated open chromatin. Deletion of TRß2 resulted in poorly distinguished cones regardless of retinal location. We suggest that TRß2 controls a bipotential transcriptional state to promote cone diversity and the chromatic potential of the species.

A PTIP-PA1 subcomplex promotes transcription for IgH class switching independently from the associated MLL3/MLL4 methyltransferase complex.

Class switch recombination (CSR) diversifies antibodies for productive immune responses while maintaining stability of the B-cell genome. Transcription at the immunoglobulin heavy chain (Igh) locus targets CSR-associated DNA damage and is promoted by the BRCT domain-containing PTIP (Pax transactivation domain-interacting protein). Although PTIP is a unique component of the mixed-lineage leukemia 3 (MLL3)/MLL4 chromatin-modifying complex, the mechanisms for how PTIP promotes transcription remain unclear. Here we dissected the minimal structural requirements of PTIP and its different protein complexes using quantitative proteomics in primary lymphocytes. We found that PTIP functions in transcription and CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage. We identified a tandem BRCT domain of PTIP that is sufficient for CSR and identified PA1 as its main functional protein partner. Collectively, we provide genetic and biochemical evidence that a PTIP-PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription during CSR. These results further our understanding of how multifunctional chromatin-modifying complexes are organized by subcomplexes that harbor unique and distinct activities.

Sub-10 nm Precision Engineering of Solid-State Defects via Nanoscale Aperture Array Mask.

Engineering a strongly interacting uniform qubit cluster would be a major step toward realizing a scalable quantum system for quantum sensing and a node-based qubit register. For a solid-state system that uses a defect as a qubit, various methods to precisely position defects have been developed, yet the large-scale fabrication of qubits within the strong coupling regime at room temperature continues to be a challenge. In this work, we generate nitrogen vacancy (NV) color centers in diamond with sub-10 nm scale precision using a combination of nanoscale aperture arrays (NAAs) with a high aspect ratio of 10 and a secondary E-beam hole pattern used as an ion-blocking mask. We perform optical and spin measurements on a cluster of NV spins and statistically investigate the effect of the NAAs during an ion-implantation process. We discuss how this technique is effective for constructing a scalable system.

Entangling three identical particles via spatial overlap.

Quantum correlations between identical particles are at the heart of quantum technologies. Several studies with two identical particles have shown that the spatial overlap and indistinguishability between the particles are necessary for generating bipartite entanglement. On the other hand, researches on the extension to more than two-particle systems are limited by the practical difficulty to control multiple identical particles in laboratories. In this work, we propose schemes to generate two fundamental classes of genuine tripartite entanglement, i.e., GHZ and W classes, which are experimentally demonstrated using linear optics with three identical photons. We also show that the tripartite entanglement class decays from the genuine entanglement to the full separability as the particles become more distinguishable from each other. Our results support the prediction that particle indistinguishability is a fundamental element for entangling identical particles.

Demonstration of Complete Information Trade-Off in Quantum Measurement.

While an information-disturbance trade-off in quantum measurement has been at the core of foundational quantum physics and constitutes a basis of secure quantum information processing, recently verified reversibility of a quantum measurement requires to refine it toward a complete version of information trade-off in quantum measurement. Here we experimentally demonstrate a trade-off relation among all information contents, i.e., information gain, disturbance, and reversibility in quantum measurement. By exploring quantum measurements applied on a photonic qutrit, we observe that the information of a quantum state is split into three distinct parts accounting for the extracted, disturbed, and reversible information. We verify that such different parts of information are in trade-off relations not only pairwise but also triplewise all at once, and find that the triplewise relation is tighter than any of the pairwise relations. Finally, we realize optimal quantum measurements that inherently preserve quantum information without loss of information, which offer wider applications in measurement-based quantum information processing.

Comparison of precutting endoscopic mucosal resection and endoscopic submucosal dissection for large (20-30 mm) flat colorectal lesions.

BACKGROUND AND AIM: The complete and safe removal of large (≥ 20 mm) colorectal lesions is an area of concern. Endoscopic submucosal dissection (ESD) effectively removes these lesions compared with endoscopic mucosal resection (EMR). However, ESD requires advanced techniques, longer procedure time, and high cost. Precutting EMR (EMR-P) is a modified EMR method that overcomes the limitations of EMR. This study aimed to compare the efficacy and safety of EMR-P and ESD in large (20-30 mm) flat colorectal lesions. METHODS: This was a retrospective analysis of cases in which 20- to 30-mm flat colorectal lesions were resected at Seoul St. Mary's Hospital from January 2014 to December 2019. Propensity score matching was performed to control for possible confounders. RESULTS: Two hundred and ninety-nine patients were included in this study. After matching, 90 patients were assigned to each group. There were no significant difference in complete resection rates (92.2% vs 92.2%, P = 1.000), en bloc resection rates (95.6% vs 97.8%, P = 0.682), and mean size of lesions (22.9 ± 3.1 mm vs 23.0 ± 3.1 mm, P = 0.867) between EMR-P and ESD. Procedure time was significantly shorter with EMR-P (11.0 ± 6.5 min vs 37.0 ± 19.3 min, P < 0.001). The adverse events rate was not significantly different between both groups. No local recurrence occurred in both groups. CONCLUSIONS: Precutting EMR was not significantly different to ESD in terms of complete resection rate and en bloc resection rate for 20- to 30-mm flat colorectal lesions without fibrosis. Furthermore, EMR-P has shorter procedure time than ESD. EMR-P could be considered one of standard treatments for large flat colorectal lesions.

H2B ubiquitylation enhances H3K4 methylation activities of human KMT2 family complexes.

In mammalian cells, distinct H3K4 methylation states are created by deposition of methyl groups by multiple complexes of histone lysine methyltransferase 2 (KMT2) family proteins. For comprehensive analyses that directly compare the catalytic properties of all six human KMT2 complexes, we employed a biochemically defined system reconstituted with recombinant KMT2 core complexes (KMT2CoreCs) containing minimal components required for nucleosomal H3K4 methylation activity. We found that each KMT2CoreC generates distinct states and different levels of H3K4 methylation, and except for MLL3 all are stimulated by H2Bub. Notably, SET1BCoreC exhibited the strongest H3K4 methylation activity and, to our surprise, did not require H2B ubiquitylation (H2Bub); in contrast, H2Bub was required for the H3K4me2/3 activity of the paralog SET1ACoreC. We also found that WDR5, RbBP5, ASH2L and DPY30 are required for efficient H3K4 methyltransferase activities of all KMT2CoreCs except MLL3, which could produce H3K4me1 in the absence of WDR5. Importantly, deletion of the PHD2 domain of CFP1 led to complete loss of the H3K4me2/3 activities of SET1A/BCoreCs in the presence of H2Bub, indicating a critical role for this domain in the H2Bub-stimulated H3K4 methylation. Collectively, our results suggest that each KMT2 complex methylates H3K4 through distinct mechanisms in which individual subunits differentially participate.

Implementation of a 3 × 3 directionally-unbiased linear optical multiport.

Linear optical multiports are widely used in photonic quantum information processing. Naturally, these devices are directionally-biased since photons always propagate from the input ports toward the output ports. Recently, the concept of directionally-unbiased linear optical multiports was proposed. These directionally-unbiased multiports allow photons to propagate along a reverse direction, which can greatly reduce the number of required linear optical elements for complicated linear optical quantum networks. Here, we report an experimental demonstration of a 3 × 3 directionally-unbiased linear optical fiber multiport using an optical tritter and mirrors. Compared to the previous demonstration using bulk optical elements which works only with light sources with a long coherence length, our experimental directionally-unbiased 3 × 3 optical multiport does not require a long coherence length since it provides negligible optical path length differences among all possible optical trajectories. It can be a useful building block for implementing large-scale quantum walks on complex graph networks.

Entangling bosons through particle indistinguishability and spatial overlap.

Particle identity and entanglement are two fundamental quantum properties that work as major resources for various quantum information tasks. However, it is still a challenging problem to understand the correlation of the two properties in the same system. While recent theoretical studies have shown that the spatial overlap between identical particles is necessary for nontrivial entanglement, the exact role of particle indistinguishability in the entanglement of identical particles has never been analyzed quantitatively before. Here, we theoretically and experimentally investigate the behavior of entanglement between two bosons as spatial overlap and indistinguishability simultaneously vary. The theoretical computation of entanglement for generic two bosons with pseudospins is verified experimentally in a photonic system. Our results show that the amount of entanglement is a monotonically increasing function of both quantities. We expect that our work provides an insight into deciphering the role of the entanglement in quantum networks that consist of identical particles.

Diamond photonic crystal mirror with a partial bandgap by two 2D photonic crystal layers.

In this study, photonic crystals with a partial bandgap are demonstrated in the visible region using single-crystal diamonds. Quasi-three-dimensional photonic crystal structures are fabricated in the surface of the single-crystal diamonds using a tetrahedron Faraday cage that enables angled dry etching in three directions simultaneously. The reflection spectra can be controlled by varying the lattice constant of the photonic crystals. In addition, nitrogen-vacancy center single-photon sources are implanted on top of the diamond photonic crystals, and doubled collection efficiency from the light sources is achieved.

Reference-frame-independent, measurement-device-independent quantum key distribution using fewer quantum states.

Reference-frame-independent quantum key distribution (RFI-QKD) provides a practical way to generate secret keys between two remote parties without sharing common reference frames. On the other hand, measurement-device-independent QKD (MDI-QKD) offers a high level of security, as it is immune to all quantum hacking attempts to measurement devices. The combination of these two QKD protocols, i.e., RFI-MDI-QKD, is one of the most fascinating QKD protocols, since it holds advantages of both practicality and security. For further practicality of RFI-MDI-QKD, it is beneficial to reduce the implementation complexity. Here, we show that RFI-MDI-QKD can be implemented using fewer quantum states than those of its original proposal. We find that, in principle, the number of quantum states for one of the parties can be reduced from six to three without compromising security. Compared to conventional RFI-MDI-QKD where both parties transmit six quantum states, it significantly simplifies the implementation of the QKD protocol. We also verify the feasibility of the scheme with a proof-of-principle experiment.

Universal Compressive Characterization of Quantum Dynamics.

Recent quantum technologies utilize complex multidimensional processes that govern the dynamics of quantum systems. We develop an adaptive diagonal-element-probing compression technique that feasibly characterizes any unknown quantum processes using much fewer measurements compared to conventional methods. This technique utilizes compressive projective measurements that are generalizable to an arbitrary number of subsystems. Both numerical analysis and experimental results with unitary gates demonstrate low measurement costs, of order O(d^{2}) for d-dimensional systems, and robustness against statistical noise. Our work potentially paves the way for a reliable and highly compressive characterization of general quantum devices.

Informationally symmetrical Bell state preparation and measurement.

Bell state measurement (BSM) plays crucial roles in photonic quantum information processing. The standard linear optical BSM is based on Hong-Ou-Mandel interference where two photons meet and interfere at a beamsplitter (BS). However, a generalized two-photon interference is not based on photon-photon interaction, but interference between two-photon probability amplitudes. Therefore, it might be possible to implement BSM without interfering photons at a BS. Here, we investigate a linear optical BSM scheme which does not require two photon overlapping at a BS. By unleashing the two photon coexistence condition, it can be symmetrically divided into two parties. The symmetrically dividable property suggests an informationally symmetrical BSM between remote parties without a third party. We also present that our BSM scheme can be used for Bell state preparation between remote parties without a third party. Since our BSM scheme can be easily extended to multiple photons, it can be useful for various quantum communication applications.

Limits on manipulating conditional photon statistics via interference of weak lasers.

Photon anti-bunching, measured via the Hanbury-Brown-Twiss experiment, is one of the key signatures of quantum light and is tied to sub-Poissonian photon number statistics. Recently, it has been reported that photon anti-bunching or conditional sub-Poissonian photon number statistics can be obtained via second-order interference of mutually incoherent weak lasers and heralding based on photon counting [Phys. Rev. A92, 033855 (2015)10.1103/PhysRevA.92.033855; Opt. Express24, 19574 (2016)10.1364/OE.24.019574; https://arxiv.org/abs/1601.08161]. Here, we report theoretical analysis on the limits of manipulating conditional photon statistics via interference of weak lasers. It is shown that conditional photon number statistics can become super-Poissonian in such a scheme. We, however, demonstrate explicitly that it cannot become sub-Poissonian, i.e., photon anti-bunching cannot be obtained in such a scheme. We point out that incorrect results can be obtained if one does not properly account for seemingly negligible higher-order photon number expansions of the coherent state.

Methylsulfonylmethane inhibits NLRP3 inflammasome activation.

Methylsulfonylmethane (MSM) is an organosulfur compound and the health benefits associated with MSM include inflammation. Although MSM has been shown to have various physiological effects, no study has yet focused on inflammasome activation. The inflammasome is a multiprotein complex that serves as a platform for caspase 1-dependent proteolytic maturation and secretion of interleukin-1ß (IL-1ß). In this study, we tested the effect of MSM on inflammasome activation using mouse and human macrophages. In our results, MSM significantly attenuated NLRP3 inflammasome activation in lipopolysaccharide-primed macrophages, although it had no effect on NLCR4 or AIM2 inflammasome activation. Extracts of MSM-enriched vegetables presented the same inhibitory effect on NLRP3 inflammasome activation as MSM. MSM also attenuated the transcriptional expression of IL-1α, IL-1ß, IL-6, and NLRP3. Taken together, these results show that MSM has anti-inflammatory characteristics, interrupts NLRP3 inflammasome activation, and inhibits pro-cytokine expression. We further confirmed the intracellular mechanism of MSM in relation to NLRP3 inflammasome activation, followed by comparison with that of DMSO. Both chemicals showed a synergic effect on anti-NLRP3 activation and attenuated production of mitochondrial reactive oxygen species (ROS). Thus, MSM is a selective inhibitor of NLRP3 inflammasome activation and can be developed as a supplement to control several metabolic disorders.

UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity.

To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/ß-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development.

Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.

Loss of function of mouse Pax-Interacting Protein 1-associated glutamate rich protein 1a (Pagr1a) leads to reduced Bmp2 expression and defects in chorion and amnion development.

BACKGROUND: Human PAX-Interacting Protein 1 (PAXIP1)-associated glutamate rich protein 1 (PAGR1, also known as PA1) originally was discovered as part of a complex containing PAXIP1 and histone H3K4 methyltransferases MLL3 and MLL4, suggesting a role in epigenetic gene regulation. Further in vitro studies suggested additional functions in DNA damage repair and transcription. However, in vivo analysis of PAGR1 function has been lacking. RESULTS: Here we show that expression of the cognate mouse gene Pagr1a is found predominately in the extraembryonic and chorionic ectoderm from pregastrulation stages and is up-regulated within the embryo proper after gastrulation. Embryos with a germ line deletion of Pagr1a establish the anterior-posterior axis, and show normal neuroectodermal, mesodermal, and endodermal patterning, but fail to develop beyond the four- to five-somite stage or to undergo axial rotation. Pagr1a(-) (/) (-) embryos also show abnormal development of extraembryonic tissues with defects seen in the amnion, chorion and visceral yolk sac. At the molecular level, Pagr1a(-) (/) (-) embryos have reduced expression of BMP2, a known regulator of extraembryonic development. CONCLUSIONS: Loss of mouse Pagr1a function leads to defective extraembryonic development, likely due at least in part to altered BMP signaling, contributing to developmental arrest.