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Undesired coupling to the surrounding environment destroys long-range correlations in quantum processors and hinders coherent evolution in the nominally available computational space. This noise is an outstanding challenge when leveraging the computation power of near-term quantum processors1. It has been shown that benchmarking random circuit sampling with cross-entropy benchmarking can provide an estimate of the effective size of the Hilbert space coherently available2–8. Nevertheless, quantum algorithms’ outputs can be trivialized by noise, making them susceptible to classical computation spoofing. Here, by implementing an algorithm for random circuit sampling, we demonstrate experimentally that two phase transitions are observable with cross-entropy benchmarking, which we explain theoretically with a statistical model. The first is a dynamical transition as a function of the number of cycles and is the continuation of the anti-concentration point in the noiseless case. The second is a quantum phase transition controlled by the error per cycle; to identify it analytically and experimentally, we create a weak-link model, which allows us to vary the strength of the noise versus coherent evolution. Furthermore, by presenting a random circuit sampling experiment in the weak-noise phase with 67 qubits at 32 cycles, we demonstrate that the computational cost of our experiment is beyond the capabilities of existing classical supercomputers. Our experimental and theoretical work establishes the existence of transitions to a stable, computationally complex phase that is reachable with current quantum processors.

The mammalian gut microbiota plays diverse and essential roles in modulating host physiology. Key mediators determining the outcome of the microbiota-host interactions are the small molecule metabolites produced by the gut microbiota. The liver is a major organ exposed to gut microbial metabolites, and it serves as the nexus for maintaining healthy interactions between the gut microbiota and the host. At the same time, the liver is the primary target of potentially harmful gut microbial metabolites. In this review, we provide an up-to-date list of gut microbial metabolites that have been identified to either increase or decrease host susceptibility to acetaminophen (APAP)-induced liver injury. The signaling pathways and molecular factors involved in the progression of APAP-induced hepatotoxicity are well-established, and we propose that the mouse model of APAP-induced hepatotoxicity serves as a model system for uncovering gut microbial metabolites with previously unknown functions. Furthermore, we envision that gut microbial metabolites identified to alter APAP-induced hepatotoxicity likely have broader implications in other liver diseases.SIGNIFICANCE STATEMENTThis review provides an overview of the role of the gut microbiota in modulating the host susceptibility to acetaminophen (APAP)-induced liver injury. It focuses on the roles of gut bacterial small molecule metabolites as mediators of the interaction between the gut microbiota and the liver. It also illustrates the utility of APAP-induced liver injury as a model to identify gut microbial metabolites with biological function.

Improvement of hard magnetic property for melt spun CeCo5 ribbons by doping proper Fe and C is demonstrated. Low magnetic properties, remanence ( $B_{r}$ ) of 4.2 kG, coercivity ( ${}_{i}H{}_{c}$ ) of 1.6 kOe, and energy product [ $(\textit {BH})_{\max }$ ] of 1.8 MGOe, are found for binary CeCo5 ribbons due to extremely large size of grains, even prepared at a high wheel speed of 40 m/s. ${}_{i}H{}_{c}$ is largely enhanced to 12.8 kOe by doping C and 15.0 kOe by co-doping Fe and C, and therefore, $(\textit {BH})_{\max }$ is increased to 3.5 and 5.1 MGOe, respectively. The coercivity achieved in this work is superior to those reported ever before, and $(\textit {BH})_{\max }$ is also larger than the theoretical value of 4.7 MGOe for isotropic CeCo5 alloy. X-ray diffraction (XRD) and thermomagnetic analysis (TMA) results reveal Fe and C enter into the 1:5 phase to modify the lattice constant and increase $T_{C}$ , and the increased $c/a$ ratio of the 1:5 phase may improve $H_{a}$ and contribute to enhancing the coercivity. Microstructure analysis indicates the grain size is effectively refined by doping C and co-doping Fe and C. Fine microstructure for C-containing ribbons contributes to attaining a high coercivity of 12.8–15.0 kOe. Besides, Fe-doping may increase the magnetization of the 1:5 phase, and therefore improve the remanence and $(\textit {BH})_{\max }$ . The results of this work suggest that the magnetic properties of CeCo5 ribbons could be improved by modification of 1:5 crystal and microstructure refinement due to proper Fe and C-codoping.

We investigated phase constitutions, ferroelectric (FE), and magnetic characteristics of BiFeO3 (BFO) films with Tb substitution. Bi1-xTbxFeO3 (BTFO) ( ${x}$ = 0.00–0.15) thin films were prepared on the Pt-buffered glass substrates by pulsed laser deposition (PLD). BTFO films with ${x}$ = 0.00–0.15 were confirmed to mainly consist of the perovskite phase. The structure in the studied films is transformed from rhombohedral for ${x}$ = 0.00 to pseudo-cubic for ${x}$ = 0.05–0.10, and orthorhombic for ${x}$ = 0.15. The studied BTFO polycrystalline films exhibit the desired FE and ferromagnetic properties at the same time. The remanent polarization ( $2P_{r}$ ) of $157 ~\mu \text{C}$ /cm2 and electrical coercive field ( $E_{c}$ ) of 485 kV/cm are obtained for BTFO films at ${x}$ = 0.05. Besides, the saturation magnetization ( $M_{s}$ ) of 15.0 emu/cm3 is found for $x$ = 0.05 film. The enhanced $M_{s}$ with Bi0.95Tb0.05FeO3 is due to the magnetic moment of the doped Tb $^{3+}$ ion in addition to the suppressed spiral spin configuration. The result of this work indicates that the radius and magnetic moment of the Tb $^{3+}$ ions play a critical role in the structural evolution, refined microstructure, and therefore, enhanced multiferroic (MF) properties for Tb-substituted BFO polycrystalline films.

Coercivity enhancement of hot-deformed (HD) NdFeB magnets by doping low-cost Ce80M20-xZnx ( $M$ = Cu and Al; $x$ = 0–20) alloy powders is compared. By doping Ce80M20 -xZnx powders, coercivity ( $_{i}H_{c}$ ) is increased from 15.0 kOe for the as-upset magnet to 17.2–18.5 kOe for $M$ = Cu and 17.0–19.1 kOe for $M$ = Al, respectively. Compared to the magnet doped with Ce80Al20 ( $_{i}H_{c}$ = 17.0 kOe), the magnet doped with Ce80Al10Zn10 exhibits a higher $_{i}H_{c}$ of 19.1 kOe. In addition, the grain morphology of the magnet doped with Ce80Al10Zn10 is more platelet-like than that doped with Ce80Al20. The platelet grain morphology contributes to the good (00L) texture, and thus, higher remanence is obtained. Microstructure and element analysis show Ce, Al, Cu, and Zn prefer to distribute at grain boundary, which can strengthen the decoupling effect between the adjacent Nd2Fe14B (2:14:1) grains. Almost unchanged Curie temperature ( $T_{C}$ ) of 2:14:1 phase for the magnet doped with Ce80Al10Zn10 also indicates Ce mostly distributes at the grain boundary. The effect of doping Ce–Al–Zn-containing alloys on the coercivity enhancement and mechanism for HD NdFeB magnets is also discussed in this work.

Meniscus injuries are extremely common with approximately one million patients undergoing surgical treatment annually in the U.S. alone, but no regenerative therapy exist. Previously, we showed that controlled applications of connective tissue growth factor (CTGF) and transforming growth factor beta 3 (TGFβ3) via fibrin-based bio-glue facilitate meniscus healing by inducing recruitment and stepwise differentiation of synovial mesenchymal stem/progenitor cells. Here, we first explored the potential of genipin, a natural crosslinker, to enhance fibrin-based glue's mechanical and degradation properties. In parallel, we identified the harmful effects of lubricin on meniscus healing and investigated the mechanism of lubricin deposition on the injured meniscus surface. We found that the pre-deposition of hyaluronic acid (HA) on the torn meniscus surface mediates lubricin deposition. Then we implemented chemical modifications with heparin conjugation and CD44 on our bioactive glue to achieve strong initial bonding and integration of lubricin pre-coated meniscal tissues. Our data suggested that heparin conjugation significantly enhances lubricin-coated meniscal tissues. Similarly, CD44, exhibiting a strong binding affinity to lubricin and hyaluronic acid (HA), further improved the integrated healing of HA/lubricin pre-coated meniscus injuries. These findings may represent an important foundation for developing a translational bio-active glue guiding the regenerative healing of meniscus injuries.

Purpose: The ideal analgesic regimen for the anterior approach to scoliosis repair is not clearly defined. The purpose of the study was to summarize and identify gaps in the current literature specific to the anterior approach to scoliosis repair. Methods: A scoping review was conducted in July 2022 utilizing PubMed, Cochrane, and Scopus databases guided by the PRISMA-ScR framework. Results: The database search generated 641 possible articles, 13 of which met all inclusion criteria. All articles focused on the effectiveness and safety of regional anesthetic techniques, while a minority also provided both opioid and non-opioid medication frameworks. Conclusion: Continuous Epidural Analgesia (CEA) is the most well-studied intervention for pain control in anterior scoliosis repair, but other, more novel regional anesthetic techniques offer safe and effective potential alternatives. More research is indicated to compare the effectiveness of different regional techniques and perioperative medication regimens specific to anterior scoliosis repair.

Full transposition of superconducting wires within a conductor may not be a requirement for high temperature superconductor (HTS) magnet for fusion applications. Already, conduction-cooled 20 T model coil built with non-transposed HTS stacks has been demonstrated by Commonwealth Fusion Systems (CFS). Here, we discuss 3 possible stacked HTS cryogen-cooled conductor concepts for toroidal field (TF) magnet applications. The first one is somewhat like LTS conductors, the second, HTS stacks are capped by copper stabilizer, the last one, only stacks without copper. We simulate a simplified TF magnet model, 12 T, size of KSTAR, using the 3 conceptual HTS conductor designs. A comparative thermo-hydraulic analysis for a fast charging case has been carried out and its implications on HTS conductor design are further discussed.

Paragangliomas in the central nervous system account for 0.6% of all head and neck neoplasms, with glomus tympanicum being the most common middle ear tumor. Carcinoid tumors are neuroendocrine tumors, representing less than 1% of neuroendocrine neoplasms in the middle ear. Misdiagnoses have been reported in the literature regarding glomus and carcinoid tumors, however, none have been in the central nervous system or middle ear.

The inevitable gap between in vitroand in vivodegradation rate of biomaterials has been a challenging factor in the optimal designing of scaffold's degradation to be balanced with new tissue formation. To enable non-/minimum-invasive tracking of in vivoscaffold degradation, chemical modifications have been applied to label polymers with fluorescent dyes. However, the previous approaches may have limited expandability due to complicated synthesis processes. Here, we introduce a simple and efficient method to fluorescence labeling of polymeric scaffolds via blending with near-infrared (NIR) quantum dots (QDs), semiconductor nanocrystals with superior optical properties. QDs-labeled, 3D-printed PCL scaffolds showed promising efficiency and reliability in quantitative measurement of degradation using a custom-built fiber-optic imaging modality. Furthermore, QDs-PCL scaffolds showed neither cytotoxicity nor secondary labeling of adjacent cells. QDs-PCL scaffolds also supported the engineering of fibrous, cartilaginous, and osteogenic tissues from mesenchymal stem/progenitor cells (MSCs). In addition, QDs-PCL enabled a distinction between newly forming tissue and the remaining mass of scaffolds through multi-channel imaging. Thus, our findings suggest a simple and efficient QDs-labeling of PCL scaffolds and minimally invasive imaging modality that shows significant potential to enable in vivotracking of scaffold degradation as well as new tissue formation.

Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely mobilization of multipotential progenitors from the bone marrow. It remains unknown what triggers the mobilization of bone marrow ILC progenitors (ILCPs). We report that ILCPs are regulated by the circadian clock to emigrate and generate mature ILCs in the periphery. We found that circadian-clock-defective ILCPs fail to normally emigrate and generate ILCs. We identified circadian-clock-controlled endocrine and cytokine cues that, respectively, regulate the retention and emigration of ILCPs at distinct times of each day. Activation of the stress-hormone-sensing glucocorticoid receptor upregulates CXCR4 on ILCPs for their retention in the bone marrow, while the interleukin-18 (IL-18) and RORα signals upregulate S1PR1 on ILCPs for their mobilization to the periphery. Our findings establish important roles of circadian signals for the homeostatic efflux of bone marrow ILCPs.

Wire bonding is a key integrated circuit (IC) interconnect technology, and it adheres metal wires to the IC pad and substrate by applying significant compression and energic loading. On the other hand, the Cu/low-k technology of the advanced IC industry is driven by the market demands of small size, and low resistance-capacitance delay applications. Because material properties of Cu/low-k back end of line (BEOL) exhibit significant differences from the conventional Al-based system, 3 new reliability failure modes are introduced after the wire bonding process, including the Al pad lift, Cu pad lift and the nanoscaled Cu diffusion barrier crack. To study the mechanical characteristics of the Cu/low-k BEOL under the wire bonding process loading, this research establishes a set of transient numerical models with mesh control and computation acceleration techniques. The mechanical characteristics of the wire bonding process and the differences between the conventional and Cu/low-k BEOLs are analyzed via the detailed analysis of the historical stress plots over the wire bonding process time. Moreover, the risks of wire bonding induced the failure modes against different Cu/low-k designs are studied by the proper mechanical indices, and optimized design trends are suggested.

Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality.

Innate lymphoid cells (ILCs) rapidly undergo expansion in population size and functional maturation in response to cytokines that signal infection, tissue damage, or changes in physiology. Optimal ILC responses are shaped, in part, by the microbiota but the mechanisms remain unclear. We report that short-chain fatty acids (SCFAs), produced by the commensal microbiota from dietary fibers, support optimal expansion of ILCs, including ILC1, ILC2, and ILC3 in the intestines through their G-protein-coupled receptors (GPCRs). While this function is primarily important for intestinal ILC populations, it can also boost ILC responses in other tissues depending on host condition. ILCs express multiple GPCRs that detect SCFAs. Interestingly, we found that the expression of SCFA receptors, such as Ffar2 and Ffar3, by ILCs is induced by SCFAs. GPCR triggering by SCFAs co-stimulates the activation of phosphoinositide 3-kinase (PI3K), Stat3, Stat5, and mammalian target of rapamycin (mTOR), which is important for ILC proliferation. While Ffar2 signaling promotes ILC2 proliferation, SCFAs can suppress ILC2 proliferation through a non-Ffar2-mediated mechanism. In conclusion, our findings indicate that SCFAs, as the major mediator of healthy microbiota and nutritional status, function to maintain optimal numbers of ILCs in peripheral tissues during infection and inflammatory responses.

Innate lymphoid cells (ILCs) rapidly undergo expansion in population size and functional maturation in response to cytokines that signal infection, tissue damage, or changes in physiology. Optimal ILC responses are shaped, in part, by the microbiota but the mechanisms remain unclear. We report that short-chain fatty acids (SCFAs), produced by the commensal microbiota from dietary fibers, support optimal expansion of ILCs, including ILC1, ILC2, and ILC3 in the intestines through their G-protein-coupled receptors (GPCRs). While this function is primarily important for intestinal ILC populations, it can also boost ILC responses in other tissues depending on host condition. ILCs express multiple GPCRs that detect SCFAs. Interestingly, we found that the expression of SCFA receptors, such as Ffar2 and Ffar3, by ILCs is induced by SCFAs. GPCR triggering by SCFAs co-stimulates the activation of phosphoinositide 3-kinase (PI3K), Stat3, Stat5, and mammalian target of rapamycin (mTOR), which is important for ILC proliferation. While Ffar2 signaling promotes ILC2 proliferation, SCFAs can suppress ILC2 proliferation through a non-Ffar2-mediated mechanism. In conclusion, our findings indicate that SCFAs, as the major mediator of healthy microbiota and nutritional status, function to maintain optimal numbers of ILCs in peripheral tissues during infection and inflammatory responses.

To describe the temporal association and identify risk factors between cancer diagnosis and various types of arterial thromboembolism (ATE).

ABSTRACTAn optical method is proposed to real-time monitor the order transformation of FePt thin films. By measuring the surface reflection amplitude, onset temperature can be determined correctly. In a heating process, order transformation drastically increases the surface roughness due to recrystallization and grain growth, resulting in rapid drop of surface reflectivity. By tracking this drop, the kinetic ordering temperature can be determined. Experimentally measured kinetic ordering temperature for Fe50.4Pt49.6, Fe46.6Pt53.4, and Fe52.7Pt47.3thin films of 60 nm in thickness are 396°C, 437°C, and 368°C, respectively. They are in good agreement with the published DSC data.

ABSTRACTThe influence of combined corrosion and vibration to the anti-loosening performance of a precision locknut used in a machine tool is investigated. Firstly, the locknut was submerged in 5% NaCl solution according to ASTM B895 standard for corrosion testing. The locknuts, after submerged in 1-hr, 2-hr and 4-hr periods, respectively, were then installed on the rotating spindle in a vertical dynamic impact tester for performing anti-loosening test. The initial installed pretension was 9800 N and the spindle was rotating in a constant speed of 1000 rpm. Turmogrease Li 802 EP lubricant was used on the contact surface between spindle thread and locknut. The set screws on the locknut were tightened sequentially and evenly in three-stage of torque: 1.96 N-m, 3.92 N-m and 5.88 N-m. Its real-time pretension variation with the periodic transverse impact and its final loosening torque were measured. Accordingly, the axial force ratio and anti-loosening torque ratio were calculated and discussed. It was found that corrosion treatment had similar influence on both the axial force ratio and the anti-loosening torque ratio. More corrosion on the locknut with longer submersion in NaCl solution deteriorated its anti-loosening characteristics. The result could serve as the reference for evaluating the fastening performance of precision locknut and guide the design and manufacturing for the application improvement.

The influence of combined corrosion and vibration to the anti-loosening performance of a precision locknut used in a machine tool is investigated. Firstly, the locknut was submerged in 5% NaCl solution according to ASTM B895 standard for corrosion testing. The locknuts, after submerged in 1-hr, 2-hr and 4-hr periods, respectively, were then installed on the rotating spindle in a vertical dynamic impact tester for performing anti-loosening test. The initial installed pretension was 9800 N and the spindle was rotating in a constant speed of 1000 rpm. Turmogrease Li 802 EP lubricant was used on the contact surface between spindle thread and locknut. The set screws on the locknut were tightened sequentially and evenly in three-stage of torque: 1.96 N-m, 3.92 N-m and 5.88 N-m. Its real-time pretension variation with the periodic transverse impact and its final loosening torque were measured. Accordingly, the axial force ratio and anti-loosening torque ratio were calculated and discussed. It was found that corrosion treatment had similar influence on both the axial force ratio and the anti-loosening torque ratio. More corrosion on the locknut with longer submersion in NaCl solution deteriorated its anti-loosening characteristics. The result could serve as the reference for evaluating the fastening performance of precision locknut and guide the design and manufacturing for the application improvement.

The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (∼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46(ABBV-744).

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1–5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7–9and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10–13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

•Cervical spinal hemangioblastoma (CSHBs) has rarely been reported in the cervical spine, and microsurgical treatment even less.•The study included eleven patients with CSHB treated by total tumor resection from January 2005 to December 2015.•Finding and blocking nutrient arteries during the operation is necessary to reduce bleeding.•All patients in this study were in good postoperative health, without recurrence during 6–48 months’ follow-up.•A discussion of a series deals with surgical considerations.