Erratum: Lower Bounds on Quantum Annealing Times [Phys. Rev. Lett. 130, 140601 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.140601.

Experimentally generated randomness certified by the impossibility of superluminal signals.

From dice to modern electronic circuits, there have been many attempts to build better devices to generate random numbers. Randomness is fundamental to security and cryptographic systems and to safeguarding privacy. A key challenge with random-number generators is that it is hard to ensure that their outputs are unpredictable1-3. For a random-number generator based on a physical process, such as a noisy classical system or an elementary quantum measurement, a detailed model that describes the underlying physics is necessary to assert unpredictability. Imperfections in the model compromise the integrity of the device. However, it is possible to exploit the phenomenon of quantum non-locality with a loophole-free Bell test to build a random-number generator that can produce output that is unpredictable to any adversary that is limited only by general physical principles, such as special relativity1-11. With recent technological developments, it is now possible to carry out such a loophole-free Bell test12-14,22. Here we present certified randomness obtained from a photonic Bell experiment and extract 1,024 random bits that are uniformly distributed to within 10-12. These random bits could not have been predicted according to any physical theory that prohibits faster-than-light (superluminal) signalling and that allows independent measurement choices. To certify and quantify the randomness, we describe a protocol that is optimized for devices that are characterized by a low per-trial violation of Bell inequalities. Future random-number generators based on loophole-free Bell tests may have a role in increasing the security and trust of our cryptographic systems and infrastructure.

Risk factor analysis and establishment of a nomogram model to predict blood loss during total knee arthroplasty.

PURPOSE: The risk factors for excessive blood loss and transfusion during total knee arthroplasty (TKA) remain unclear. The present study aimed to determine the risk factors for excessive blood loss and establish a predictive model for postoperative blood transfusion. METHODS: This retrospective study included 329 patients received TKA, who were randomly assigned to a training set (n = 229) or a test set (n = 100). Univariate and multivariate linear regression analyses were used to determine risk factors for excessive blood loss. Univariate and multivariate logistic regression analyses were used to determine risk factors for blood transfusion. R software was used to establish the prediction model. The accuracy and stability of the models were evaluated using calibration curves, consistency indices, and receiver operating characteristic (ROC) curve analysis. RESULTS: Risk factors for excessive blood loss included timing of using a tourniquet, the use of drainage, preoperative ESR, fibrinogen, HCT, ALB, and free fatty acid levels. Predictors in the nomogram included timing of using a tourniquet, the use of drainage, the use of TXA, preoperative ESR, HCT, and albumin levels. The area under the ROC curve was 0.855 (95% CI, 0.800 to 0.910) for the training set and 0.824 (95% CI, 0.740 to 0.909) for the test set. The consistency index values for the training and test sets were 0.855 and 0.824, respectively. CONCLUSIONS: Risk factors for excessive blood loss during and after TKA were determined, and a satisfactory and reliable nomogram model was designed to predict the risk for postoperative blood transfusion.

One-Pot Analytical Pipeline for Efficient and Sensitive Proteomic Analysis of Extracellular Vesicles.

Extracellular vesicle (EV) proteomics emerges as an effective tool for discovering potential biomarkers for disease diagnosis, monitoring, and therapeutics. However, the current workflow of mass spectrometry-based EV proteome analysis is not fully compatible in a clinical setting due to inefficient EV isolation methods and a tedious sample preparation process. To streamline and improve the efficiency of EV proteome analysis, here we introduce a one-pot analytical pipeline integrating a robust EV isolation approach, EV total recovery and purification (EVtrap), with in situ protein sample preparation, to detect urinary EV proteome. By incorporating solvent-driven protein capture and fast on-bead digestion, the one-pot pipeline enabled the whole EV proteome analysis to be completed within one day. In comparison with the existing workflow, the one-pot pipeline was able to obtain better peptide yield and identify the equivalent number of unique EV proteins from 1 mL of urine. Finally, we applied the one-pot pipeline to profile proteomes in urinary EVs of bladder cancer patients. A total of 2774 unique proteins were identified in 53 urine samples using a 15 min gradient library-free data-independent acquisition method. Taken altogether, our novel one-pot analytical pipeline demonstrated its potential for routine and robust EV proteomics in biomedical applications.

Lower Bounds on Quantum Annealing Times.

The adiabatic theorem provides sufficient conditions for the time needed to prepare a target ground state. While it is possible to prepare a target state much faster with more general quantum annealing protocols, rigorous results beyond the adiabatic regime are rare. Here, we provide such a result, deriving lower bounds on the time needed to successfully perform quantum annealing. The bounds are asymptotically saturated by three toy models where fast annealing schedules are known: the Roland and Cerf unstructured search model, the Hamming spike problem, and the ferromagnetic p-spin model. Our bounds demonstrate that these schedules have optimal scaling. Our results also show that rapid annealing requires coherent superpositions of energy eigenstates, singling out quantum coherence as a computational resource.

Mass spectrometry-based phosphoproteomics in clinical applications.

Protein phosphorylation is an essential post-translational modification that regulates many aspects of cellular physiology, and dysregulation of pivotal phosphorylation events is often responsible for disease onset and progression. Clinical analysis on disease-relevant phosphoproteins, while quite challenging, provides unique information for precision medicine and targeted therapy. Among various approaches, mass spectrometry (MS)-centered characterization features discovery-driven, high-throughput and in-depth identification of phosphorylation events. This review highlights advances in sample preparation and instrument in MS-based phosphoproteomics and recent clinical applications. We emphasize the preeminent data-independent acquisition method in MS as one of the most promising future directions and biofluid-derived extracellular vesicles as an intriguing source of the phosphoproteome for liquid biopsy.

Fluorides immobilization through calcium aluminate cement-based backfill: Accessing the detailed leaching characterization under torrential rainfall.

Urbanization and economic development have increased the demand for fertilizers to sustain food crop yields. Huge amounts of by-products, especially phosphogypsum (PG), are generated during the wet processing of rock phosphate to produce fertilizers. Chronic exposure to fluoride in phosphogypsum in groundwater as a result of the weathering of fluoride-containing waste poses a significant health risk to millions of people. We propose a method for using calcium aluminate cement (CAC) to remediate high fluoride contents in solid waste. Column leaching tests under harsh rainfall conditions confirmed the efficient fluoride immobilization capacity of a CAC binder. Although the fluoride concentrations in leachates during the first 1-2 days (1.25 mg/L) slightly exceeded the threshold of 1.00 mg/L, the concentrations over 3-28 days (ranging from 0.98 to 0.83 mg/L) consistently remained well within the acceptable range. Furthermore, our characterization and geochemical modeling revealed the fluoride retention mechanisms of CAC-stabilized PG under laboratory-simulated conditions of torrential rainfall. During leaching, physical encapsulation prevents fluoride from contacting leachate. However, an unfavorable pH value can cause the release of fluoride from the cement matrix, which is subsequently captured by aluminate hydrate through adsorption or co-precipitation. We quantified the carbon footprint of CAC for immobilizing 1 mg of fluoride in PG, obtaining a remarkably low value of 4.4 kg of CO2, in contrast to the emissions associated with the use of ordinary Portland cement (OPC). The findings suggest a unique opportunity for extensive PG remediation. This opportunity extends the horizons of achieving zero-waste emissions in the phosphorus industry and has practical significance in the context of reducing carbon emissions.

Pharmacokinetics, optimal dosages and withdrawal time of florfenicol in Asian seabass (Lates calcarifer) after oral administration via medicated feed.

Asian seabass (Lates calcarifer) is an economically important fish in Asian and Australian markets, but few pharmacokinetic (PK) data of antimicrobial drugs in this species is available. The present study investigated the PK behaviour of florfenicol (FF) through medicated feed in Asian seabass cultured at 25°C. The serum and muscle/skin concentrations of FF and its metabolite florfenicol amine (FFA) were determined by the HPLC-FLD method and analysed by one-compartmental model. The optimal dosages were determined by pharmacokinetic-pharmacodynamic (PK-PD) approach and the linear regression analysis was used to determine the withdrawal time (WDT). The PK study following a single oral administration of 15 mg/kg FF via medicated feed revealed that the absorption half-life (t1/2Ka ), elimination half-life (t1/2K ), peak concentration (Cmax ), area under the concentration-time curve (AUC), volume of distribution (Vd/F) and clearance (CL/F) were 1.47 h, 8.07 h, 8.61 µg/ml, 146.41 h·µg/ml, 1.19 L/kg and 0.102 L/kg/h, respectively. The muscle/skin concentration-time profile was similar to that of the serum, suggesting well distribution but only a small fraction of FF was metabolized to FFA. The optimal dosage for a minimum inhibitory concentration of 2 µg/ml was calculated as 13.38 mg/kg/day. The appropriate WDT after multiple oral medications with 15 mg/kg FF once daily for 7 days was determined as 8 days. Information obtained from the current study can potentially be applied for the treatment of bacterial diseases in farming Asian seabass.

Prospective randomized controlled trial on the accuracy of prosthesis positioning in total hip arthroplasty assisted by a newly designed whole-process robotic arm.

INTRODUCTION: The purpose of this article is to study whether the newly designed whole-process total hip arthroplasty (THA) robotic arm can improve the accuracy of prosthesis placement in THA. METHOD: In this study, 72 patients undergoing THA were prospectively included and randomly divided into two groups. The experimental group was treated with THA assisted by a newly designed robotic arm. The control group received THA with conventional surgical methods. The imaging data were compared after operation. RESULT: Compared with the conventional operation, the whole-process robotic arm can more accurately place the acetabular prosthesis in the anteversion safe zone of 5 ~ 25°, but in terms of the inclination angle, whether the reference is the safe zone of 30 ~ 50° or 30 ~ 45°, there is no statistical difference between the two groups. The average lower limb length discrepancy (LLLD) in the experimental group was 3.77 ± 8.31 mm longer than contralateral side, while the counterpart in the control group was 8.39 ± 9.11 mm, with significant difference (P = 0.029). The femoral prosthesis was fixed in neutral position in 35 (100%) cases in the experimental group and only 30 (83.3%) in the control group (P = 0.036). There was no significant difference in the recovery of hip offset, femoral anteversion, and canal fill ratio (CFR) between the two groups. CONCLUSION: Robotic arm can improve the accuracy of anteversion of acetabular cup, restore the consistency of the length of lower limbs, and more accurately implant the femoral prosthesis to the neutral position in the coronal position. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2100044124 (date of registration: 2021-3-11).

Integrated biochemical and transcriptomic analysis reveals the effects of Burkholderia sp. SRB-1 on cadmium accumulating in Chrysopogon zizanioides L. under Cd stress.

Application of plant growth-promoting rhizobacteria plays a vital role in enhancing phytoremediation efficiency. In this study, multiple approaches were employed to investigate the underlying mechanisms of Burkholderia sp. SRB-1 (SRB-1) on elevating Cd uptake and accumulation. Inoculation experiment indicated that SRB-1 could facilitate plant growth and Cd tolerance, as evidenced by the enhanced plant biomass and antioxidative enzymes activities. Cd content in plant shoots and roots increased about 36.56%-39.66% and 25.97%-130.47% assisted with SRB-1 when compared with control. Transcriptomics analysis revealed that SRB-1 upregulated expression of amiE, AAO1-2 and GA2-ox related to auxin and gibberellin biosynthesis in roots. Auxin and gibberellin, as hormone signals, regulated plant Cd tolerance and growth through activating hormone signal transduction pathways, which might also contribute to 67.94% increase of dry weight. The higher expression levels of ATP-binding cassette transporter subfamilies (ABCB, ABCC, ABCD and ABCG) in Chrysopogon zizanioides roots contributed to higher Cd uptake in Cd15 B (323.83 mg kg-1) than Cd15 (136.28 mg kg-1). Further, SRB-1 facilitated Cd migration from roots to shoots via upregulating the expression of Nramp, ZIP and HMA families. Our integrative analysis provided a molecular-scale perspective on Burkholderia sp. SRB-1 contributing to C. zizanioides performance.

Supramolecular Combination Chemotherapy: Cucurbit[8]uril Complex Enhanced Platinum Drug Infiltration and Modified Nanomechanical Property of Colorectal Cancer Cells.

Combination chemotherapy is recognized as a vital medical treatment for cancer, but it has not achieved clinical ideal effects of combination therapy. Herein, we designed a supramolecular combination chemotherapy strategy based on cucurbit[8]uril (CB[8]), which can be facilely assembled into dual platinum drugs. Interestingly, employing the CB[8] carrier led to a greater than 10-fold intracellular Pt content compared to that of dual drugs at 4 h, and the CB[8] complex (CLE) can enhance the infiltration of platinum drugs in colorectal tumor cells tremendously. The platinum drugs can be released from CLE through consuming more tumor biomarker spermidine. Through analyzing the nanomechanical property of the colorectal tumor cellular surface by bioscope AFM, it was revealed that CLE modified the property by decreasing the adhesion and increasing the stiffness. This study provided a facile and sensitive strategy for improving combination chemotherapy by supramolecular materials.

Retention of phosphorus and fluorine in phosphogypsum for cemented paste backfill: Experimental and numerical simulation studies.

The solidification/stabilization of phosphogypsum using cemented paste backfill (OCPB) provides a low-cost and alternative in-situ technique for recycling phosphogypsum stockpiles. But the OCPB is far from obtaining steady states in which the pollutants would redistribute as a response to dynamic environmental conditions. Further, the associated chemical interactions and the mineralogy information of the solubility-controlling phases of contaminants (fluorine and phosphorus) have not been thoroughly studied or fully understood. In this study, a framework coupling the chemical, mineralogical, and morphological analyses is used to determine the fluoride and phosphate retention mechanisms of immobilized OCPB. Then the pH-dependent leaching tests and numerical simulation is applied as a useful tool to identify the minerals controlling stabilized OCPB leaching behavior. The overall findings proved that aluminate-rich calcium silicate hydrates play an essential role in fluoride and phosphate retention. Both experimental and simulational acid neutralization and leaching curves indicate that the cementitious matrix works as a strong buffering material ensuring high pH conditions that are necessary for fluorine and phosphorus retention. Although discrepancies were observed in absolute fluorine and phosphorus leaching values at highly acidic conditions, the simulations are able to describe highly amphoteric leaching behavior. The simulation suggests that the aluminum species and calcium phosphates governed the solubility of fluorine and phosphorus, respectively. The results of this work would have implications for predicting the leaching behavior of OCPB in detrimental and multiple environments.

The effect of BMI on the mid-term clinical outcomes of mobile-bearing unicompartmental knee arthroplasty.

OBJECTIVE: To evaluate the impact of body mass index (BMI) on the mid-term clinical outcomes and survival in patients receiving a mobile-bearing unicompartmental knee arthroplasty (UKA). METHODS: We retrospectively collected data from 355 patients who underwent UKA from June 2006 to June 2015, with a mean follow-up of 106.5 ± 22.5 months. Patients were assigned into four groups based on their BMI before surgery: normal weight group (BMI 18.5 ~ 22.9 kg/m2), overweight group (23 ~ 24.9 kg/m2), obesity group (25 ~ 29.9 kg/m2), and severe obesity group (≥ 30 kg/m2). The knee society score (KSS), knee society function score (KSFS), hospital for special surgery score (HSS), and range of motion (ROM) were assessed before the operation and at the last follow-up. The femorotibial angle (FTA) was assessed after the operation immediately and at the last follow-up. Kaplan-Meier survival analysis was performed among the four groups. RESULTS: The KSS, KSFS, and HSS in all groups were markedly improved compared with the preoperative values (p<0.001), but the ROM score was not significantly different (p>0.05). There were significant differences in KSS (p<0.001) and HSS (p = 0.004) across the four BMI groups, and these differences were due to the severe obesity group. All groups exhibited an inclination of knee varus deformity at the last follow-up (p < 0.05). Moreover, no marked difference in the implant survival rate was found among the different groups (p = 0.248), or in the survival curves (p = 0.593). CONCLUSIONS: BMI does not influence the implant survival rate. The postoperative functional and quality-of-life scores were significantly improved in all groups. Obese (BMI ≥30 kg/m2) individuals should not be excluded from UKA.

Kinetic Characterization and Inhibitor Screening for the Proteases Leading to Identification of Drugs against SARS-CoV-2.

Coronavirus (CoV) disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has claimed many lives worldwide and is still spreading since December 2019. The 3C-like protease (3CLpro) and papain-like protease (PLpro) are essential for maturation of viral polyproteins in SARS-CoV-2 life cycle and thus regarded as key drug targets for the disease. In this study, 3CLpro and PLpro assay platforms were established, and their substrate specificities were characterized. The assays were used to screen collections of 1,068 and 2,701 FDA-approved drugs. After excluding the externally used drugs which are too toxic, we totally identified 12 drugs as 3CLpro inhibitors and 36 drugs as PLpro inhibitors active at 10 µM. Among these inhibitors, six drugs were found to suppress SARS-CoV-2 with the half-maximal effective concentration (EC50) below or close to 10 µM. This study enhances our understanding on the proteases and provides FDA-approved drugs for prevention and/or treatment of COVID-19.

G protein coupled estrogen receptor attenuates mechanical stress-mediated apoptosis of chondrocyte in osteoarthritis via suppression of Piezo1.

BACKGROUND: Apoptosis of chondrocyte is involved in osteoarthritis (OA) pathogenesis, and mechanical stress plays a key role in this process by activation of Piezo1. However, the negative regulation of signal conduction mediated by mechanical stress is still unclear. Here, we elucidate that the critical role of G protein coupled estrogen receptor (GPER) in the regulation of mechanical stress-mediated signal transduction and chondrocyte apoptosis. METHODS: The gene expression profile was detected by gene chip upon silencing Piezo1. The expression of GPER in cartilage tissue taken from the clinical patients was detected by RT-PCR and Western blot as well as immunohistochemistry, and the correlation between GPER expression and OA was also investigated. The chondrocytes exposed to mechanical stress were treated with estrogen, G-1, G15, GPER-siRNA and YAP (Yes-associated protein)-siRNA. The cell viability of chondrocytes was measured. The expression of polymerized actin and Piezo1 as well as the subcellular localization of YAP was observed under laser confocal microscope. Western blot confirmed the changes of YAP/ Rho GTPase activating protein 29 (ARHGAP29) /RhoA/LIMK /Cofilin pathway. The knee specimens of osteoarthritis model were stained with safranin and green. OARSI score was used to evaluate the joint lesions. The expressions of GPER and YAP were detected by immunochemistry. RESULTS: Expression profiles of Piezo1- silenced chondrocytes showed that GPER expression was significantly upregulated. Moreover, GPER was negatively correlated with cartilage degeneration during OA pathogenesis. In addition, we uncovered that GPER directly targeted YAP and broadly restrained mechanical stress-triggered actin polymerization. Mechanism studies revealed that GPER inhibited mechanical stress-mediated RhoA/LIMK/cofilin pathway, as well as the actin polymerization, by promoting expression of YAP and ARHGAP29, and the YAP nuclear localization, eventually causing the inhibition of Piezo1. YAP was obviously decreased in degenerated cartilage. Silencing YAP caused significantly increased actin polymerization and activation of Piezo1, and an increase of chondrocyte apoptosis. In addition, intra-articular injection of G-1 to OA rat effectively attenuated cartilage degeneration. CONCLUSION: We propose a novel regulatory mechanism underlying mechanical stress-mediated apoptosis of chondrocyte and elucidate the potential application value of GPER as therapy targets for OA.

Utilization of modified copper slag activated by Na2SO4 and CaO for unclassified lead/zinc mine tailings based cemented paste backfill.

Serious heavy metals pollution was characterized in the lead/zinc mine tailings dam and surrounding soils, as well as copper slag disposal sites. This study investigates the efficacy of modified granulated copper slag (MGCS) as a partial replacement of ordinary Portland cement (OPC) for lead/zinc mine tailings-based cemented paste backfill (CPB) application using Na2SO4 (CSN) and CaO (CSC) as alkali-activated materials. The effect of different scenarios was ascertained by unconfined compressive strength (UCS). Also, the correlated microstructural evolution and mineralogical phase generation were obtained by scanning electron microscopy (SEM), mercury intrusion porosimetry (MIP), and X-ray diffraction (XRD). The main findings proved that CSN was more effective in improving mechanical performance. Na2SO4 was found associated with C-S-H gel formation accompanied by a compact microstructure and better pore distribution with lower porosity. However, deposition of chloride compound was found in the surface layer of CSN samples, which could bring deterioration to the mechanical properties. Results above extend the knowledge of reusing MGCS as supplementary material to CPB, promoting the concept of a circular economy demand for both lead/zinc mine extraction and copper industries.

ATP alters protein folding and function of Escherichia coli uridine phosphorylase.

Uridine phosphorylase is one of the critical enzymes in the pyrimidine salvage pathway. Cells regenerate uridine for nucleotide metabolism by incorporating uracil with ribose-1-phosphate with this enzyme. Recent studies indicate that Escherichia coli uridine phosphorylase is destabilized in the presence of ATP. However, the mechanism underlying the destabilization process and its influence on uridine phosphorylase function remain to be established. Here, we comprehensively investigated the effects of ATP on protein folding and function of Escherichia coli uridine phosphorylase. Our results demonstrate that ATP apparently decreases the stability of uridine phosphorylase in a concentration-dependent manner. Additionally, simply increasing the level of ATP led to a reduction of enzymatic activity to complete inhibition. Further studies showed that uridine phosphorylase accumulates as a partially unfolded state in the presence of ATP. Moreover, ATP specifically accelerated the unfolding rate of uridine phosphorylase with no observable effects on the refolding process. Our preliminary findings suggest that ATP can alter the protein folding and function of enzymes via apparent destabilization. This mechanism may be significant for proteins functioning under conditions of high levels of ATP, such as cancer cell environments.

Post-quantum cryptography and the quantum future of cybersecurity.

We review the current status of efforts to develop and deploy post-quantum cryptography on the Internet. Then we suggest specific ways in which quantum technologies might be used to enhance cybersecurity in the near future and beyond. We focus on two goals: protecting the secret keys that are used in classical cryptography, and ensuring the trustworthiness of quantum computations. These goals may soon be within reach, thanks to recent progress in both theory and experiment. This progress includes interactive protocols for testing quantumness as well as for performing uncloneable cryptographic computations; and experimental demonstrations of device-independent random number generators, device-independent quantum key distribution, quantum memories, and analog quantum simulators.

Unbiasing Enhanced Sampling on a High-Dimensional Free Energy Surface with a Deep Generative Model.

Biased enhanced sampling methods that utilize collective variables (CVs) are powerful tools for sampling conformational ensembles. Due to their large intrinsic dimensions, efficiently generating conformational ensembles for complex systems requires enhanced sampling on high-dimensional free energy surfaces. While temperature-accelerated molecular dynamics (TAMD) can trivially adopt many CVs in a simulation, unbiasing the simulation to generate unbiased conformational ensembles requires accurate modeling of a high-dimensional CV probability distribution, which is challenging for traditional density estimation techniques. Here we propose an unbiasing method based on the score-based diffusion model, a deep generative learning method that excels in density estimation across complex data landscapes. We demonstrate that this unbiasing approach, tested on multiple TAMD simulations, significantly outperforms traditional unbiasing methods and can generate accurate unbiased conformational ensembles. With the proposed approach, TAMD can adopt CVs that focus on improving sampling efficiency and the proposed unbiasing method enables accurate evaluation of ensemble averages of important chemical features.

A compartment model for subcutaneous injection of monoclonal antibodies.

Despite the growing popularity of subcutaneous (SC) administration for monoclonal antibodies (mAbs), there remains a limited understanding of the significance of mAb transport rate constants within the interstitial space and the lymphatic system on their pharmacokinetics. To bridge this knowledge gap, we introduce a compartmental model for subcutaneously administered mAbs. Our model differentiates FcRn-expressing cells across various sites, and the model predictions agree with experimental data from both human and rat studies. Our findings indicate that the time to reach the maximum mAb concentration in the plasma, denoted by Tmax, displays a weak positive correlation with mAb half-life and a negligible correlation with bioavailability. In contrast, the half-life of mAbs exhibits a strong positive correlation with bioavailability. Moreover, the rate of mAb transport from lymph to plasma significantly affects the mAb half-life. Increasing the transport rates of mAbs from the injection site to the lymph or from lymph to plasma enhances bioavailability. These insights, combined with our compartmental model, contribute to a deeper understanding of the pharmacokinetics of subcutaneously administered mAbs.