Photopolymerized maleilated chitosan/methacrylated silk fibroin micro/nanocomposite hydrogels as potential scaffolds for cartilage tissue engineering

Hydrogels composed of natural materials exhibit great application potential in artificial scaffolds for cartilage repair as they can resemble the extracellular matrices of cartilage tissues comprised of various glycosaminoglycan and collagen. Herein, the natural polymers with vinyl groups, i.e. maleilated chitosan (MCS) and methacrylated silk fibroin (MSF) micro/nanoparticles, were firstly synthesized. The chemical structures of MCS and MSF micro/nanoparticles were investigated using Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (1H NMR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). Then MCS/MSF micro/nanocomposite hydrogels were prepared by the photocrosslinking of MCS and MSF micro/nanoparticles in aqueous solutions in the presence of the photoinitiator Darocur 2959 under UV light irradiation. A series of properties of the MCS/MSF micro/nanocomposite hydrogels including rheological property, equilibrium swelling, sol content, compressive modulus, and morphology were examined. The results showed that these behaviors could be tunable via the control of MSF content. When the MSF content was 0.1%, the hydrogel had the compressive modulus of 0.32±0.07MPa, which was in the range of that of articular cartilage. The in vitro cytotoxic evaluation and cell culture of the micro/nanocomposite hydrogels in combination with mouse articular chondrocytes were also investigated. The results demonstrated that the micro/nanocomposite hydrogels with TGF-β1 was biocompatible to mouse articular chondrocytes and could support cells attachment well, indicating their potential as tissue engineering scaffolds for cartilage repair.This study was supported by National Natural Science Foundation of China (Grant No. 51203123, 51403165, 51503161) and the National Key Research and Development Program of China (No.2016YFA0101102)

Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases

Abnormal focal segments in left uncinate fasciculus in adults with obsessive–compulsive disorder

BackgroundAlthough the specific role of the uncinate fasciculus (UF) in emotional processing in patients with obsessive–compulsive disorder (OCD) has been investigated, the exact focal abnormalities in the UF have not been identified. The aim of the current study was to identify focal abnormalities in the white matter (WM) microstructure of the UF and to determine the associations between clinical features and structural neural substrates.MethodsIn total, 71 drug-naïve patients with OCD and 81 age- and sex-matched healthy controls (HCs) were included. Automated fiber quantification (AFQ), a tract-based quantitative approach, was adopted to measure alterations in diffusion parameters, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD), along the trajectory of the UF. Additionally, we utilized partial correlation analyses to explore the relationship between the altered diffusion parameters and clinical characteristics.ResultsOCD patients showed significantly higher FA and lower RD at the level of the temporal and insular portions in the left UF than HCs. In the insular segments of the left UF, increased FA was positively correlated with the Hamilton Anxiety Scale (HAMA) score, while decreased RD was negatively correlated with the duration of illness.ConclusionWe observed specific focal abnormalities in the left UF in adult patients with OCD. Correlations with measures of anxiety and duration of illness underscore the functional importance of the insular portion of left UF disturbance in OCD patients

Integrin αvβ3-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergistically enhances anti-tumor efficacy.

RATIONALE(#br)Radiotherapy combined with immunotherapy has revealed promising outcomes in both preclinical studies and ongoing clinical trials. Targeted radionuclide therapy (TRT) is a branch of radiotherapy concerned with the use of radioisotopes, radiolabeled molecules or nanoparticles that deliver particulate radiation to cancer cells. TRT is a promising approach in cases of metastatic disease where conventional treatments are no longer effective. The increasing use of TRT raises the question of how to best integrate TRT with immunotherapy. In this study, we proposed a novel therapeutic regimen that combined programmed death ligand 1 (PD-L1)-based immunotherapy with peptide-based TRT (177Lu as the radionuclide) in the murine colon cancer model.(#br)METHODS(#br)To explore the most appropriate timing of immunotherapy after radionuclide therapy, the anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner when 177Lu TRT was given.(#br)RESULTS(#br)The results demonstrated that TRT led to an acute increase in PD-L1 expression on T cells, and TRT in combination with αPD-L1 mAb stimulated the infiltration of CD8+ T cells, which improved local tumor control, overall survival and protection against tumor rechallenge. Moreover, our data revealed that the time window for this combination therapy may be critical to outcome.(#br)CONCLUSIONS(#br)This therapeutic combination may be a promising approach to treating metastatic tumors in which TRT can be used. Clinical translation of the result would suggest that concurrent rather than sequential blockade of the PD-1/PD-L1 axis combined with TRT improves overall survival and long-term tumor control

High levels of soluble CD25 in COVID-19 severity suggest a divergence between anti-viral and pro-inflammatory T-cell responses

Objectives: We aimed to gain an understanding of the paradox of the immunity in COVID-19 patients with T cells showing both functional defects and hyperactivation and enhanced proliferation. Methods: A total of 280 hospitalised patients with COVID-19 were evaluated for cytokine profiles and clinical features including viral shedding. A mouse model of acute infection by lymphocytic choriomeningitis virus (LCMV) was applied to dissect the relationship between immunological, virological and pathological features. The results from the mouse model were validated by published data set of single-cell RNA sequencing (scRNA-seq) of immune cells in bronchoalveolar lavage fluid (BALF) of COVID-19 patients. Results: The levels of soluble CD25 (sCD25), IL-6, IL-8, IL-10 and TNF-α were higher in severe COVID-19 patients than non-severe cases, but only sCD25 was identified as an independent risk factor for disease severity by multivariable binary logistic regression analysis and showed a positive association with the duration of viral shedding. In agreement with the clinical observation, LCMV-infected mice with high levels of sCD25 demonstrated insufficient anti-viral response and delayed viral clearance. The elevation of sCD25 in mice was mainly contributed by the expansion of CD25 CD8 T cells that also expressed the highest level of PD-1 with pro-inflammatory potential. The counterpart human CD25 PD-1 T cells were expanded in BALF of COVID-19 patients with severe disease compared to those with modest disease. Conclusion: These results suggest that high levels of sCD25 in COVID-19 patients probably result from insufficient anti-viral immunity and indicate an expansion of pro-inflammatory T cells that contribute to disease severity.We acknowledge the Biological Resources Facility and Cytometry Facility (Translational Research Institute). This work was supported by the Australian National Health and Medical Research Council (GNT1147769), Eureka TechIN special grant for Immunology and Virology of COVID-19, the Bellberry-Viertel Senior Medical Research Fellowship to DY, and Natural Science Foundation of Shandong Province (Major Basic Program, ZR2020ZD41) to YW

Quantum Neuronal Sensing of Quantum Many-Body States on a 61-Qubit Programmable Superconducting Processor

Classifying many-body quantum states with distinct properties and phases of matter is one of the most fundamental tasks in quantum many-body physics. However, due to the exponential complexity that emerges from the enormous numbers of interacting particles, classifying large-scale quantum states has been extremely challenging for classical approaches. Here, we propose a new approach called quantum neuronal sensing. Utilizing a 61 qubit superconducting quantum processor, we show that our scheme can efficiently classify two different types of many-body phenomena: namely the ergodic and localized phases of matter. Our quantum neuronal sensing process allows us to extract the necessary information coming from the statistical characteristics of the eigenspectrum to distinguish these phases of matter by measuring only one qubit. Our work demonstrates the feasibility and scalability of quantum neuronal sensing for near-term quantum processors and opens new avenues for exploring quantum many-body phenomena in larger-scale systems.Comment: 7 pages, 3 figures in the main text, and 13 pages, 13 figures, and 1 table in supplementary material

Experimental quantum computational chemistry with optimised unitary coupled cluster ansatz

Simulation of quantum chemistry is one of the most promising applications of quantum computing. While recent experimental works have demonstrated the potential of solving electronic structures with variational quantum eigensolver (VQE), the implementations are either restricted to nonscalable (hardware efficient) or classically simulable (Hartree-Fock) ansatz, or limited to a few qubits with large errors for the more accurate unitary coupled cluster (UCC) ansatz. Here, integrating experimental and theoretical advancements of improved operations and dedicated algorithm optimisations, we demonstrate an implementation of VQE with UCC for H_2, LiH, F_2 from 4 to 12 qubits. Combining error mitigation, we produce high-precision results of the ground-state energy with error suppression by around two orders of magnitude. For the first time, we achieve chemical accuracy for H_2 at all bond distances and LiH at small bond distances in the experiment. Our work demonstrates a feasible path towards a scalable solution to electronic structure calculation, validating the key technological features and identifying future challenges for this goal.Comment: 8 pages, 4 figures in the main text, and 29 pages supplementary materials with 16 figure

The ABC130 barrel module prototyping programme for the ATLAS strip tracker

For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector, consisting of silicon pixel, silicon strip and transition radiation sub-detectors, will be replaced with an all new 100 % silicon tracker, composed of a pixel tracker at inner radii and a strip tracker at outer radii. The future ATLAS strip tracker will include 11,000 silicon sensor modules in the central region (barrel) and 7,000 modules in the forward region (end-caps), which are foreseen to be constructed over a period of 3.5 years. The construction of each module consists of a series of assembly and quality control steps, which were engineered to be identical for all production sites. In order to develop the tooling and procedures for assembly and testing of these modules, two series of major prototyping programs were conducted: an early program using readout chips designed using a 250 nm fabrication process (ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm processing (ABC130 and HCC130 chips). This second generation of readout chips was used for an extensive prototyping program that produced around 100 barrel-type modules and contributed significantly to the development of the final module layout. This paper gives an overview of the components used in ABC130 barrel modules, their assembly procedure and findings resulting from their tests.Comment: 82 pages, 66 figure