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The A-kinase anchoring protein 150 (AKAP150) organizes kinases and phosphatases to regulate AMPA receptors (AMPARs) that are pivotal for synaptic plasticity. AKAP150 itself undergoes S-palmitoylation. However, the roles of AKAP150 and its palmitoylation in spinal nociceptive processing remain unknown. In this study, we found that intraplantar injection of complete Freund's adjuvant (CFA) significantly increased the synaptic expression of AKAP150 and caused a reorganization of AKAP150 signaling complex in spinal dorsal horn. Knockdown of AKAP150 or interruption of its interactions with kinases effectively suppressed the CFA-induced synaptic expression of GluA1 subunit of AMPARs. Our data also showed that an upregulation of AKAP150 palmitoylation was involved in the synaptic redistribution of AKAP150. Inhibition of AKAP150 palmitoylation by expression of palmitoylation-defective mutant AKAP150 (C36, 123S) effectively repressed the CFA-induced phosphorylation and synaptic expression of GluA1 subunit, meanwhile, attenuated the development of mechanical allodynia and thermal hyperalgesia. Furthermore, we found that an increased expression of palmitoyl acyltransferase ZDHHC2 contributed to the upregulation of AKAP150 palmitoylation and GluA1 accumulation in inflamed mouse. These data indicated that AKAP150 and its palmitoylation were involved in AMPA receptor-dependent modification of nociceptive transmission, and the manipulations of AKAP150 signaling complex and palmitoylation might serve as potential therapeutic strategies for persistent pain after inflammation.

Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

In this paper, X-ray diffraction spectroscopy (XRD), Raman spectroscopy (RS), firing temperature analysis, pore size distribution analysis, Fourier infrared spectroscopy (FTIR), scanning electron microscopy-energy dispersive spectroscopy (SEM–EDS), and transmission electron microscopy (TEM) were utilized to analyze the unearthed vulnerable terracotta figures of Emperor Qin Shihuang's Terracotta Army, as well as the unknown precipitated white crystals and black substances. The results show that the firing temperature of the vulnerable terracotta figure is much lower than those of similar terracotta figures and red terracotta figures with good texture. The pore size of this kind of vulnerable pottery is smaller and the specific surface area is larger. In the pores, there is an alkaline solution containing Ca2+ that accounted for approximately 4.3% of the total mass of the sample. Along with the fracture of the delicate pottery matrix, the solution in the pores migrated to the fracture surface and chemically reacted with CO2 in the air, generating a layer of white calcium carbonate crust. The black matter on the fracture surface of the vulnerable terracotta figure is mainly composed of amorphous carbon and graphitized carbon, which shows high activity under the catalysis of Fe and Ti elements and alkaline soil. The discovery and analysis of amorphous carbon, graphitized carbon, and white calcium carbonate crystals on the fracture surface of the Qin Shihuang’s Terracotta Army provide a theoretical foundation for in-depth analysis of the terracotta warriors and horses' composition and structure, as well as scientific protection and restoration, and the stability of the original site display.

Colorectal cancer (CRC) is a common cancer with high metastatic property. Circular RNAs (circRNAs) have important involvement in cancer processes. This study focused on the regulation of circRNA RAD23 homologue B (circRAD23B) in CRC. The levels of circRAD23B, microRNA-1205 (miR-1205), and tripartite motif-44 (TRIM44) were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Functional analyses were performed by Cell Counting Kit-8 (CCK-8) for cell proliferation, flow cytometry for cell cycle or cell apoptosis, and transwell assay for cell migration and invasion. Western blot was administrated for protein detection. The interaction of targets was analyzed by dual-luciferase reporter and RNA pull-down assays. The in vivo experiment was conducted via xenograft tumor in mice. We identified that circRAD23B was overexpressed in CRC tissues and cells. CRC cell proliferation, cell cycle progression, and cell metastasis were inhibited, while apoptosis was promoted by downregulating circRAD23B. Target analysis indicated that circRAD23B-targeted miR-1205 and TRIM44 were downstream genes of miR-1205. Moreover, the antitumor response of circRAD23B downregulation and miR-1205 overexpression was, respectively, achieved by increasing miR-1205 and decreasing TRIM44. CircRAD23B could regulate TRIM44 level by sponging miR-1205. In vivo, circRAD23B knockdown also reduced CRC tumorigenesis via the miR-1205/TRIM44 axis. These results suggested that the inhibition of circRAD23B retarded the progression of CRC via acting on the miR-1205/TRIM44 axis. CircRAD23B might be a novel target in CRC treatment.

A highly selective turn-on fluorescent and naked-eye colourimetric dual-channel probe for cyanide anions (CNˉ) has been designed and characterized. In the mixed solution (DMSO / H2O, 9:1, v / v), only CNˉ could cause an increase in the UV absorption intensity and the corresponding fluorescence intensity increased, and other anions had no significant effect on the probe. After treatment with cyanide in the probe solution, the solution showed a noticeable colour change, from light yellow to purple. Moreover, a fluorescence spectrophotometer can be used to observe that the fluorescence intensity of the solution is significantly enhanced. The response of the colourimetric and fluorescent dual-channel probe to CNˉ was attributed to nucleophilic addition, and the mechanism was determined by 1H NMR spectroscopy. In addition, this probe was used to detect CNˉ in actual water samples, including river water, drinking water, and tap water. The spiked CNˉ recovery rate is very high (97.2%-100.06%), and analytical precision is also very high (RSD

Although the roles of the Hippo pathway in organogenesis and tumorigenesis have been well studied in multiple organs, its role in sperm maturation and male fertility has not been investigated. The initial segment (IS) of the epididymis plays a critical role in sperm maturation. IS differentiation is governed by ERK1/2, but the mechanisms of ERK1/2 activation in IS are not fully understood. Here we show that double knockout (dKO) of mammalian sterile 20-like kinases 1 and 2 (Mst1 and Mst2), homologs of Hippo in Drosophila, in the epididymal epithelium led to male infertility in mice. Sperm in the cauda epididymides of mutant mice were immotile with flagellar angulation and severely disorganized structures. Loss of Mst1/2 activated YAP and increased proliferation and cell death in all the segments of epididymis. The mutant mice showed substantially suppressed MEK/ERK signaling in the IS and failed IS differentiation. Deletion of Yap restored the reduced MEK/ERK signaling, and partially rescued the defective IS differentiation and fertility in Mst1/2 dKO mice. Our results demonstrate that YAP inhibits the MEK/ERK pathway in IS epithelial cells, and MST1/2 control IS differentiation and fertility at least partially by repressing YAP. Taken together, the Hippo pathway is essential for sperm maturation and male fertility.

Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system. In this Review, Tan et al. provide an overview of the clinical and preclinical evidence that immune system dysfunction is involved in Parkinson disease, and discuss how increasing knowledge of the underlying mechanisms is driving development of immune-based therapeutic approaches.

Three Ni(II) complexes {[NiL(μ-OAc)(CH3CH2OH)]2Ni} (1), {[NiL(μ-OAc)(CH3OH)]2Ni]·2CH2Cl2·2CH3OH (2) and {[NiL(μ-OAc)(CH3OH)]2Ni}·1.5CH3OH (3) based on a Salamo-type bis-oxime ligand (H2L = 2,2′-[ethylenedioxybis(nitrilo-methylidyne)]dinaphthol) have been synthesized and characterized by physicochemical and spectroscopic methods. The complexes 1, 2 and 3 are all trinuclear structures, and the center Ni(II) ions are six-coordinated and show the slightly distorted octahedral coordination. They all consist of three Ni(II) ions, two deprotonated L2- units, two μ-acetato ligands and two coordinated solvent molecules, as well as the crystallizing solvent molecules. Although the molecular structures of the Ni(II) complexes 1, 2 and 3 are similar to each other, obtained in different solvents, the supramolecular structures are entirely different. The complexes 1, 2 and 3 possess the self-assembled infinite 1D, 3D and 2D supramolecular structures via different intermolecular interactions (hydrogen bonds, C–H···π and π···π stacking interaction), respectively. But complex 2 formed a 3D structures by intramolecular hydrogen bonds. It is significant that the solvent molecules have obvious effects on the optical properties and molecular configuration. The Hirshfeld surface analysis showed that the short-range forces of the hydrogen bonds in complexes 1, 2 and 3 accounted for 67.8%, 44.6% and 52.7%, respectively. The molecular orbital energies for ligand H2L and complex 1 were obtained by DFT calculation, and the electron distribution, energy level and energy gap of HOMO and LUMO were given.

This paper presents the visible light-assisted synthesis of surfactant-free Pt nanoparticles (Pt-NPs) supported on multi-walled carbon nanotubes (MWCNTs) at ambient condition. Transmission electron microscopy (TEM) images indicate that Pt-NPs with high density and relative small in size (about 2 nm) were monodispersed on the surface of MWCNTs. The characterizations of Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), X-ray diffractometer (XRD) and ultraviolet–visible spectroscopy (UV–Vis) prove that visible light irradiation significantly affect the species distribution of [PtCl4]2− precursor in the hydrolysis and then promote hydrolysate Pt oxides loading on MWCNTs. The loading process decides the morphology of Pt-NPs rather than the following precursor reduction, which does not change the morphology but only the valance state of platinum. The catalytic activity of Pt/MWCNTs was tested in subsequent methanol electrochemical reactions and 4-nitrophenol (4-NP) reduction.

A simple Schiff base fluorescent probe (SW) composed of oxime and salicylaldehyde units was designed and synthesized. The probe has high selectivity and sensitivity for Zn2+ ion in mixed solvent (DMSO/H2O, V/V = 9:1). The fluorescence has obvious redshift phenomenon and visible color change. The stoichiometric ratio of the probe to Zn2+ ion was confirmed to be 1:2 (mole) by 1H NMR, MS analysis and job curves. And the detection limit of fluorescence response of the SW to Zn2+ is down to 2.53 × 10–8 mol/L. At the same time, the probe SW can be applied to the test paper detection of Zn2+ ions under 365 nm UV light and the detection of Zn2+ ions in actual water samples.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.

Formation and evolution of topological defects in course of non-equilibrium symmetry breaking phase transitions is of wide interest in many areas of physics, from cosmology through condensed matter to low temperature physics. Its study in strongly coupled systems, in absence of quasiparticles, is especially challenging. We investigate breaking of U(1) symmetry and the resulting spontaneous formation of vortices in a $(2+1)$-dimensional holographic superconductor employing gauge/gravity duality, a `first-principles' approach to study strongly coupled systems. Magnetic fluxons with quantized fluxes are seen emerging in the post-transition superconducting phase. As expected in type II superconductors, they are trapped in the cores of the order parameter vortices. The dependence of the density of these topological defects on the quench time, the dispersion of the typical winding numbers in the superconductor, and the vortex-vortex correlations are consistent with predictions of the Kibble-Zurek mechanism., Comment: 14+3 pages, 5+2 figures

In this paper, the effect of binder decay rather than a change in the pigments on the blurring of ancient wall paintings was researched. The simulated wall paintings were prepared by brushing an aqueous solution containing gelatine and ochre grains on the surface of cylindrical compressed soil samples. Then, the dried samples were calcined at 650 °C for 2 h to obtain the simulated wall paintings with the degraded binder gelatine. Next, the calcined samples were brushed with a certain amount of acetone solution containing an ionic liquid ([BMIm]PF6) to obtain the corresponding repaired samples. Based on the results from various characterization methods (UV–vis, FTIR, XRD, XPS, SEM, TG), the following conclusions were drawn. The degradation of the binder caused by calcination increases the surface roughness of the painting layer, resulting in enhanced scattering. In this case, because scattering decrease the light absorption by the pigments, even if unchanged pigment exists in the painting layer, its colour can become blurred. The filling of the ionic liquid into the pores caused by gelatine decay in the painting layer can decrease the scattering, and the blurred colour can be restored to some extent. As typical examples, this principle was successfully applied to restore the blurred colour of an ancient Chinese wall painting (Tang Dynasty) and a pottery (Eastern Han Dynasty).

Ni−Al bimetallic catalysis proves to be an efficient catalytic strategy for unreactive bond transformations. Recently, chiral bifunctional ligands, especially amphoteric secondary phosphine oxide (SPO) ligand, are used for a more powerful synergistic effect in the bimetal-catalyzed reactions, providing not only milder reaction conditions and higher reactivity but also excellent reaction selectivity. Herein, we give a brief review on the development of Ni−Al bimetallic catalytic system and highlight recent advances in enantioselective Ni−Al bimetallic catalysis for unreactive bond transformation.

While tuberculosis (TB) in pregnant women is reported globally, clinical data is unavailable in China. To describe clinical features and identify difficulties in the diagnosis of pregnancy-related TB, we performed a retrospective study of 28 TB inpatients at Beijing Chest Hospital. The results were presented in terms of interquartile range (IQR) for age, and medians and percentages with respect to the categorical variables. One patient (3.6%) was immediately diagnosed; for 27 patients (96.4%), the median interval from the initial onset of symptoms to diagnosis was five weeks. Eight cases (28.6%) were microbiologically confirmed. 22 (78.6%) were pulmonary TB (PTB), while six (21.4%) were extrapulmonary TB (EPTB). In addition, eight (28.6%) were miliary TB and six (21.4%) were cerebral TB. 27 (96.4%) were cured and one (3.6%) died. 15 neonates were identified, nine of which were healthy. Two were small for the gestational age (SGA) and one was a stillbirth. Three had neonatal TB, one of which died. Nine were legal abortions and four were spontaneous abortions. Indeed, there was a substantial delay in the diagnosis of TB in the pregnant women and a high incidence of both miliary and cerebral TB was evident. With timely treatment, prognosis is positive.

Motivated by applications in genomics, we study in this paper four interrelated high-dimensional hypothesis testing problems on dependence structures among multiple populations. A new test statistic is constructed for testing the global hypothesis that multiple covariance matrices are equal, and its limiting null distribution is established. Correction methods are introduced to improve the accuracy of the test for finite samples. It is shown that the proposed tests are powerful against sparse alternatives and enjoy certain optimality properties. We then propose a multiple testing procedure for simultaneously testing the equality of the entries of the covariance matrices across multiple populations. The proposed method is shown to control the false discovery rate. A simulation study demonstrates that the proposed tests maintain the desired error rates under the null and have good power under the alternative. The methods are also applied to a Novartis multi-tissue analysis. In addition, testing and support recovery of submatrices of multiple covariance matrices are studied.

For forty years, there has been a widely held belief that over 2,000 years ago the Chinese Qin developed an advanced chromate conversion coating technology (CCC) to prevent metal corrosion. This belief was based on the detection of chromium traces on the surface of bronze weapons buried with the Chinese Terracotta Army, and the same weapons’ very good preservation. We analysed weapons, lacquer and soils from the site, and conducted experimental replications of CCC and accelerated ageing. Our results show that surface chromium presence is correlated with artefact typology and uncorrelated with bronze preservation. Furthermore we show that the lacquer used to cover warriors and certain parts of weapons is rich in chromium, and we demonstrate that chromium on the metals is contamination from nearby lacquer after burial. The chromium anti-rust treatment theory should therefore be abandoned. The good metal preservation probably results from the moderately alkaline pH and very small particle size of the burial soil, in addition to bronze composition.

Image-based tracking for motion compensation is an important topic in image-guided interventions, as it enables physicians to operate in a less complex space. In this paper, we propose an automatic motion compensation scheme to boost image guidence power in transcatheter aortic valve implantation (TAVI). The proposed tracking algorithm automatically discovers reliable regions that correlate strongly with the target. These discovered regions can assist to estimate target motion under severe occlusion, even if target tracker fails. We evaluate the proposed method for pigtail tracking during TAVI. We obtain significant improvement (12 %) over the baseline in a clinical dataset. Calcification regions are automatically discovered during tracking, which would aid TAVI processes. In this work, we open a new paradigm to provide dynamic real-time guidance for TAVI without user interventions, specially in case of severe occlusion where conventional tracking methods are challenged.