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Ibrutinib is a drug that inhibits the protein Burton’s tyrosine kinase and thereby the nuclear translocation of Nrf2, which played a key role in mediating the activation of antioxidants during stress conditions and ferroptosis resistance. This study aimed to identify the effect of Ibrutinib and ferroptosis inducer on colorectal cancer (CRC) treatment and its underlying mechanism. In our study, we found the upregulation of Nrf2 was correlated with CRC progression and antioxidant proteins. Ibrutinib sensitized CRC to ferroptosis inducers, suggested by further reduced CRC cell viability, proliferation and decreased antioxidant protein levels in CRC cells after combination treatment of Ibrutinib and RSL3 or Ibrutinib and Erastin both in vivo and in vitro. Knockout of Nrf2 diminished the regulatory effect of Ibrutinib on CRC sensitivity to ferroptosis inducers. Altogether, this study demonstrated that Ibrutinib increases the sensitivity of CRC cell to ferroptosis inducers by inhibiting Nrf2.

Information-rich molecules provide opportunities for evolution. Genetically engineered materials are superior in that their properties are coded within genetic sequences and could be fine-tuned. In this review, we elaborate the concept of genetically engineered materials (GEMs) using examples ranging from engineered protein materials to engineered living materials. Protein-based materials are the materials of choice by nature. Recent progress in protein engineering has led to opportunities to tune their sequences for optimal material performance. Proteins also play a central role in living materials where they act in concert with other biological components as well as nonbiological cofactors, giving rise to living features. While the existing GEMs are often limited to those constructed by building blocks of biological origin, being genetically engineerable does not preclude nonbiologic or synthetic materials, the latter of which have yet to be fully explored.

BACKGROUND Liver cancer is one of the most highly malignant cancers, characterized by easy metastasis and chemoradiotherapy resistance. Emerging evidence indicates that long noncoding RNAs (LncRNAs), including Lnc524369, are highly involved in the initiation, progression, radioresistance, and chemoresistance of hepatocellular carcinoma (HCC). However, the function of Lnc524369 remains unclear. AIM To explore the function of Lnc524369 in HCC. METHODS To investigate the effect of Lnc524369, tissue from 41 HCC patients were analyzed using CCK8, migration, and invasion assays. Lnc524369 and YWHAZ (also named 14-3-3ζ) mRNA were detected by qPCR, and YWHAZ and RAF1 proteins were detected by western blot in liver cancer cell lines and human HCC tissues. The Cancer Cell Line Encyclopedia (CCLE) databases, STRING database, Human Protein Atlas database, and the TCGA database were used for bioinformatic analysis. RESULTS Lnc524369 was significantly upregulated in the nucleus of liver cancer cells and human HCC tissues. Overexpression of Lnc524369 was associated with the proliferation, migration, and invasion of liver cancer cells. YWHAZ and RAF1 proteins and YWHAZ mRNA were overexpressed in liver cancer, which could be attenuated by overexpression of Lnc524369. Lnc524369 and its downstream target YWHAZ and RAF1 proteins were negatively associated with overall survival time. CONCLUSION Lnc524369 might be a promising target of HCC as it can enhance liver cancer progression and decrease the overall survival time of HCC by activating the YWHAZ/RAF1 pathway.

Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels function as pacemaker channels in spontaneously active cells. We studied the existence of HCN channels and their functional roles in the interstitial cells of Cajal (ICC) from the mouse colon using electrophysiological, immunohistochemical and molecular techniques. HCN1 and HCN3 channels were detected in anoctamin‐1 (Ca2+‐activated Cl− channel; ANO1)‐positive cells within the muscular and myenteric layers in colonic tissues. The mRNA transcripts of HCN1 and HCN3 channels were expressed in ANO1‐positive ICC. In the deletion of HCN1 and HCN3 channels in colonic ICC, the pacemaking potential frequency was reduced. Basal cellular adenylate cyclase activity was decreased by adenylate cyclase inhibitor in colonic ICC, whereas cAMP‐specific phosphodiesterase inhibitors increased it. 8‐Bromo‐cyclic AMP and rolipram increased spontaneous intracellular Ca2+ oscillations. In addition, Ca2+‐dependent adenylate cyclase 1 (AC1) mRNA was detected in colonic ICC. Sulprostone, a PGE2‐EP3 agonist, increased the pacemaking potential frequency, maximum rate of rise of resting membrane in pacemaker potentials and basal cellular adenylate cyclase activity in colonic ICC. These results indicate that HCN channels exist in colonic ICC and participate in generating pacemaking potentials. Thus, HCN channels may be therapeutic targets in disturbed colonic motility disorders.

In the electromagnetic channel, chaotic gravitational lensing is a peculiar phenomenon in strong gravitational lensing. In this work, we analyze the properties and emergence of chaotic gravitational lensing in the Manko-Novikov black hole spacetime. Aiming to understand better the underlying physics, we elaborate on the boundaries of the accessible region in terms of the analyses of the contours of the effective potentials. The latter is associated with the two roots of a quadratic equation. In particular, we explore its interplay with ergoregion, which leads to specific features of the effective potentials, such as the emergence of cuspy edge and the formation of {\it pocket}, that serves as a static constraint on the geodesics. Besides, we investigate the properties of the radial and angular accelerations at the turning points in photons' trajectories. Moreover, the accelerations are analyzed, which is argued to provide a kinematic constraint on the geodesics. It is concluded that the onset of the chaotic lensing is crucially related to both constraints, and as a result, an arbitrarily slight deviation in the incident photon is significantly amplified during the course of evolution through an extensive period, demonstrating the complexity in the highly nonlinear deterministic gravitational system., Comment: 18 pages, 13 figures

BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin's lymphoma. R-CHOP is a protocol for long-term chemotherapy for DLBCL patients. Long-term chemotherapy can lead to low immunity and increase the risk of opportunistic pathogen infections in immunocompromised patients. CASE SUMMARY We report a case of coinfection with Pneumocystis jirovecii (P. jirovecii) and Legionella pneumophila (L. pneumophila) in a patient with DLBCL. The patient was a 40-year-old female who was diagnosed with DLBCL and was admitted due to pulmonary infection. P. jirovecii and L. pneumophila were detected in her bronchoalveolar lavage fluid by hexamine silver staining, isothermal amplification and metagenomic sequencing. CONCLUSION To the best of our knowledge, this is the first case of P. jirovecii and L. pneumophila coinfection found in a DLBCL patient. Clinicians should be aware of the risk of complicated infection in patients undergoing long-term chemotherapy.

Background Inborn error of bile acid synthesis type 4 is a peroxisomal disease with impaired bile acid synthesis caused by a-methylacyl-CoA racemase (AMACR) gene mutation. The disease is usually found in children with mild to severe liver disease, cholestasis and poor fat-soluble vitamin absorption. At present, there is no report of inborn errors of bile acid synthesis type 4 in adults with liver disease and poor fat-soluble vitamin absorption. Case summary A 71-year-old man was hospitalized in our department for recurrent liver dysfunction. The clinical manifestations were chronic liver disease and yellow skin and sclera. Serum transaminase, bilirubin and bile acid were abnormally increased; and fat-soluble vitamins decreased. Liver cirrhosis and ascites were diagnosed by computed tomography. The patient had poor coagulation function and ascites and did not undergo liver puncture. Genetic testing showed AMACR gene missense mutation. The patient was diagnosed with inborn error of bile acid synthesis type 4. He was treated with ursodeoxycholic acid, liver protection and vitamin supplementation, and jaundice of the skin and sclera was reduced. The indicators of liver function and the quality of life were significantly improved. Conclusion When adults have recurrent liver function abnormalities, physicians should be alert to genetic diseases and provide timely treatment.

Bioconjugation is a powerful protein modification strategy to improve protein properties. Herein, we report mechano-bioconjugation as a novel approach to empower fusion protein therapeutics and demonstrate its utility by a protein heterocatenane (

The search for dynamically screening the coupling between the scalar field and matter in high-density environment is achievable with the symmetron model. The high-accuracy and short-range gravity experiment is proposed to test the symmetron model. In this Letter, the data of the HUST-2020 torsion pendulum experiment testing the inverse-square law at submillimeter range is analyzed to constrain the symmetron model. The results show that the HUST-2020 experiment is uniquely sensitive to probe the symmetron model with a mass scale of μ=7.2×10^{-3} eV, and the self-coupling parameter λ≲105 is excluded at mass scale M=0.3 TeV. Especially, at the dark energy scale μ=2.4×10^{-3} eV, the constraint at M=1.3 TeV is improved by about 10 times the previous constraints on the torsion pendulum experiment.

Nontuberculous mycobacteria infections present mostly pulmonary characteristics. However, the incidence of skin and soft tissue infections caused by nontuberculous mycobacteria has increased in part due to the increased popularity of cosmetic and plastic surgery. Here, we report a case of Mycobacterium agri infection. The patient underwent a one-year course of anti-infection therapy. To the best of our knowledge, this is the first report of a previously healthy patient presenting a skin and soft tissue infection caused by Mycobacterium agri. Clinical personnel should be aware of possible causes of persistent skin and soft tissue infection after cosmetic and plastic surgery.

BACKGROUND Primary bone lymphoma (PBL) is an uncommon extranodal disease that represents approximately 1%-3% of lymphomas. Anaplastic lymphoma kinase (ALK) positive anaplastic large-cell lymphoma (ALCL) is an extremely rare type of PBL. The aim of this report is describe the symptoms, diagnosis, and treatment of primary bone ALK-positive ALCL. CASE SUMMARY A 66-year-old man presented to our hospital with neck and shoulder pain and intermittent fever that lasted for 1 mo. After extensive evaluation, positron emission tomography-computed tomography (CT) examination showed multiple osteolytic bone lesions without other sites lesions. CT-guided biopsy of the T10 vertebral body was performed, and the pathology results showed that neoplastic cells were positive for ALK-1, CD30, and CD3. A diagnosis of primary bone ALK positive ALCL was ultimately made. The patient was in partial response after four cycle soft cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, and we planned to repeat the biopsy and radiological examination after completion of the fifth cycle of therapy. CONCLUSION Primary bone ALK positive ALCL is a rare disease and physicians should keep in mind that ALCL can present with isolated osseous involvement without nodal involvement, and lymphoma should be considered in the differential diagnosis of primary bone lesions.

We report the robust growth of an entirely protein-based, photo- and thermoresponsive Layer-by-Layer nanofilm using genetically encoded SpyTag/SpyCatcher chemistry. The process was facilitated by AdoB

Herein, we report the facile conjugation between proteins and water-soluble [60]fullerene derivatives (DC60) under native conditions using SpyTag as a reactive handle. Water-soluble [60]fullerene derivatives were first prepared via sequential Bingel-Hirsch reaction and “clicked” with SpyTag to give DC60-SpyTag for native conjugation with proteins by the highly efficient SpyTag-SpyCatcher chemistry. The bioconjugation was confirmed by MALDI-TOF MS spectra and SDS-PAGE analysis. The TEM and UV-vis spectroscopic study further revealed that the DC60 could alter the optical performance and induce aggregation of the target proteins. It thus provides a general and robust method for modifying proteins with C60 derivatives and could potentially be adapted for native conjugation between proteins and other nonbiological motifs as well.

A novel high-spin Co(II) complex, named [CoII2(μ-L1)(μ-L2)(μ-Cl)Cl]n (1), was achieved through the reaction of Co(II) salts with two kinds of pyrazolate ligands (HL1 = 2-(5-methyl-1H-pyrazol-3-yl) pyridine; HL2 = 2-(5-methyl-4H-1,2,4-triazol-3-yl)phenol) using a solvothermal method. Structurally, two types of Co(II) ions, octahedral and tetrahedral, bridged by three types of linkers (μ-Cl, μ-(N–N), μ-O), extend into 1D chains. Additionally, the interchain connections are weak, facilitating the occurrence of single-chain magnetic behavior. Magnetically, considerable frequency dependence of slow magnetic relaxation is observed below 5 K and the compound behaves like a single-chain magnet. Both the simulation of the coupling constant from the χMT vs. T curve and DFT computations reveal that the μ-O linker in the Co2O2 system transmits ferromagnetic coupling.

Background/Aims To investigate an effect of ML204 (an inhibitor of transient receptor potential canonical 4 and 5 [TRPC4/5] channels) on interstitial cells of Cajal (ICCs) and therefore determine whether TRPC4/5 channels act on ICC-generated pacemaker activity. Methods We enforced whole cell patch clamp analysis, measurements of the intracellular Ca2+ concentration, and reverse transcription polymerase chain reaction to determine the effect of ML204 (10 μM) or englerin A (a selective activator of TRPC4/5 channeles, 10 μM) and the existence of TRPC4/5 in mouse small intestinal ICC. Results Treatment of ICCs with ML204 or englerin A caused the membrane potentials to depolarize. This depolarization effect of membrane potentials by ML204 in ICCs was observed to be concentration-dependent. After treating Ca2+- and Na+-free solutions or flufenamic acid (a non-selective cation channel blocker), the pacemaker potentials in the ICCs were abolished. A specific anoctamin 1 channel blocker did not have any effect on the pacemaker activity in ML204-untreated control cells; however, they blocked ML204-induced pacemaker activity in ICCs. Specific primers designed against TRPC4 and TRPC5 detected the presence of TRPC4/5 in small intestinal ICCs, and the application of ML204 increased raise the frequency of Ca2+ oscillations in ICCs, as assessed using Fluo-4 AM. Conclusion The results implied that ML204 could not inhibit the pacemaker activity but depolarized the membrane potential of ICCs by regulating intracellular Ca2+ oscillations and anoctamin 1 channels. (J Neurogastroenterol Motil 2020;26:521-528)

Entangled proteins have attracted significant research interest. Herein, we report the first rationally designed lasso proteins, or protein [1]rotaxanes, by using a p53dim-entwined dimer for intramolecular entanglement and a SpyTag-SpyCatcher reaction for side-chain ring closure. The lasso structures were confirmed by proteolytic digestion, mutation, NMR spectrometry, and controlled ligation. Their dynamic properties were probed by experiments such as end-capping, proteolytic digestion, and heating/cooling. As a versatile topological intermediate, a lasso protein could be converted to a rotaxane, a heterocatenane, and a "slide-ring" network. Being entirely genetically encoded, this robust and modular lasso-protein motif is a valuable addition to the topological protein repertoire and a promising candidate for protein-based biomaterials.

The interplay between protein folding and chemical reaction has been an intriguing subject. In this contribution, we report the study of SpyTag and SpyCatcher reactive mutants using a combination of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, liquid chromatography and mass spectrometry, circular dichroism, and NMR spectroscopy. It was found that the wild-type SpyCatcher is well-folded in solution and docks with SpyTag to form an intermediate that promotes isopeptide bond formation. By contrast, the double mutant SpyCatcherVA is disordered in solution yet remains reactive toward SpyTag, forming a well-folded covalent complex. Control experiments using the catalytically inactive mutants further reveal the critical role of the isopeptide bond in stabilizing the otherwise loose SpyTag-SpyCatcherVA complex, amplifying the effect of the minute sequence disparity. We believe that the synergy between protein folding and isopeptide bonding is an effective way to enhance protein stability and engineer protein-protein interactions.

Living organisms have evolved cyclic or multicyclic peptides and proteins with enhanced stability and high bioactivity superior to their linear counterparts for diverse purposes. Herein, we review recent progress in applying this concept to artificial peptides and proteins to exploit the functional benefits of these macrocycles. Not only have simple cyclic forms been prepared, numerous macrocycle variants, such as knots and links, have also been developed. The chemical tools and synthetic strategies are summarized for the biological synthesis of these macrocycles, demonstrating it as a powerful alternative to chemical synthesis. Its further application to therapeutic peptides/proteins has led to biomedicines with profoundly improved pharmaceutical performances. Finally, we present our perspectives on the field and its future developments.

The spatial-temporal baseline threshold method is commonly used to select interferograms for the Small BAseline Subset interferometric synthetic aperture radar (SBAS-InSAR) technique. However, this selection strategy is rather empirical and prone to including highly contaminated interferograms or excluding those with high quality. To overcome these limitations, this study first derives the relationship between the measurement accuracy of unknown parameters and the number of selected interferograms with their corresponding qualities. Subsequently, an adaptive interferogram selection method is proposed on the basis of Graph Theory (GT) and the turbulence atmospheric effects of interferogram. This proposed method first identifies and deletes the SAR image that is severely polluted by atmospheric phase. Second, high-quality interferograms are selected for SBAS-InSAR based on their corresponding turbulence atmospheric variance. Compared with the traditional selection method, this approach can significantly reduce the effect of turbulence atmosphere on SBAS-InSAR. A set of simulated experiments and real Sentinel-1A data in Hawaii, United States, validate the good performance of the proposed method.

Recently, a vertebrate assemblage of the Jehol Biota has been reported from the Early Cretaceous Hengtongshan Formation of Xingling Town, Meihekou City, Jilin Province, China. It is dominated by the fishes Lycoptera and Sinamia and the sinemydid turtle Ordosemys. Here, we describe the turtle specimens and referral to Ordosemys liaoxiensis, otherwise known from the older Yixian Formation of the Jehol Biota. It is characterized by a subcircular shell, wide vertebral scales, well-developed plastral fenestrae, and a major contribution from the xiphiplastra to enclose the hypo-xiphiplastral fenestra. As the first Mesozoic turtle of Jilin Province, this record represents the first tetrapod to indicate the presence of the Jehol Biota in the region. Given the geographic and temporal distance from the Yixian Formation, future collections from the Hengtongshan Formation have good potential for evaluating spatiotemporal patterns of the Jehol Biota.

Radium, which is naturally present in many rocks, decays to the radioactive gas radon, which is then exhaled from the surface of underground tunnels and other underground buildings and is a major source of human exposure to radioactivity. A mathematical model for the migration of radon from a circular tubular emanation medium was established based on the seepage–diffusion migration theory for radon in porous emanation media, such as artificial retaining walls and the surrounding rocks in these locations. An analytical solution for the distribution of radon concentrations and the calculation formula for the radon exhalation rate under steady-state conditions were then obtained. An experimental device was designed to determine the radon exhalation rate under different pressure gradients. The theoretical calculation values for the radon exhalation rate and the total amount of radon exhalation are in good agreement with the experimental results. The radon exhalation rate at the low-pressure side increases with an increase in seepage velocity (pressure difference), while the radon exhalation rate at the high-pressure side is on the contrary. The total amount of radon exhalation increased over time with an increase in the seepage velocity and tended towards a maximum value.

Exosomes, one of three main types of extracellular vesicles, are ~30-100 nm in diameter and have a lipid bilayer membrane. They are widely distributed in almost all body fluids. Exosomes have the potential to regulate unknown cellular and molecular mechanisms in intercellular communication, organ homeostasis, and diseases. They are critical signal carriers that transfer nucleic acids, proteins, lipids, and other substances into recipient cells, participating in cellular signal transduction and material exchange. ncRNAs are non-protein-coding genes that account for over 90% of the genome and include microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). ncRNAs are crucial for physiological and pathological activities in the liver by participating in gene transcription, posttranscriptional epigenetic regulation, and cellular processes through interacting with DNA, RNA, or proteins. Recent evidence from both clinical and preclinical studies indicates that exosome-derived noncoding RNAs (ncRNAs) are highly involved in the progression of acute and chronic liver diseases by regulating hepatic lipid metabolism, innate immunity, viral infection, fibrosis, and cancer. Therefore, exosome-derived ncRNAs have promising potential and clinical implications for the early diagnosis, targeted therapy, and prognosis of liver diseases.

Introduction: Pyogenic liver abscess (PLA) is a serious infectious disease of the liver. Pyogenic liver abscess caused by Fusobacterium nucleatum is extremely rare. Here we report the first case of liver abscess caused by F. nucleatum in China. Case Presentation: The case was a 34-year-old female patient admitted to the hospital due to high fever. The diagnosis of liver abscess was confirmed by imaging studies and liver puncture. We finally confirmed the pathogen as F. nucleatum by next-generation sequencing (NGS). After the targeted anti-infective treatment, the patient recovered and discharged. Conclusions: As a new microbial detection method, NGS can still help in clinical practice. In addition, to improve the positive rate of anaerobic bacteria culture, we should pay attention to avoid contact with air in the process of specimen collection when the pathogenic bacteria are suspected to be anaerobic bacteria.

Background The chronic visceral subtype of acid sphingomyelinase deficiency, commonly known as Niemann Pick disease type B (NPDB), is a relatively rare autosomal recessive genetic disorder that is caused by mutations in the SMPD1 gene. NPDB with sea-blue histiocytes (SBH) clinically mimics Budd-Chiari syndrome (BCS), as it lacks specific clinical characteristics. This makes its diagnosis difficult. Case presentation Here, we report a case of NPDB with SBH that was misdiagnosed as BCS for three years. A 20-year-old female with abdominal distension, hepatosplenomegaly, and haematological anomalies was initially diagnosed with BCS based on her imaging finding of a thin hepatic vein and rapid blood flow at the confluence of the hepatic vein and inferior vena cava. Her bone marrow cytology found sea-blue histiocytes. Liver biopsy showed foamy cytoplasm in hepatocytes surrounded by numerous Kupffer cells. Sequencing analysis of the SMPD1 gene led to the finding of two missense mutations in the heterozygous state: C.829 T > C (p.Trp277Arg) in exon 2 (novel) and c.1805G > A (p.Arg602His) in exon 6 (already described). These findings established the diagnosis of NPDB. Conclusion The patient presented with hepatosplenomegaly, haematological anomalies, and dyslipidaemia. Thus, NPDB should be considered following the exclusion of related diseases. The diagnosis of NPDB was suspected by clinical symptoms and routine laboratory tests and was confirmed by liver biopsy and gene sequencing. The novel mutation c.829 T > C in exon 2 of the SMPD1 gene has never been reported and needs to be further investigated.

The chameleon model was proposed as a promising candidate for the dark energy screening mechanism. It is not straightforward to detect the fifth force mediated by the chameleon scalar field in a high-density environment, such as those in a ground-based laboratory. Nevertheless, short-range gravitational experiments such as the torsion pendulum experiment can provide strong constraints on the chameleon model. In this work, we constrain the chameleon model from a precise test of the inverse-square law at Huazhong University of Science and Technology. In particular, we take full advantage of the regular flat-plate structure of the test and attraction mass, which gives rise to accurate modeling for the chameleon force and torque. The derived analytical results on the chameleon torque are shown to agree well with those by numerical calculations. Subsequently, based on the experimental data, the parameter space of the chameleon model is analyzed, and the results are presented in terms of a more stringent constraint on the model parameters.

Strontium oxide (SrO) is an effective catalyst for transesterification. SrO powder that is firmly deposited onto a light titanium plate (TiO2_P), denoted as SrO/TiO2_P, can be reinforced by forming strontium titanate (SrTiO3) at the interface. Exposed SrO agglomerates can promote subsequent continuous transesterification process. In this work, conversion efficiency and production of biodiesel from olive oil on SrO/TiO2_P is investigated. The as-designed SrO/TiO2_P was followed by dip-coating and heat treatment. The physical properties of SrO/TiO2_P were verified through ASTM D3359, the chemical structures before and after transesterification, were respectively identified by X-ray photoelectron spectroscopy and Raman spectroscopy. A focused microwave heating system was utilized for transesterification. In the optimized sample SrO/TiO2_P (x) (x = 0.5 M), SrO firmly bonds with TiO2_P and forms the SrTiO3 structure. With the support of TiO2_P, the tested oil with SrO agglomerates subsequently reacts with SrO under microwave heating. The biodiesel conversion rate reaches 87.7% after a reaction time of 4 min, while the biodiesel product has an average of 39.37 MJ/kg of combustion heat and less than 1 vol% of water content. The as-designed SrO/TiO2_P (0.5) thus has great potential for biodiesel production and is promising with high stability in particular for a continuous fluid flow system.