Search

Abstract Natural proteins exhibit rich structural diversity based on the folds of an invariably linear chain. Macromolecular catenanes that cooperatively fold into a single domain do not belong to the current protein universe, and their design and synthesis open new territories in chemistry. Here, we report the design, synthesis, and properties of a single-domain green fluorescent protein catenane via rewiring the connectivity of GFP’s secondary motifs. The synthesis could be achieved in two steps via a pseudorotaxane intermediate or directly via expression in cellulo. Various proteins-of-interest may be inserted at the loop regions to give fusion protein catenanes where the two subunits exhibit enhanced thermal resilience, thermal stability, and mechanical stability due to strong conformational coupling. The strategy can be applied to other proteins with similar fold, giving rise to a family of single-domain fluorescent proteins. The results imply that there may be multiple protein topological variants with desirable functional traits beyond their corresponding linear protein counterparts, which are now made accessible and fully open for exploration.

Abstract 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.

Objective To undertake a network meta-analysis to compare the relative efficacy of a dual peroxisome proliferator-activated receptor (PPAR)α and PPARγ agonist, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and metformin in patients with non-alcoholic fatty liver disease (NAFLD). Methods Electronic databases, including Embase®, PubMed® and The Cochrane Library, were searched systematically for eligible studies from inception to 20 July 2022. Randomized controlled trials (RCTs) that investigated aspartate aminotransferase, alanine aminotransferase (ALT) and triglyceride levels were considered for inclusion. Data were extracted using a standardized data collection table. A network meta-analysis was performed. Relative risk and 95% confidence interval were calculated for continuous data and I 2 was used to assess the heterogeneity of studies. Results A total of 22 RCTs involving 1698 patients were eligible for inclusion in the analysis. Both direct analysis and indirect analysis showed that saroglitazar was significantly superior to GLP-1RAs in improving ALT levels. Metformin improved ALT levels, but the effect was not as good as saroglitazar. Conclusion Saroglizatar was the most effective drug for improving NAFLD. INPLASY registration number: INPLASY202340066

Abstract 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.

Unique large-scale cooperation and fairness norms are essential to human society, but the emergence of prosocial behaviors is elusive. The fact that heterogeneous social networks prevail raised a hypothesis that heterogeneous networks facilitate fairness and cooperation. However, the hypothesis has not been validated experimentally, and little is known about the evolutionary psychological basis of cooperation and fairness in human networks. Fortunately, research about oxytocin, a neuropeptide, may provide novel ideas for confirming the hypothesis. Recent oxytocin-modulated network game experiments observed that intranasal administration of oxytocin to a few central individuals significantly increases global fairness and cooperation. Here, based on the experimental phenomena and data, we show a joint effect of social preference and network heterogeneity on promoting prosocial behaviors by building evolutionary game models. In the network ultimatum game and the prisoner’s dilemma game with punishment, inequality aversion can lead to the spread of costly punishment for selfish and unfair behaviors. This effect is initiated by oxytocin, then amplified via influential nodes, and finally promotes global cooperation and fairness. In contrast, in the network trust game, oxytocin increases trust and altruism, but these effects are confined locally. These results uncover general oxytocin-initiated mechanisms underpinning fairness and cooperation in human networks.

Topology has been recognized as a unique dimension in molecular engineering, yet the topological diversity remains largely untapped, especially in macromolecules. Herein, we report the molecular design, cellular synthesis, and detailed characterization of protein pretzelanes with a chemical topology of a bridged Hopf link. The synergy between the intramolecular chain entwining guided by the p53dim (X) domains and the genetically encoded side-chain coupling by SpyTag(A)-SpyCatcher(B) reaction facilitates the direct synthesis of the model protein pretzelane BXA-BXA in Escherichia coli. The approach tolerates the insertion of various proteins-of-interest, such as elastin-like protein (ELP), superfolder green fluorescent protein (GFP) and dihydrofolate reductase (DHFR), at the bridge region between two rings, giving rise to three protein pretzelanes BXA-ELP-BXA, BXA-GFP-BXA, and BXA-DHFR-BXA. Their topology has been verified by combined techniques of MALDI-TOF mass spectrometry, ion mobility-mass spectrometry, site-specific mutation, and orthogonal proteolytic digestion experiments. Not only are the fluorescent properties of GFP and the catalytic properties of DHFR fully retained, the pretzelane topology also renders BXA-DHFR-BXA more thermally resilient than the wild-type DHFR. These results expand the topological diversity of proteins and demonstrate protein stabilization as a potential functional benefit for the pretzelane topology.

Abstract Novel coronavirus pneumonia (NCP) has been widely spread in China and several other countries. Early finding of this pneumonia from huge numbers of suspects gives clinicians a big challenge. The aim of the study was to develop a rapid screening model for early predicting NCP in a Zhejiang population, as well as its utility in other areas. A total of 880 participants who were initially suspected of NCP from January 17 to February 19 were included. Potential predictors were selected via stepwise logistic regression analysis. The model was established based on epidemiological features, clinical manifestations, white blood cell count, and pulmonary imaging changes, with the area under receiver operating characteristic (AUROC) curve of 0.920. At a cut-off value of 1.0, the model could determine NCP with a sensitivity of 85% and a specificity of 82.3%. We further developed a simplified model by combining the geographical regions and rounding the coefficients, with the AUROC of 0.909, as well as a model without epidemiological factors with the AUROC of 0.859. The study demonstrated that the screening model was a helpful and cost-effective tool for early predicting NCP and had great clinical significance given the high activity of NCP.

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.

Abstract Background Tracheal injury could cause intratracheal scar hyperplasia which in turn causes benign tracheal stenosis (TS). With the increasing use of mechanical ventilation and ventilator, the incidence of TS is increasing. However, the molecular mechanisms of TS have not been elucidated. It is significant to further explore the molecular mechanisms of TS. Methods The repeatability of public data was verified. Differently expressed genes (DEGs) and most significant genes were identified between TS and normal samples. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed. The comparative toxicogenomics database were analyzed. TS patients were recruited and RT‐qPCR were performed to verify the most significant genes. Results There exist strong correlations among samples of TS and normal group. There was a total of 194 DEGs, including 61 downregulated DEGs and 133 upregulated DEGs. GO were significantly enriched in mitotic nuclear division, cell cycle, and cell division. Analysis of KEGG indicated that the top pathways were cell cycle, and p53 pathway. MKI67(OMIM:176741), CCNB1(OMIM:123836), and CCNB2(OMIM:602755) were identified as the most significant genes of TS, and validated by the clinical samples. Conclusion Bioinformatics methods might be useful method to explore the mechanisms of TS. In addition, MKI67, CCNB1, and CCNB2 might be the most significant genes of TS.

Electrocardiograms (ECGs) provide important information for diagnosing cardiovascular diseases. In clinical practice, the conventional Ag/AgCl electrode is generally used; however, it is not suitable for long-term ECG measurement because of the risk of allergic reactions on the skin and the dying issue of electrolytic gels. In previous studies, several dry electrodes have been proposed to address these issues. However, most dry electrodes, which are the mode of conductive materials, have to contact the skin well and are easily affected by motion artifacts in daily life. In the smart clothes developed in this study, a noncontact electrode was used to assess the biopotential across the clothes to prevent skin irritation and discomfort. Moreover, a three-dimensional parametric model based on anthropometric data was built, and the technique of customized product design was introduced into the smart clothes development process to reduce the influence of motion artifacts. The experimental results show that the proposed smart clothes can maintain a good ECG signal quality stably under motion from different activities.

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.

We theoretically propose a method based on the combination of a nonlinear optical mass sensor using a hybrid spin-microcantilever and the nanoparticle-enhanced technique, to detect and monitor DNA mutations. The technique theoretically allows the mass of external particles (ssDNA) landing on the surface of a hybrid spin-microcantilever to be detected directly and accurately at 300 K with a mass responsivity 0.137 Hz/ag in situ in liquid. Moreover, combined with the nanoparticle-enhanced technique, even only one base pair mutation in the target DNA sequence can be identified in real time accurately, and the DNA hybridization reactions can be monitored quantitatively. Furthermore, in situ detection in liquid and measurement of the proposed nonlinear optical spin resonance spectra will minimize the experimental errors.

In the Early Cretaceous Jehol Biota, the toothless pterosaurs flourished with the chaoyangopterids and tapejarids playing a key role in understanding the early diversity and evolution of the Azhdarchoidea. Unlike the more diverse tapejarids, the rarer chaoyangopterids are characterized by a long and low rostrum, supporting a close relationship with the huge azhdarchids. Unfortunately, our knowledge is still limited in the osteology, paleoecology, and taxonomy of the Chaoyangopteridae. As one of the best preserved skeletons, the type and only specimen of Jidapterus edentus provides an opportunity to understand the morphology and paleoecology of the chaoyangopterids.Our study of the osteology of Jidapterus edentus reveals valuable information about the morphology of the Chaoyangopteridae such as a rostrum with a curved dorsal profile, high Rostral Index (RI), larger angle between the dorsal and postorbital processes of the jugal, sequentially shorter fourth to seventh cervical vertebrae, sternum with a plate wider than long, contact of the metacarpal I with the distal syncarpal, pneumatic foramen on first wing phalanx, hatchet-like postacetabular process with unconstricted neck and small dorsal process, distinctly concave anterior margin of pubis, subrectangular pubic plate with nearly parallel anterior and posterior margins, longer proximal phalanges of pedal digits III and IV, as well as reduced and less curved pedal unguals. These features further support the validity of Jidapterus edentus as a distinct species and the close relationship of the chaoyangopterids with the azhdarchids. Paleoecologically, the chaoyangopterids are probably like the azhdarchids, more terrestrial than the contemporaneous and putatively arboreal tapejarids, which may have been limited to the forest-dominated ecosystem of the Jehol Biota.The osteology of Jidapterus edentus further supports the close relationship of the Chaoyangopteridae with the Azhdarchidae in sharing a high RI value and reduced and mildly-curved pedal unguals, and it also implies a possible paleoecological similarity in their terrestrial capability. Combined with the putatively arboreal and herbivorous tapejarids, this distinct lifestyle of the chaoyangopterids provides new insights into the diversity of pterosaurs in the ecosystem of the Jehol Biota.

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. [ABSTRACT FROM AUTHOR]

Background Myocardial injury caused by microvascular obstruction (MVO) is characterized by persistent ischemia/hypoxia (IH) of cardiomyocytes after microembolization. Autophagy and Egr-1 were closely associated with various cardiovascular diseases, including MVO. Bim and Beclin-1 are the important genes for autophagy and apoptosis. We aimed to explore whether the Egr-1/Bim/Beclin-1 pathway is involved in regulating autophagy and apoptosis in IH-exposed cardiomyocytes. Methods Neonatal rat cardiomyocytes exposed to the IH environment in vitro were transfected with lentivirus expressing Egr-1 or Egr-1 shRNA, or further treated with 3-methyladenine (3-MA). The expressions of autophagy and apoptosis-associated genes were evaluated using RT-qPCR and Western blots assays. Autophagic vacuoles and autophagic flux were detected by transmission electron microscopy (TEM) and confocal microscope, respectively. Cell injury was assessed by lactate dehydrogenase (LDH) leakage, and apoptosis was determined by flow cytometry. Results IH exposure elevated Egr-1 and Bim expressions, and decreased Beclin-1 expression in rat cardiomyocytes. Egr-1 overexpression in IH-exposed cardiomyocytes significantly up-regulated the levels of Egr-1 and Bim, and down-regulated the level of Beclin-1. Egr-1 knockdown resulted in down-regulated expressions of Egr-1 and Bim, as well as up-regulated expression of Beclin-1. In addition, Egr-1 knockdown induced autophagy was suppressed by 3-MA treatments. TEM and autophagic flux experiments also confirmed that Egr-1 inhibited autophagy progression in IH-exposed cardiomyocytes. Egr-1 suppression protected cardiomyocytes from IH-induced injury, as evidenced by the positive correlations between Egr-1 expression and LDH leakage or apoptosis index in IH-exposed cardiomyocytes. Conclusions IH-induced cardiomyocyte autophagy and apoptosis are regulated by the Egr-1/Bim/Beclin-1 pathway, which is a potential target for treating cardiomyocyte injury caused by MVO in the IH environment. [ABSTRACT FROM AUTHOR]

Background: Polydeoxyribonucleotide (PDRN) influencing cellular growth and differentiation is recognized to promote wound healing by stimulating tissue repair. Although PDRN can be extracted from human placentas, PDRN medications have recently been extracted from the semen of trout (Oncorhynchus mykiss) and salmon (Oncorhynchus keta). The present study was designed to evaluate the wound healing effects of O. keta -derived PDRN for injection (Rejuvenex) and PDRN cream (Rejuvenex Cream) in comparison with those of O. mykiss -derived PDRN injection (Placentex). Methods: Full-thickness skin defects were made on the back of mice (n=60). The mice were divided into the following four groups according to the dressing used for the wounds: O. mykiss -derived PDRN injection group, O. keta -derived PDRN injection group, O. keta - derived PDRN cream group, and normal saline soaked dressing group (control group). We analyzed the gross findings, wound sizes, histological findings, immunohistochemistry and enzyme-linked immunosorbent assays for the groups immediately after the treatment, and again after 4, 7, and 10 days of treatment. Results: The wound healing effects were the greatest in the O. keta -derived PDRN injection and O. mykiss -derived PDRN injection groups, which showed similar scores, followed by the O. keta -derived cream and normal saline soaked dressing groups. Conclusion: The injection of PDRN extracted from O. keta was found to be as effective at healing full-thickness skin defects as the O. mykiss -derived PDRN injection, which is currently used in the clinic. Moreover, the O. keta -derived PDRN injection was also found to reduce the time required for wound healing. [ABSTRACT FROM AUTHOR]

The use of a high k composite dielectric composed of La2O3 and HfO2 layers as the gate dielectric for In0.53Ga0.47As MOS application is proposed. Two multi-layer structures of La2O3 (1 nm)/HfO2 (1 nm) and La2O3 (0.5 nm)/HfO2 (0.5 nm) were deposited and annealed at 450 and 500°C for device performance comparison. X-ray photoelectron spectroscopy, TEM and C-V measurements were used for the interface analysis between the oxide and the semiconductor. Finally, a 1 nm equivalent-oxide-thickness dielectric with small hysteresis of 88 mV and Dit of 1.9 × 1012 cm-2 eV-1 was achieved for six layers of an La2O3 (0.5 nm)/HfO2 (0.5 nm) composite oxide structure on an In0.53Ga0.47As MOS capacitor with a post-deposition annealing temperature of 450°C. [ABSTRACT FROM AUTHOR]

Improved device performance to enable high-linearity power applications has been discussed in this study. We have compared the La2O3/SiO2 AlGaN/GaN metal–oxide–semiconductor high-electron-mobility transistors (MOS-HEMTs) with other La2O3-based (La2O3/HfO2, La2O3/CeO2 and single La2O3) MOS-HEMTs. It was found that forming lanthanum silicate films can not only improve the dielectric quality but also can improve the device characteristics. The improved gate insulation, reliability, and linearity of the 8 nm La2O3/SiO2 MOS-HEMT were demonstrated. [ABSTRACT FROM AUTHOR]

Motivated by recent experimental progress towards the detection and manipulation of Majorana fermions in ferromagnetic atomic chains on a superconductor, we present a novel proposal based on a single-crystal diamond (SCD) microcantilever with a single nitrogen-vacancy (NV) center spin embedded in ultrapure diamond substrate to probe Majorana fermions in an all-optical domain. With this scheme, a possible distinct Majorana signature is investigated via the electron spin resonance spectrum. In the proposal, the SCD microcantilever behaves as a phonon cavity and is robust for detecting of Majorana fermions, while the NV center spin can be considered as a sensitive probe. Further, the vibration of the microcantilever will enhance the coupling effect, which makes the Majorana fermions more sensitive to detection and the well-established optical NV spin readout technology will certainly promote the detection. This proposed method may provide a potential supplement for the detection of Majorana fermions. [ABSTRACT FROM AUTHOR]

Nowadays hybrid spin-micro/nanomechanical systems are being actively explored for potential quantum sensing applications. In combination with the pump-probe technique or the spin resonance spectrum, we theoretically propose a realistic, feasible, and an exact way to measure the cantilever frequency in a hybrid spin-micromechanical cantilever system which has a strong coherent coupling of a single nitrogen vacancy center in the single-crystal diamond cantilever with the microcantilever. The probe absorption spectrum which exhibits new features such as mechanically induced three-photon resonance and ac Stark effect is obtained. Simultaneously, we further develop this hybrid spin-micromechanical system to be an ultrasensitive mass sensor, which can be operated at 300 K with a mass responsivity 0.137 Hz ag−1, for accurate sensing of gaseous or aqueous environments, chemical vapors, and biomolecules. And the best performance on the minimum detectable mass can be in vacuum. Finally, we illustrate an in situ measurement to detect Angiopoietin-1, a marker of tumor angiogenesis, accurately with this hybrid microcantilever at room temperature. [ABSTRACT FROM AUTHOR]