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Objective: To construct the deep learning convolution neural network (CNN) model and machine learning support vector machine (SVM) model of bone remodeling of chronic maxillary sinusitis (CMS) based on CT image data to improve the accuracy of image diagnosis., Methods: Maxillary sinus CT data of 1000 samples in 500 patients from January 2018 to December 2021 in our hospital was collected. The first part is the establishment and testing of chronic maxillary sinusitis detection model by 461 images. The second part is the establishment and testing of the detection model of chronic maxillary sinusitis with bone remodeling by 802 images. The sensitivity, specificity and accuracy and area under the curve (AUC) value of the test set were recorded, respectively., Results: Preliminary application results of CT based AI in the diagnosis of chronic maxillary sinusitis and bone remodeling. The sensitivity, specificity and accuracy of the test set of 93 samples of CMS, were 0.9796, 0.8636 and 0.9247, respectively. Simultaneously, the value of AUC was 0.94. And the sensitivity, specificity and accuracy of the test set of 161 samples of CMS with bone remodeling were 0.7353, 0.9685 and 0.9193, respectively. Simultaneously, the value of AUC was 0.89., Conclusion: It is feasible to use artificial intelligence research methods such as deep learning and machine learning to automatically identify CMS and bone remodeling in MSCT images of paranasal sinuses, which is helpful to standardize imaging diagnosis and meet the needs of clinical application., (© 2024. The Author(s).)

This study aims to develop and validate a brief bedside tool to screen women survivors presenting for emergency care following sexual assault for risk of persistent elevated posttraumatic stress symptoms (PTSS) six months after assault. Participants were 547 cisgender women sexual assault survivors who presented to one of 13 sexual assault nurse examiner (SANE) programs for medical care within 72 h of a sexual assault and completed surveys one week and six months after the assault. Data on 222 potential predictors from the SANE visit and the week one survey spanning seven broadly-defined risk factor domains were candidates for inclusion in the screening tool. Elevated PTSS six months after assault were defined as PCL-5 > 38. LASSO logistic regression was applied to 20 randomly selected bootstrapped samples to evaluate variable importance. Logistic regression models comprised of the top 10, 20, and 30 candidate predictors were tested in 10 cross-validation samples drawn from 80% of the sample. The resulting instrument was validated in the remaining 20% of the sample. AUC of the finalized eight-item prediction tool was 0.77 and the Brier Score was 0.19. A raw score of 41 on the screener corresponds to a 70% risk of elevated PTSS at 6 months. Similar performance was observed for elevated PTSS at one year. This brief, eight-item risk stratification tool consists of easy-to-collect information and, if validated, may be useful for clinical trial enrichment and/or patient screening., Competing Interests: Declaration of competing interest None. All authors have completed COI forms., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We report an experimental study of quantum point contacts defined in a high-quality strained germanium quantum well with layered electric gates. At a zero magnetic field, we observed quantized conductance plateaus in units of 2 e 2 / h . Bias-spectroscopy measurements reveal that the energy spacing between successive one-dimensional subbands ranges from 1.5 to 5 meV as a consequence of the small effective mass of the holes and the narrow gate constrictions. At finite magnetic fields perpendicular to the device plane, the edges of the conductance plateaus get split due to the Zeeman effect and Landé g factors were estimated to be ∼6.6 for the holes in the germanium quantum well. We demonstrate that all quantum point contacts in the same device have comparable performances, indicating a reliable and reproducible device fabrication process. Thus, our work lays a foundation for investigating multiple forefronts of physics in germanium-based quantum devices that require quantum point contacts as building blocks.

We study the current-phase relation (CPR) of an InSb-Al nanowire Josephson junction in parallel magnetic fields up to 700 mT. At high magnetic fields and in narrow voltage intervals of a gate under the junction, the CPR exhibits π shifts. The supercurrent declines within these gate intervals and shows asymmetric gate voltage dependence above and below them. We detect these features sometimes also at zero magnetic field. The observed CPR properties are reproduced by a theoretical model of supercurrent transport via interference between direct transmission and a resonant localized state.

Tunneling spectroscopy is widely used to examine the subgap spectra in semiconductor-superconductor nanostructures when searching for Majorana zero modes (MZMs). Typically, semiconductor sections controlled by local gates at the ends of hybrids serve as tunnel barriers. Besides detecting states only at the hybrid ends, such gate-defined tunnel probes can cause the formation of non-topological subgap states that mimic MZMs. Here, we develop an alternative type of tunnel probes to overcome these limitations. After the growth of an InSb-Al hybrid nanowire, a precisely controlled in-situ oxidation of the Al shell is performed to yield a nm-thick AlOx layer. In such thin isolating layer, tunnel probes can be arbitrarily defined at any position along the hybrid nanowire by shadow-wall angle-deposition of metallic leads. In this work, we make multiple tunnel probes along single nanowire hybrids and successfully identify Andreev bound states (ABSs) of various spatial extension residing along the hybrids., (© 2023. Springer Nature Limited.)

We report an experimental study of proximity induced superconductivity in planar Josephson junction devices made from free-standing InAs nanosheets. The nanosheets are grown by molecular beam epitaxy, and the Josephson junction devices are fabricated by directly contacting the nanosheets with superconductor Al electrodes. The fabricated devices are explored by low-temperature carrier transport measurements. The measurements show that the devices exhibit a gate-tunable supercurrent, multiple Andreev reflections, and a good quality superconductor-semiconductor interface. The superconducting characteristics of the Josephson junctions are investigated at different magnetic fields and temperatures and are analyzed based on the Bardeen-Cooper-Schrieffer (BCS) theory. The measurements of the ac Josephson effect are also conducted under microwave radiations with different radiation powers and frequencies, and integer Shapiro steps are observed. Our work demonstrates that InAs nanosheet based hybrid devices are desired systems for investigating the forefront of physics, such as two-dimensional topological superconductivity.

Highly efficient extraction of glycopeptides prior to mass spectrometry detection is extremely crucial for glycoproteomic research, especially in disease biomarker research. Reported here is the first time by applying two-dimensional (2D) covalent organic framework (COFs) nanosheets for highly efficient enrichment of glycopeptides. Particularly, by incorporating hydrophilic monomers through a bottom-up strategy, the 2D COF nanosheets (denoted as NUS-9) displayed an ultra-high graft density of sulfonic groups and super-hydrophilicity. In addition, because of the large surface area, low steric hindrance, high chemical stability, and abundant accessibility sites of 2D COF nanosheets, NUS-9 exhibited remarkable efficiency for glycopeptide enrichment, involving excellent detection sensitivity (0.01 fmol μL -1 ), outstanding enrichment capability, and good enrichment selectivity (1:1500, horseradish peroxidase (HRP) tryptic digest to bovine serum albumin (BSA) tryptic digest), and recovery (92.2 ± 2.0%). Moreover, the NUS-9 was able to unambiguously detect 631 endogenous glycopeptides from human saliva, demonstrating an unparalleled high efficiency in glycopeptide enrichment. Gene ontology analyses of proteins from human saliva enriched by NUS-9 demonstrated its potential for comprehensive glycoproteome analysis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Semiconducting nanowire Josephson junctions represent an attractive platform to investigate the anomalous Josephson effect and detect topological superconductivity. However, an external magnetic field generally suppresses the supercurrent through hybrid nanowire junctions and significantly limits the field range in which the supercurrent phenomena can be studied. In this work, we investigate the impact of the length of InSb-Al nanowire Josephson junctions on the supercurrent resilience against magnetic fields. We find that the critical parallel field of the supercurrent can be considerably enhanced by reducing the junction length. Particularly, in 30 nm long junctions supercurrent can persist up to 1.3 T parallel field─approaching the critical field of the superconducting film. Furthermore, we embed such short junctions into a superconducting loop and obtain the supercurrent interference at a parallel field of 1 T. Our findings are highly relevant for multiple experiments on hybrid nanowires requiring a magnetic-field-resilient supercurrent.

The proximity effect in semiconductor-superconductor nanowires is expected to generate an induced gap in the semiconductor. The magnitude of this induced gap, together with the semiconductor properties like spin-orbit coupling and g-factor, depends on the coupling between the materials. It is predicted that this coupling can be adjusted through the use of electric fields. We study this phenomenon in InSb/Al/Pt hybrids using nonlocal spectroscopy. We show that these hybrids can be tuned such that the semiconductor and superconductor are strongly coupled. In this case, the induced gap is similar to the superconducting gap in the Al/Pt shell and closes only at high magnetic fields. In contrast, the coupling can be suppressed which leads to a strong reduction of the induced gap and critical magnetic field. At the crossover between the strong-coupling and weak-coupling regimes, we observe the closing and reopening of the induced gap in the bulk of a nanowire. Contrary to expectations, it is not accompanied by the formation of zero-bias peaks in the local conductance spectra. As a result, this cannot be attributed conclusively to the anticipated topological phase transition and we discuss possible alternative explanations., (© 2023. The Author(s).)

The tachinid fly, Exorista sorbillans, is a notorious ovolarviparous endoparasitoid of the silkworm, Bombyx mori, causing severe damage to silkworm cocoon industry. Silkworm larvae show typically precocious wandering behavior after being parasitized by E. sorbillans; however, the underlying molecular mechanism remains unexplored. Herein, we investigated the changes in the levels of 20-hydroxyecdysone (20E) and juvenile hormone (JH) titer, and they both increased in the hemolymph of parasitized silkworms. Furthermore, we verified the expression patterns of related genes, which showed an upregulation of 20E signaling and biosynthesis genes but a significant downregulation of ecdysone oxidase (EO), a 20E inactivation enzyme, in parasitized silkworms. In addition, related genes of the JH signaling were activated in parasitized silkworms, while related genes of the JH degradation pathway were suppressed, resulting in an increase in JH titer. Notably, the precocious wandering behavior of parasitized silkworms was partly recoverable by silencing the transcriptions of BmCYP302A1 or BmCYP307A1 genes. Our findings suggest that the developmental duration of silkworm post parasitism could be shortened by regulation of 20E and JH titers, which may help silkworm to resist the E. sorbillans infestation. These findings provide a basis for deeper insight into the interplay between silkworms and E. sorbillans and may serve as a reference for the development of a novel approach to control silkworm myiasis., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America.)

Introduction: The clinical implication of intrarenal venous flow patterns in decompensated heart failure with worsening renal function is unknown. We aimed to study the relationship between intrarenal venous flow patterns, inferior vena cava volume status, caval index, clinical degree of congestion and the renal outcome in patients with decompensated heart failure and worsening renal function. Secondary objectives were to study the combined endpoint of readmission and mortality rate within 30 days (after the last scan) among intrarenal venous flow patterns and the effect of congestion status on the renal outcome., Methods: Twenty-three patients admitted for decompensated heart failure (ejection fraction ⩽40%) with worsening renal function (absolute increase in serum creatinine of 26.5 µmol/L or ⩾1.5-fold increment from baseline) were enrolled in this study. A total of 64 scans were performed. Patients were visited on day 0, 2, 4 and 7 (or earlier if discharged). Patients were called 30 days after discharge to evaluate readmission or mortality. Intrarenal venous flow patterns were ranked from continuous, interrupted, biphasic, to monophasic. Clinical congestion was scored from 0 to 7., Results: Intrarenal venous flow patterns had statistically significant positive correlations with inferior vena cava volume status (Spearman's ρ, 0.51; p  < 0.01) and congestion score ( ρ , 0.65; p  < 0.01) and a significant negative correlation with caval index ( ρ , -0.53; p  < 0.01). Intrarenal venous flow patterns were not significant in predicting estimated glomerular filtration rate improvement or the combined endpoint. Reduced congestion significantly predicted an estimated glomerular filtration rate improvement on the following scan day ( p  = 0.04, odds ratio = 4.3, 95% confidence interval = 1.1-17.2)., Conclusion: Although intrarenal venous flow patterns correlate with other congestive parameters, clinical congestion status rather than intrarenal venous flow patterns predicted the renal outcome., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2022.)

Enzyme immobilization is critical to boosting its application in various areas. Covalent organic frameworks (COFs) are ideal hosts for enzyme immobilization due to their porous and predesignable structures. Nevertheless, the construction of COFs-based enzyme immobilization systems with high activity via existing immobilization methods (including covalent linkages and channel entrapment) remains a considerable challenge. Herein, a versatile approach was introduced to encapsulate enzymes within hollow COF capsule (named enzyme@COF) using metal-organic frameworks (including ZPF-1(C 8 H 11 N 4 O 4.5 Zn), ZIF-8(C 8 H 10 N 4 Zn), and ZIF-90(C 8 H 6 N 4 O 2 Zn)) as sacrificial templates. The obtained porous COF capsule could not only facilitate the efficient mass transfer of enzymatic reactions but also protect enzymes against the incompatible conditions, resulting in enhanced activity and stability of the encapsulated enzymes. Moreover, this approach offered an opportunity to spatially organize multienzymes in COF capsule to construct enzyme cascade system. For instance, glucose oxidase (GOx) and cytochrome c (Cyt c) were coencapsulated within COF capsule to construct GOx-Cyt c cascade. The integration of GOx and Cyt c within COF capsule achieved ∼1.6-fold improvement in catalytic activity than that of free enzymes and the resultant GOx-Cyt c@COF was successfully adopted as a nanoreactor for the sensitive determination of glucose in serum. This work provided a new insight into the design of COFs-based enzyme immobilization systems.

Majorana bound states constitute one of the simplest examples of emergent non-Abelian excitations in condensed matter physics. A toy model proposed by Kitaev shows that such states can arise at the ends of a spinless p-wave superconducting chain 1 . Practical proposals for its realization 2,3 require coupling neighbouring quantum dots (QDs) in a chain through both electron tunnelling and crossed Andreev reflection 4 . Although both processes have been observed in semiconducting nanowires and carbon nanotubes 5-8 , crossed-Andreev interaction was neither easily tunable nor strong enough to induce coherent hybridization of dot states. Here we demonstrate the simultaneous presence of all necessary ingredients for an artificial Kitaev chain: two spin-polarized QDs in an InSb nanowire strongly coupled by both elastic co-tunnelling (ECT) and crossed Andreev reflection (CAR). We fine-tune this system to a sweet spot where a pair of poor man's Majorana states is predicted to appear. At this sweet spot, the transport characteristics satisfy the theoretical predictions for such a system, including pairwise correlation, zero charge and stability against local perturbations. Although the simple system presented here can be scaled to simulate a full Kitaev chain with an emergent topological order, it can also be used imminently to explore relevant physics related to non-Abelian anyons., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The development of novel stationary phases with specific functionality is of great importance in chromatographic separation. Herein, we fabricated fluoro-functionalized spherical covalent organic frameworks (S F-COFs ) via a bottom-up strategy as stationary phases for high-performance liquid chromatography (HPLC). Benefiting from the significant monodispersity, narrow size distribution, and high fluorine content, the S F-COFs packed column showed high column efficiency and excellent resolution for the separation of the organic fluorides involving polyfluorobenzenes, polychlorobenzenes, polybromobenzenes, perfluoroalkyl methacrylates, and halogenated trifluorotoluenes, which cannot be separated on the fluorine-free spherical covalent organic frameworks packed column. Especially, the column efficiency of 20 100-38 500 plates/m was obtained for polyfluorobenzenes, and the relative standard deviations of the retention time for continuous 10 separations of polychlorobenzenes and polybromobenzenes were less than 0.98%. Furthermore, the prepared S F-COFs packed column showed overwhelming superiority in the separation of organic halides compared with commercial C18 and pentafluorophenyl (PFP) packed columns. In addition, the compounds with different hydrophobicity or aromatic ring structure were also successfully separated on the S F-COFs packed column. This work extended the application of spherical COFs and provided a new way to introduce specific functional groups into the COF-based stationary phase for HPLC.

We report the realization of a coupled quantum dot (QD) system containing two single QDs made in two adjacent InAs nanowires. One QD (sensor QD) was used as a charge sensor to detect the charge state transitions in the other QD (target QD). We investigated the effect of the tunneling barrier asymmetry of the target QD on the detection visibility of the charge state transitions in the target QD. The charge stability diagrams of the target QD under different configurations of barrier-gate voltages were simultaneously measured via the direct signals of electron transport through the target QD and via the detection signals of the charge state transitions in the target QD revealed by the sensor QD. We find that the complete Coulomb diamond boundaries of the target QD and the transport processes involving the excited states in the target QD can be observed in the transconductance signals of the sensor QD only when the tunneling barriers of the target QD are nearly symmetric. These observations were explained by analyzing the effect of the ratio of the two tunneling rates on the electron transport processes through the target QD. Our results imply that it is important to consider the symmetry of the tunnel couplings when constructing a charge sensor integrated QD device.

Highly efficient enrichment of N -glycopeptides from complicated biosamples based on mass spectrometry is essential for biomedical applications, especially in disease biomarker research. In this work, glutathione (GSH)-modified hierarchical flower-like hollow covalent organic frameworks loaded with Au nanoparticles (HFH-COFs@Au@GSH) were synthesized for N -glycopeptide enrichment. Due to the abundant accessibility sites, high specific surface area, and inherent high stability of the hierarchical flower-like hollow structure, a large number of Au NPs and hydrophilic GSH can be modified on the HFH-COFs. The HFH-COFs@Au@GSH displayed excellent hydrophilicity and remarkable enrichment performance for N -glycopeptides: low detection limit (0.1 fmol μL -1 ), large adsorption capacity (200 μg mg -1 ), great selectivity (1 : 1000, HRP to BSA), and good reusability (at least 5 times). Furthermore, the HFH-COFs@Au@GSH were successfully applied to capture N-linked glycopeptides in human serum, and 308 N -glycosylation peptides corresponding to 84 N -glycosylation proteins with 123 N -glycosylation sites were detected. Gene ontology analyses were used to elucidate the cellular component, biological process and molecular function of detected glycoproteins in human serum, demonstrating the great potential of the HFH-COFs@Au@GSH in N -glycopeptide enrichment for glycoproteomic analysis of complex biological samples.

In superconducting quantum circuits, aluminum is one of the most widely used materials. It is currently also the superconductor of choice for the development of topological qubits. However, aluminum-based devices suffer from poor magnetic field compatibility. Herein, this limitation is resolved by showing that adatoms of heavy elements (e.g., platinum) increase the critical field of thin aluminum films by more than a factor of two. Using tunnel junctions, it is shown that the increased field resilience originates from spin-orbit scattering introduced by Pt. This property is exploited in the context of the superconducting proximity effect in semiconductor-superconductor hybrids, where it is shown that InSb nanowires strongly coupled to Al/Pt films can maintain superconductivity up to 7 T. The two-electron charging effect is shown to be robust against the presence of heavy adatoms. Additionally, non-local spectroscopy is used in a three-terminal geometry to probe the bulk of hybrid devices, showing that it remains free of sub-gap states. Finally, it is demonstrated that proximitized semiconductor states maintain their ability to Zeeman-split in an applied magnetic field. Combined with the chemical stability and well-known fabrication routes of aluminum, Al/Pt emerges as the natural successor to Al-based systems and is a compelling alternative to other superconductors, whenever high-field resilience is required., (© 2022 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Aberrant protein N -glycosylation is a cancer hallmark, which has great potential for cancer detection. However, large-scale and in-depth analysis of N -glycosylation remains challenging because of its high heterogeneity, complexity, and low abundance. Human saliva is an attractive diagnostic body fluid, while few efforts explored its N -glycoproteome for lung cancer. Here, we utilized a zwitterionic-hydrophilic interaction chromatography-based strategy to specifically enrich salivary glycopeptides. Through quantitative proteomics analysis, 1492 and 1234 intact N -glycopeptides were confidently identified from pooled saliva samples of 10 subjects in the nonsmall-cell lung cancer group and 10 subjects in the normal control group. Accordingly, 575 and 404 N -glycosites were revealed for the lung cancer group and normal control group. In particular, 154 N -glycosites and 259 site-specific glycoforms were significantly dysregulated in the lung cancer group. Several N -glycosites located at the same glycoprotein and glycans attached to the same N -glycosites were observed with differential expressions, including haptoglobin, Mucin-5B, lactotransferrin, and α-1-acid glycoprotein 1. These N -glycoproteins were mainly related to inflammatory responses, infectious diseases, and cancers. Our study achieved comprehensive characterization of salivary N -glycoproteome, and dysregulated site-specific glycoforms hold promise for noninvasive detection of lung cancer.

Carbamazepine (CBZ) and its metabolite carbamazepine-10,11-epoxide (CBZEP) play vital role in the treatment of epilepsy. It is of great importance to develop a method for rapid and sensitive monitoring of CBZ and CBZEP due to their narrow therapeutic index. Herein, an imine-linked-based covalent organic framework was synthesized by using 1,3,5-tris (4-aminophenyl) benzene (TPB) and 1,3,5-triformylbenzene (TFB) (denoted as TPB-TFB-COF)，and applied as a solid-phase microextraction (SPME) probe for extracting CBZ and CBZEP. The TPB-TFB-COF showed large surface areas (371 m 2  g -1 ), high regular porosity (1.23 nm) and extraordinary stability, which rendered it an ideal adsorbent for highly efficient enrichment of CBZ and CBZEP. Accordingly, an attractive strategy of the combination of the TPB-TFB-COF-based SPME probe and electrospray ionization mass spectrometry system (ESI/MS) was proposed for rapid screening and sensitive monitoring of CBZ and CBZEP. Under the optimized parameters, the developed method exhibited good linearity for CBZ and CBZEP in the range of 4-1000 μg L -1 with correlation coefficient (r) no less than 0.9953, and the corresponding limits of detection (LODs) were 0.4 and 2.5 μg L -1 , respectively. Moreover, high enrichment factors (EFs, 202-351 folds) and satisfactory relative standard deviations (RSDs) of one probe (3.3-5.1%) and probe-to-probe (4.8-5.6%) were obtained. By using the proposed method, sensitive screening and quantitative evaluation of CBZ and CBZEP in mice whole blood and tissue homogenates were successfully achieved, indicating the promising applicability of the TPB-TFB-COF-SPME-AMIS as a powerful tool for drug monitoring., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Extracellular vesicles (EVs) play critical roles in intercellular communications, which contain valuable biomarkers for the detection of cancers. Phosphoproteomics analysis of human saliva EVs (sEVs) can help to discover lung cancer-related candidates. Due to the low abundance of phosphoproteins in sEVs, an efficient, reproducible, and cost-effective strategy is required for their enrichment. Here, we compared the latest phosphopeptide techniques, including TiO 2 , ZrO 2 , CaTiO 3 , and Ti 4+ -IMAC (immobilized metal affinity chromatography) methods, for phosphopeptide isolation. Our data demonstrated that Ti 4+ -IMAC was the superior one. By using the optimized Ti 4+ -IMAC approach, we identified more than 500 sEV phosphopeptides. Quantitative proteomics was employed to comprehensively decipher the sEV phosphoproteome of the normal group (n = 6) and lung cancer group (n = 6). Accordingly, 524 and 333 phosphopeptides were enriched, respectively, which corresponded to 439 and 282 phosphoproteins. In total, 857 unique sEV phosphopeptides corresponding to 721 phosphoproteins were revealed. Among 493 identified phosphosites, 37 were upregulated (> 1.5) and 217 were downregulated (< 0.66) in the cancer group. Our data collectively demonstrated that Ti 4+ -IMAC is an efficient and reproducible technology for comprehensive analysis of sEV phosphoproteome. Differentially expressed sEV phosphoproteins and phosphosites might be used for the detection of lung cancer non-invasively., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

We study a Cooper pair transistor realized by two Josephson weak links that enclose a superconducting island in an InSb-Al hybrid nanowire. When the nanowire is subject to a magnetic field, isolated subgap levels arise in the superconducting island and, because of the Coulomb blockade, mediate a supercurrent by coherent cotunneling of Cooper pairs. We show that the supercurrent resulting from such cotunneling events exhibits, for low to moderate magnetic fields, a phase offset that discriminates even and odd charge ground states on the superconducting island. Notably, this phase offset persists when a subgap state approaches zero energy and, based on theoretical considerations, permits parity measurements of subgap states by supercurrent interferometry. Such supercurrent parity measurements could, in a series of experiments, provide an alternative approach for manipulating and protecting quantum information stored in the isolated subgap levels of superconducting islands.

Background: Many stage II/III colorectal cancer (CRC) patients may relapse after routine treatments. Aberrant phosphorylation can regulate pathophysiological processes of tumors, and finding characteristic protein phosphorylation is an efficient approach for the prediction of CRC relapse., Research Design and Methods: We compared the tissue proteome and phosphoproteome of stage II/III CRC patients between the relapsed group (n = 5) and the non-relapsed group (n = 5). Phosphopeptides were enriched with Ti 4+ -IMAC material. We utilized label-free quantification-based proteomics to screen differentially expressed proteins and phosphopeptides between the two groups. Gene Ontology (GO) analysis and Ingenuity Pathway Analysis (IPA) were used for bioinformatics analysis., Results: The immune response of the relapsed group (Z-score -2.229) was relatively poorer than that of the non-relapsed group (Z-score 1.982), while viability of tumor was more activated (Z-score 2.895) in the relapsed group, which might cause increased relapse risk. The phosphorylation degrees of three phosphosites (phosphosite 1362 of TP53BP1, phosphosite 809 of VCL and phosphosite 438 of STK10) might be reliable prognostic biomarkers., Conclusions: Some promising proteins and phosphopeptides were discovered to predict the relapse risk in postoperative follow-ups.

Highly efficient extraction of phospho- and glycopeptides from complicated biological samples is extremely crucial for comprehensive characterization of protein phosphorylation and glycosylation based on mass spectrometry (MS). In this work, a new synergistic strategy that combined surface covalent modification and alkaline etching was developed to synthesize hydrophilic hollow zirconium-organic frameworks (HHZr-MOFs) for simultaneous recognition and capture of phospho- and N-glycopeptides. The unique properties including high specific surface area, mesoporous shell and hollow cavity endowed HHZr-MOFs with facilitated mass transport and abundant accessible active sites. Benefited from the maltose modified on the external surface and Zr-O clusters retained on the internal surface, HHZr-MOFs could act as a highly efficient bifunctional probe for simultaneous enrichment of phospho- and N-glycopeptides based on hydrophilic interaction chromatography (HILIC) and metal oxide affinity chromatography (MOAC), respectively. Finally, a total of 98 endogenous phosphopeptides and 216 endogenous N-glycopeptides were simultaneously captured by HHZr-MOFs from saliva samples of patients with oral inflammation, and several phospho- and glycoproteins related with coagulation, bacterial defense and immune response for oral inflammation were identified by Gene ontology (GO) analyses, confirming the great potential of HHZr-MOFs in rapid detection of clinical biomarkers and comprehensive profiling of phosphoproteomic and glycoproteomic for complex biological samples. This work not only provides an alternative method to precisely design and synthesize sophisticated hollow MOFs with multifunctionalities, but also offers a novel concept of multifunctional material design for bioseparation and analysis in modification-specific proteomics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Breast cancer (BC) is the most prevalent cancer among women. Long non‑coding (lnc)RNAs and microRNAs (miRs) both regulate the expression of key genes in tumorigenesis. The present study aimed to explore the molecular mechanism of the prostate cancer‑associated transcript 1 (PCAT1)/miR‑134‑3p/pituitary homeobox 2 (PITX2) in BC. Reverse transcription‑quantitative PCR was performed to examine the expression of miR‑134‑3p. Cell proliferation, viability, cell cycle, apoptosis and migration were analyzed using Cell Counting Kit‑8, colony formation, flow cytometry, wound healing and Transwell assays. Protein expression levels were determined by western blotting. The present study demonstrated that PCAT1 was significantly highly expressed in BC cells. Knockdown of PCAT1 significantly inhibited cell proliferation, migration and invasion, but promoted apoptosis in human BC cell lines. The results of the dual‑luciferase assay showed that PCAT1 targeted miR‑134‑3p, and PITX2 was a potential target of miR‑134‑3p. Western blotting results demonstrated that PCAT1 knockdown significantly reduced the protein expression levels of anti‑apoptotic protein Bcl‑2, and significantly upregulated the protein expression levels of proapoptotic proteins, Bax, cleaved caspase‑3 and cleaved caspase‑9. Furthermore, the effect of a miR‑134‑3p inhibitor on BC progression was rescued by the knockdown of PITX2 in cells transfected with short hairpin RNA‑lncRNA PCAT1. To conclude, the results of the present study indicated that the PCAT1/miR‑134‑3p/PITX2 axis could be a promising therapeutic target in BC treatment.

Vigorously developing new stationary phases to meet the requirements for the separation of positional isomers that have similar physicochemical properties is still an urgent topic in separation science. Herein, a single-crystalline covalent organic framework (COF-300) packed column for the separation of positional isomers in high-performance liquid chromatography (HPLC) was reported for the first time. Benefitting from its regular shape, excellent chemical and thermal stability, microporous feature, and strong hydrophobicity of single-crystalline COF-300, the single-crystalline COF-300-packed column showed excellent resolution for the separation of positional isomers, including nitroaniline, dichlorobenzene, dibromobenzene, diiodobenzene, diethylbenzene, chloronitrobenzene, bromonitrobenzene, and iodonitrobenzene isomers, which cannot be all separated on commercial columns and a polycrystalline COF-300-packed column. Especially, the resolution values for m -/ p- diiodobenzene and o -/ m- diiodobenzene were 4.45 and 2.53. Moreover, the alkylbenzene, monosubstituted aromatics, polycyclic aromatic hydrocarbons, and the mixture of ethylbenzene and styrene were also baseline separated on the single-crystalline COF-300-packed column. This successful application not only confirmed the great potential of single-crystalline COFs in HPLC separation of positional isomers but also pioneered the utilization of single-crystalline COFs in separation science.

In this work, core-shell structured Ti 4+ -immobilized magnetic covalent organic frameworks (denoted as Fe 3 O 4 @TAPTDHTA-Ti 4+ composites) were prepared for enhanced phosphopeptide enrichment by one-pot synthesis of COFs shell with inherent bifunctional groups on Fe 3 O 4 NPs and further Ti 4+ immobilization. The widely distributed bifunctional groups could provide abundant chelating sites for Ti 4+ immobilizing. Combining with the high specific surface area and mesoporous structure, the Fe 3 O 4 @TAPTDHTA-Ti 4+ composites exhibited excellent enrichment efficiency for phosphopeptides, such as low detection limit (0.05 fmol μL -1 ), high selectivity (1:5000 of molar ratio of β-casein/bovine serum albumin (BSA) tryptic digests), high adsorption capacity (62.9 μg mg -1 ) and strong size-exclusive effect (1:250:250 of molar ratio of β-casein tryptic digest/β-casein/BSA). In addition, this method was general for immobilizing other metal ions (Zr 4+ and Fe 3+ ). Notably, the Fe 3 O 4 @TAPTDHTA-Fe 3+ composites exhibited controllable affinity towards mono-phosphopeptides and multi-phosphopeptides. Furthermore, the Fe 3 O 4 @TAPTDHTA-Ti 4+ composites were successfully applied to selectively capture phosphopeptides from complex biological samples including the tryptic digest of nonfat milk, human serum and human saliva. More significantly, 3333 phosphopeptides derived from 1409 phosphoproteins with 3492 phosphorylation sites were clearly identified from the tryptic digest of HeLa cell lysate. In addition to providing a potential excellent enrichment probe for comprehensive phosphoproteomic analysis, this study also offers a new perspective for the functionalization of COFs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects., Methods: PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC 0-24 /MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses., Findings: The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L., Implications: PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509., Competing Interests: Disclosures The authors have indicated that they have no conflicts of interest regarding the content of this article. J. Zhang and J.-F. Wu are PI. X.-J. Wu is sub-I., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Many stage II/III colorectal cancer (CRC) patients might relapse after routine treatment and there is a great need of reliable biomarkers for predicting its reoccurrence risk. Small extracellular vesicles (sEVs) could regulate many pathophysiological processes of diseases, which are promising source for biomarker discovery. In this study, we implemented a MS-based workflow that utilizes data-dependent acquisition (DDA) for discovery and parallel reaction monitoring (PRM) for validation of high relapse risk related biomarkers. We compared the protein profiling of sEVs from CRC tissues and paired adjacent tissues in relapsed group (n = 5) and non-relapsed group (n = 5). 417 and 1140 proteins were differentially expressed between the tumor tissues and adjacent tissues in relapsed group and non-relapsed group, respectively. Bioinformatics analysis showed that immunity of the relapsed patients (Z-score - 0.69) was relatively poorer than the non-relapsed patients (Z-score 2.59), while chronic inflammatory response was activated (Z-score 3.0), which might enhance the reoccurrence risk. Four proteins (HLA-DPA1, S100P, NUP205, PCNA) showed significant expressions in the adjacent tissues of the relapsed group by PRM validation. ROC analysis of HLA-DPA1 (AUC = 0.96) achieved the best classification accuracy in separating the relapsed group and the non-relapsed group. Our data demonstrate that tissue-derived sEVs harbor prognostic proteomic signatures of CRC. SIGNIFICANCE: In this research, our proteomics analysis of tissue sEVs revealed that poor immunity as well as chronic inflammatory of the CRC relapsed patient likely lead to poor prognosis and high risk of reoccurrence. The significant expression levels of four proteins (HLA-DPA1, S100P, NUP205, PCNA) in the adjacent tissues of the relapsed group might be used to predict the risk of relapse in postoperative follow-ups., (Copyright © 2021. Published by Elsevier B.V.)

Highly specific capture of phosphopeptides, especially multi-phosphopeptides, from complex biological samples is critical for comprehensive phosphoproteomic analysis, but it still poses great challenges due to the lack of affinity material with ideal enrichment efficiency. Here, two-dimensional (2D) covalent organic framework (COFs) nanosheets was applied for selective separation of phosphopeptides for the first time. Particularly, by incorporating guanidinium units, the 2D guanidinium-based COF nanosheets (denoted as TpTG Cl CONs) exhibited controllable and specific enrichment performance towards global/multi-phosphopeptides. TpTG Cl CONs was easy to prepare and showed large surface area, low steric hindrance, abundant accessible interaction sites and high chemical stability. Taking these merits together, TpTG Cl CONs exhibited excellent efficiency for phosphopeptide enrichment, such as low detection limits (0.05 fmol μL -1 for global phosphopeptides and 0.1 fmol μL -1 for multi-phosphopeptides), high selectivity (1:5000 of molar ratios of β-casein/BSA for both global and multi-phosphopeptides), high adsorption capacity (100 mg g -1 for global phosphopeptides and 50 mg g -1 for multi-phosphopeptides). Furthermore, TpTG Cl CONs could be reused due to the high chemical stability. In addition, TpTG Cl CONs were successfully applied to controllable and specific capture of endogenous global/multi-phosphopeptides from human serum and human saliva, indicating its good potential in rapid and sensitive detection of biomarkers from biological fluid. Finally, rat liver protein digest was used to confirm the high specificity of TpTG Cl CONs towards multi-phosphopeptides and demonstrated its potential as an ideal enrichment probe for comprehensive phosphoproteomic analysis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Fibroblast growth factor receptor (FGFR) is a promising anticancer target. Currently, most FGFR inhibitors lack sufficient selectivity and have nonnegligible activity against kinase insert domain receptor (KDR), limiting their feasibility due to the serious side effects. Notably, compensatory activation occurs among FGFR1-4, suggesting the urgent need to develop selective pan-FGFR1-4 inhibitors. Here, we explored the antitumor activity of DW14383, a novel irreversible FGFR1-4 inhibitor. DW14383 exhibited equivalently high potent inhibition against FGFR1, 2, 3 and 4, with IC 50 values of less than 0.3, 1.1, less than 0.3, and 0.5 nmol/L, respectively. It is a selective FGFR inhibitor, exhibiting more than 1100-fold selectivity for FGFR1 over recombinant KDR, making it one of the most selective FGFR inhibitors over KDR described to date. Furthermore, DW14383 significantly inhibited cellular FGFR1-4 signaling, inducing G1/S cell cycle arrest, which in turn antagonized FGFR-dependent tumor cell proliferation. In contrast, DW14383 had no obvious antiproliferative effect against cancer cell lines without FGFR aberration, further confirming its selectivity against FGFR. In representative FGFR-dependent xenograft models, DW14383 oral administration substantially suppressed tumor growth by simultaneously inhibiting tumor proliferation and angiogenesis via inhibiting FGFR signaling. In summary, DW14383 is a promising selective irreversible pan-FGFR inhibitor with pan-tumor spectrum potential in FGFR1-4 aberrant cancers, which has the potential to overcome compensatory activation among FGFR1-4., (© 2020. CPS and SIMM.)

Immune checkpoint blockade (ICB) therapies such as PD-1 antibodies have produced significant clinical responses in treating a variety of human malignancies, yet only a subset of cancer patients benefit from such therapy. To improve the ICB efficacy, combinations with additional therapeutics were under intensive investigation. Recently, special dietary compositions that can lower the cancer risk or inhibit cancer progression have drawn significant attention, although few were reported to show synergistic effects with ICB therapies. Interestingly, Fucoidan is naturally derived from edible brown algae and exhibits antitumor and immunomodulatory activities. Here we discover that fucoidan-supplemented diet significantly improves the antitumor activities of PD-1 antibodies in vivo . Specifically, fucoidan as a dietary ingredient strongly inhibits tumor growth when co-administrated with PD-1 antibodies, which effects can be further strengthened when fucoidan is applied before PD-1 treatments. Immune analysis revealed that fucoidan consistently promotes the activation of tumor-infiltrating CD8 + T cells, which support the evident synergies with ICB therapies. RNAseq analysis suggested that the JAK-STAT pathway is critical for fucoidan to enhance the effector function of CD8 + T cells, which could be otherwise attenuated by disruption of the T-cell receptor (TCR)/CD3 complex on the cell surface. Mechanistically, fucoidan interacts with this complex and augments TCR-mediated signaling that cooperate with the JAK-STAT pathway to stimulate T cell activation. Taken together, we demonstrated that fucoidan is a promising dietary supplement combined with ICB therapies to treat malignancies, and dissected an underappreciated mechanism for fucoidan-elicited immunomodulatory effects in cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Yang, Pan, Wang, Lu, Zhang, Fang, Zhang, Ji, Bei, Dong, Wu, Pan, Yu, Zhou and Li.)

Background: Diffuse midline glioma (DMG) with histone H3 K27M mutation is a recently identified entity documented in the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System. Spinal cord DMGs with H3 K27M-mutant are commonly reported in adults. Herein, we reported a pediatric patient with spinal cord H3 K27M-mutant DMG. Case Report: A 7-year-old girl with 1-month history of neck pain and 3-week history of progressive weakness in the right hand was presented. Spinal magnetic resonance imaging showed an intramedullary lesion with slight enhancement at the C2-7 levels. With intraoperative neuroelectrophysiological monitoring, the lesion was subtotally resected. Histopathological examination revealed a DMG with histone H3 K27M mutation corresponding to WHO grade IV. Postoperatively, the neck pain was relieved, and the upper-extremity weakness remained unchanged. Oral temozolomide was administrated for 7 months, and radiotherapy was performed for 22 courses. After an 18-month follow-up, no tumor recurrence was noted. Conclusion: Spinal cord H3 K27M-mutant DMGs are extremely rare in pediatric patients. Preoperative differential diagnosis is challenging, and surgical resection with postoperative chemoradiotherapy may be an effective treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cheng, Li, Zhang, Zhang, Zhang, Liu, Yang and Ge.)

The ROS1 fusion kinase is an attractive antitumor target. Though with significant clinical efficacy, the well-known first-generation ROS1 inhibitor (ROS1i) crizotinib inevitably developed acquired resistance due to secondary point mutations in the ROS1 kinase. Novel ROS1is effective against mutations conferring secondary crizotinib resistance, especially G2032R, are urgently needed. In the present study, we evaluated the antitumor efficacy of SAF-189s, the new-generation ROS1/ALK inhibitor, against ROS1 fusion wild-type and crizotinib-resistant mutants. We showed that SAF-189s potently inhibited ROS1 kinase and its known acquired clinically resistant mutants, including the highly resistant G2032R mutant. SAF-189s displayed subnanomolar to nanomolar IC 50 values against ROS1 wild-type and mutant kinase activity and a selectivity vs. other 288 protein kinases tested. SAF-189s blocked cellular ROS1 signaling, and in turn potently inhibited the cell proliferation in HCC78 cells and BaF3 cells expressing ROS1 fusion wild-type and resistance mutants. In nude mice bearing BaF3/CD74-ROS1 or BaF3/CD74-ROS1 G2032R xenografts, oral administration of SAF-189s dose dependently suppressed the growth of both ROS1 wild-type- and G2032R mutant-driven tumors. In a patient-derived xenograft model of SDC4-ROS1 fusion NSCLC, oral administration of SAF-189s (20 mg/kg every day) induced tumor regression and exhibited notable prolonged and durable efficacy. In addition, SAF-189s was more potent than crizotinib and comparable to lorlatinib, the most advanced ROS1i known against the ROS1 G2032R . Collectively, these results suggest the promising potential of SAF-189s for the treatment of patients with the ROS1 fusion G2032R mutation who relapse on crizotinib. It is now recruiting both crizotinib-relapsed and naive ROS1-positive NSCLC patients in a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT04237805).

MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System X c (-) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.

Quantum dots (QDs) made from semiconductors are among the most promising platforms for the development of quantum computing and simulation chips, and they have the advantages of high density integration and compatibility with the standard semiconductor chip fabrication technology compared to other platforms. However, the development of a highly tunable semiconductor multiple QD system still remains a major challenge. Here, we demonstrate the realization of a highly tunable linear quadruple QD (QQD) in a narrow bandgap semiconductor InAs nanowire via a fine finger gate technique. The QQD is studied by electron transport measurements in the linear response regime. Characteristic two-dimensional charge stability diagrams containing four groups of resonant current lines of different slopes are obtained for the QQD. It is shown that these current lines arise from and can be individually assigned to resonant electron transport through the energy levels of different QDs. Benefitting from the excellent gate tunability, we also demonstrate the tuning of the QQD to regimes where the energy levels of two QDs, three QDs and all four QDs are energetically in resonance, respectively, with the Fermi level of the source and drain contacts. A capacitance network model is developed for the linear QQD and the simulated charge stability diagrams based on this model show good agreement with the experiments. Our work provides solid experimental evidence that narrow bandgap semiconductor nanowire multiple QDs could be used as a versatile platform to achieve integrated qubits for quantum computing and to perform quantum simulations of complex many-body systems.

A single quantum dot serving as a charge sensor is integrated to scalable double quantum dots using local top finger-gate techniques on two neighboring pure-phase InAs nanowires. The single dot built on one nanowire capacitively couples one of the double dots constructed on another nanowire via a metal bridge gate. The charge occupation states of double quantum dots can be accurately monitored by the sensor even in a few-electron regime in which transport tunneling current through the double dots vanishes. In the tunneling spectroscopy of double dots, electron inter dot tunneling process is absent; however, it can be illustrated by the sensor in terms of a transconductance line between the two closest triple points. Thus, tunnel coupling strength between the double dots is quantitatively extracted from the detectable charge transition. The highly tunable multiple quantum dots with integrated charge sensors on InAs nanowires could be an essential building block for quantum information processing technology.

We have measured the Zeeman splitting of quantum levels in few-electron quantum dots (QDs) formed in narrow bandgap InSb nanowires via the Schottky barriers at the contacts under application of different spatially orientated magnetic fields. The effective g-factor tensor extracted from the measurements is strongly anisotropic and level-dependent, which can be attributed to the presence of strong spin-orbit interaction (SOI) and asymmetric quantum confinement potentials in the QDs. We have demonstrated a successful determination of the principal values and the principal axis orientations of the g-factor tensors in an InSb nanowire QD by the measurements under rotations of a magnetic field in the three orthogonal planes. We also examine the magnetic field evolution of the excitation spectra in an InSb nanowire QD and extract a SOI strength of [Formula: see text] ∼ 180 μeV from an avoided level crossing between a ground state and its neighboring first excited state in the QD.

Human microbiome contains billions of microorganisms that play important roles in the biological system and different diseases. Due to its complexity, conventional culture-independent technology may underestimate the value of low-abundance bacteria, which calls for a highly efficient method for its enrichment and comprehensive analysis. In this study, we developed a recycling free-flow isoelectric focusing (RFFIEF) method-based electrophoresis method to separate salivary microbiome. First, we used Escherichia coli (DH5α) as a model for RFFIEF method development, which was focused in a narrow pH range (0.38 pH unit). The recovery rate was 80.81% with 5.85% relative standard deviation ( n = 5). The optimized method was then adopted to separate the human salivary microbiome into 32 fractions, followed by 16 S rRNA gene sequencing and metaproteomics analysis. After RFFIEF fractionation, we identified 508 bacterial genera, which increased by 225% on average ( n = 3) when compared to the results before fractionation. We further compared the compositional change of microbiome in the saliva of lung cancer group ( n = 22) and control group ( n = 21) through RFFIEF. Quantitative results demonstrated that six bacterial genera were upregulated dramatically in the lung cancer group, while two genera were downregulated. Through qPCR verification in an independent sample set ( n = 48), we confirmed that genus Granulicatella was significantly upregulated in the lung cancer group, whereas Pseudomonas was remarkably downregulated ( p < 0.001). RFFIEF is an efficient and reproducible technology to fractionate the microbiome for its comprehensive analysis, which can be further applied to the in-depth study of the complex microbiomes and contribute to the discovery of disease-associated bacteria.

Global prevalence of coronavirus disease 2019 (COVID-19) calls for an urgent development of anti-viral regime. Compared with the development of new drugs, drug repurposing can significantly reduce the cost, time, and safety risks. Given the fact that coronavirus harnesses spike protein to invade host cells through angiotensin-converting enzyme 2 (ACE2), hence we see if any previous anti-virtual compounds can block spike-ACE2 interaction and inhibit the virus entry. The results of molecular docking and molecular dynamic simulations revealed that remdesivir exhibits better than expected anti-viral invasion potential against COVID-19 among the three types of compounds including remdesivir, tenofovir and lopinavir. In addition, a positive correlation between the surface area occupied by remdesivir and anti-viral invasion potential was also found. As such, the structure of remdesivir was modified by linking an N-benzyl substituted diamidine derivative to its hydroxyl group through an ester bond. It was found that this compound has a higher anti-viral invasion potential and greater specificity.

Aims: SUMOylation is a posttranslational modification related to multiple human diseases. SUMOylation can be reversed by classes of proteases known as the sentrin/SUMO-specific proteases (SENPs). In the present study, we investigate the potential role of SENP1 in pericytes in the brain ischemia., Methods: Pericyte-specific deletion of senp1 mice (Cspg4-Cre; senp1 f/f ) were used for brain function and neuronal damage evaluation following brain ischemia. The cerebral blood vessels of diameter, velocity, and flux were performed in living mice by two-photon laser scanning microscopy (TPLSM). Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of pericyte-specific SENP1 in the pathological process of brain ischemia. A coculture model of HBVPs and HBMECs mimicked the BBB in vitro and was used to evaluate BBB integrity after glucose deprivation., Results: Our results showed that senp1-specific deletion in pericytes did not affect the motor function and cognitive function of mice. However, the pericyte-specific deletion of senp1 aggravated the infarct size and motor deficit following focal brain ischemia. Consistently, the TPLSM data demonstrated that SENP1 deletion in pericytes accelerated thrombosis formation in brain microvessels. We also found that pericyte-specific deletion of senp1 exaggerated the neuronal damage significantly following brain ischemia in mice. Moreover, SENP1 knockdown in pericytes could activate the apoptosis signaling and disrupt the barrier integrity in vitro coculture model., Conclusions: Our findings revealed that targeting SENP1 in pericytes may represent a novel therapeutic strategy for neurovascular protection in stroke., (© 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Glycoproteins are important biomarkers for cancers, while most glycoproteomics biomarkers suffering from low sensitivity and specificity due to their uncharacterized glycan structures. AZGP1 is a potential biomarker for salivary diagnostics of lung cancer, which is used as a model glycoprotein in this study for method development. We initially analyzed salivary N-glycoproteome by using lectin affinity chromatography and more than 300 N-glycoproteins were identified, including AZGP1. 7 gel spots of AZGP1 were resolved by two-dimensional gel electrophoresis and further confirmed by two-dimensional western blot as well as mass spectrometry. The isomeric glycan structures of AZGP1 in these spots were systematically characterized both at composition level and at structure level. Our results revealed 10 glycan compositions for salivary AZGP1, including core fucosylated glycans on Asn128 and sialylated glycans on Asn109 and Asn112. We further compared the glycan structures of salivary AZGP1 from lung cancer group and control group. Accordingly, 14 and 7 potential glycan structures were successfully revealed, respectively. In total, 15 glycan compositions and 22 potential glycan structures were identified and characterized for AZGP1, including some different structures with the same compositions. In particular, 5 potential glycan structures were identified as lung cancer unique signatures. Our developed strategy holds promise for thorough identification of glycan structures on a target glycoprotein biomarker. In-depth characterization of its glycan structures will ultimately enhance its sensitivity and specificity for cancer detection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives age-related phenotypes. The clearance of senescent cells is expected to decrease chronic, low-grade inflammation and improve tissue repair capacity, thus attenuating the decline of physical function in aged organisms. However, selective and effective clearance of senescent cells of different cell types has proven challenging. Herein, we developed a prodrug strategy to design a new compound based on the increased activity of lysosomal β-galactosidase (β-gal), a primary characteristic of senescent cells. Our prodrug SSK1 is specifically activated by β-gal and eliminates mouse and human senescent cells independently of senescence inducers and cell types. In aged mice, our compound effectively cleared senescent cells in different tissues, decreased the senescence- and age-associated gene signatures, attenuated low-grade local and systemic inflammation, and restored physical function. Our results demonstrate that lysosomal β-gal can be effectively leveraged to selectively eliminate senescent cells, providing a novel strategy to develop anti-aging interventions.

Affinity chromatography is a powerful technology for phosphopeptide enrichment from body fluids. Saliva is a non-invasive body fluid for disease diagnosis, while few studies applied affinity enrichment for saliva phosphoproteome. In this study, we tested two kinds of affinity chromatography materials, Ti 4+ -IMAC (immobilized metal affinity chromatography) and CaTiO 3 , for the enrichment of phosphopeptides. Through comparison, Ti 4+ -IMAC method was demonstrated as the superior one, which was utilized for the comprehensive analysis of salivary phosphoproteome. More than 360 phosphoproteins were specifically extracted and identified from human saliva. Ti 4+ -IMAC method was further applied to compare the phosphoprotein profiling in the saliva of lung cancer group and normal control group through label-free quantification. Accordingly, 477 and 699 phosphopeptides were enriched, respectively, which corresponded to 339 and 466 proteins. In total, 796 unique phosphopeptides were revealed for 517 saliva phosphoproteins. In particular, 709 phosphorylation sites were identified, among which 26 were up-regulated (>1.5) and 149 were down-regulated (<0.66) in lung cancer. Their corresponding proteins were mainly associated with cancer promotion, system disorder, and organismal injury. Our data collectively demonstrated that salivary phosphopeptides can be comprehensively characterized through Ti 4+ -IMAC method. These discovered phosphoprotein candidates might be used for lung cancer detection through salivary diagnostics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: There was limited study available on successful intervention for central-line-associated bloodstream infection (CLABSI) done at nonintensive care unit (ICU) and resources-limited setting. The objective of this study was to design, implement and evaluate a strategy to reduce CLABSI rate in non-ICU settings at general medical wards of Hospital Tuanku Ja'afar Seremban., Design/methodology/approach: Preinterventional study was conducted in one-month period of January 2019, followed by intervention period from February to March 2019. Postintervention study was conducted from April to July 2019. The CLABSI rates were compared between pre and postintervention periods. A multifaceted intervention bundle was implemented, which comprised (1) educational program for healthcare workers, (2) weekly audit and feedback and (3) implementation of central line bundle of care., Findings: There was a significant overall reduction of CLABSI rate between preintervention and postintervention period [incidence rate ratio (IRR) of 0.06 (95 percent CI, 0.01-0.33; P  = 0.001)]., Practical Implications: CLABSI rates were reduced by a multifaceted intervention bundle, even in non-ICU and resource-limited setting. This includes a preinterventional study to identify the risk factors followed by a local adaption of the recommended care bundles. This study recommends resources-limited hospitals to design a strategy that is suitable for their own local setting to reduce CLABSI., Originality/value: This study demonstrated the feasibility of a multifaceted intervention bundle that was locally adapted with an evidence-based approach to reduce CLABSI rate in non-ICU and resource-limited setting., (© Emerald Publishing Limited.)

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. SIGNIFICANCE: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth. See related commentary by Leithner, p. 657 ., (©2020 American Association for Cancer Research.)

Objective: The present study aims to analyze the clinical characteristics and etiology of transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC) complicated with acute respiratory distress syndrome (ARDS), in order to improve the early diagnosis rate and cure rate., Methods: A total of 816 patients with primary HCC received 2,200 TACE treatments from January 2014 to May 2018. Among these patients, 6 patients developed ARDS after TACE. The clinical data, lesion characteristics, laboratory tests, treatment process and prognosis of 6 patients were retrospectively analyzed., Results: The longest lesion diameter ranged within 5.0-10.2 cm (mean: 6.6 cm) in the 6 patients with primary HCC. Among these patients, 4 patients had lesions mainly located in the left lateral lobe of the liver, while 5 patients had no hepatic arteriovenous fistula detected before TACE. Nedaplatin, epirubicin and iodinated oil suspension chemoembolization were used in all 6 patients during TACE, and all of them experienced ARDS symptoms within 24-48 hours after TACE. However, no clear pathogenic bacteria were incubated in the sputum culture after the onset of the disease. Diffused exudative changes of both lungs were found in the chest X-ray, and the oxygenation index (PaO 2 /FiO 2 ) was within 100-300 mmHg. The symptoms of 6 patients improved after 3-6 days of hormone therapy., Conclusion: In this study, we found that although the incidence of ARDS after TACE was low in the treatment for HCC, the symptoms after onset were serious, and the early hormone therapy may be beneficial to improve the prognosis and reduce mortality. Further research with larger samples is still needed to confirm the pathogenesis of ARDS after TACE in the treatment for HCC.

Background: The merging of two divergent genomes during hybridization can result in the remodeling of parental gene expression in hybrids. A molecular basis underling expression change in hybrid is regulatory divergence, which may change with the parental genetic divergence. However, there still no unanimous conclusion for this hypothesis., Results: Three species of Camellia with a range of genetic divergence and their F 1 hybrids were used to study the effect of parental genetic divergence on gene expression and regulatory patterns in hybrids by RNA-sequencing and allelic expression analysis. We found that though the proportion of differentially expressed genes (DEGs) between the hybrids and their parents did not increase, a greater proportion of DEGs would be non-additively (especially transgressively) expressed in the hybrids as genomes between the parents become more divergent. In addition, the proportion of genes with significant evidence of cis-regulatory divergence increased, whereas with trans-regulatory divergence decreased with parental genetic divergence., Conclusions: The discordance within hybrid would intensify as the parents become more divergent, manifesting as more DEGs would be non-additively expressed. Trans-regulatory divergence contributed more to the additively inherited genes than cis, however, its contribution to expression difference would be weakened as cis mutations accumulated over time; and this might be an important reason for that the more divergent the parents are, the greater proportion of DEGs would be non-additively expressed in hybrid.

Knowledge about the chemical composition of floral volatile organic compounds (VOCs) is valuable in biological studies as well as for the flavor, cosmetic, and fragrance industries. The flowers of Chinese chestnut (Castanea mollissima) emit a distinctive semen-like odor; however, the chemical composition and biological role for the semen-like odor of chestnut flowers remain scarcely studied. Herein, we report the floral VOCs and the pollinators of chestnut flowers. A fast method based on a neutral desorption (ND) device coupled to extractive atmospheric pressure chemical ionization mass spectrometry (EAPCI-MS) was developed for the rapid identification of VOCs from freshly collected chestnut flowers without any chemical pretreatment. Chemical identification was performed using high-resolution MS analysis in combination with tandem MS analysis and whenever possible was confirmed by the analysis of standard reference compounds. Twenty volatiles were identified, most of which are nitrogen-containing. Out of the identified volatiles, 1-pyrroline is known to have a semen-like odor and is probably also responsible for the semen-like odor of the chestnut flowers. Four nitrogenous VOCs of chestnut flowers, including 1-pyrroline, 1-piperideine, 2-pyrrolidone, and phenethylamine, were also common in other semen-like odor flowers such as Photinia serrulata, Castanopsis sclerophylla, and Stemona japonica, suggesting similar chemical origin. The main visitors of chestnut flowers were dipteran species, such as Eristalis tenax, Eristalis arvorum, Episyrphus balteatus, Lucilia sericata, Chrysomya megacephala, Chrysochus asclepiadeus, and Adalia bipunctata. Our results suggest that the chestnut flowers and other semen-like odor flowers may present a new type of sapromyophily. This study also indicates that ND-EAPCI-MS provides more sensitive and simpler detection of many VOCs (particularly nitrogen-containing VOCs) than GC-MS and therefore can be used to complement traditional approaches for the higher chemical coverage of VOCs analysis. Graphical abstract ᅟ.