Publications by authors named "Xin Gao"

1,440 Publications

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Asxl1loss cooperates with oncogenic Nras in mice to reprogram immune microenvironment and drive leukemic transformation.

Blood 2021 Oct 26. Epub 2021 Oct 26.

UW-Madison, Madison, Wisconsin, United States.

Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ~40% in chronic myelomonocytic leukemia (CMML). ASXL1 mutations associate with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients with shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1-/- accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+; Asxl1-/- (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global level of H3K27ac, and Flt3 upregulation. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands, PD-L1/L2, CD155, and CD80/86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or shRNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wildtype T cells overexpressed PD-1 and TIGIT receptors, leading to a predominant exhausted T cell phenotype. Combined inhibition of MEK and BET led to downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8+ T cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.
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http://dx.doi.org/10.1182/blood.2021012519DOI Listing
October 2021

Systematic Knowledge Management of Construction Safety Standards Based on Knowledge Graphs: A Case Study in China.

Int J Environ Res Public Health 2021 Oct 12;18(20). Epub 2021 Oct 12.

School of Economics and Management, Tongji University, Shanghai 200092, China.

Construction safety standards (CSS) have knowledge characteristics, but few studies have introduced knowledge graphs (KG) as a tool into CSS management. In order to improve CSS knowledge management, this paper first analyzed the knowledge structure of 218 standards and obtained three knowledge levels of CSS. Second, a concept layer was designed which consisted of five levels of concepts and eight types of relationships. Third, an entity layer containing 147 entities was constructed via entity identification, attribute extraction and entity extraction. Finally, 177 nodes and 11 types of attributes were collected and the construction of a knowledge graph of construction safety standard (KGCSS) was completed using knowledge storage. Furthermore, we implemented knowledge inference and obtained CSS planning, i.e., the list of standard work plans used to guide the development and revision of CSS. In addition, we conducted CSS knowledge retrieval; a process which supports interrogative input. The construction of KGCSS thus facilitates the analysis, querying, and sharing of safety standards knowledge.
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http://dx.doi.org/10.3390/ijerph182010692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536078PMC
October 2021

All-Solid-State Lithium-Sulfur Batteries Enhanced by Redox Mediators.

J Am Chem Soc 2021 Oct 22. Epub 2021 Oct 22.

Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, United States.

Redox mediators (RMs) play a vital role in some liquid electrolyte-based electrochemical energy storage systems. However, the concept of redox mediator in solid-state batteries remains unexplored. Here, we selected a group of RM candidates and investigated their behaviors and roles in all-solid-state lithium-sulfur batteries (ASSLSBs). The soluble-type quinone-based RM (AQT) shows the most favorable redox potential and the best redox reversibility that functions well for lithium sulfide (LiS) oxidation in solid polymer electrolytes. Accordingly, LiS cathodes with AQT RMs present a significantly reduced energy barrier (average oxidation potential of 2.4 V) during initial charging at 0.1 C at 60 °C and the following discharge capacity of 1133 mAh g. Using sulfur K-edge X-ray absorption spectroscopy, we directly tracked the sulfur speciation in ASSLSBs and proved that the solid-polysulfide-solid reaction of LiS cathodes with RMs facilitated LiS oxidation. In contrast, for bare LiS cathodes, the solid-solid LiS-sulfur direct conversion in the first charge cycle results in a high energy barrier for activation (charge to ∼4 V) and low sulfur utilization. The [email protected] cell demonstrates superior cycling stability (average Coulombic efficiency 98.9% for 150 cycles) and rate capability owing to the effective AQT-enhanced Li-S reaction kinetics. This work reveals the evolution of sulfur species in ASSLSBs and realizes the fast Li-S reaction kinetics by designing an effective sulfur speciation pathway.
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http://dx.doi.org/10.1021/jacs.1c07754DOI Listing
October 2021

NERO: a biomedical named-entity (recognition) ontology with a large, annotated corpus reveals meaningful associations through text embedding.

NPJ Syst Biol Appl 2021 Oct 20;7(1):38. Epub 2021 Oct 20.

The Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, 60637, US.

Machine reading (MR) is essential for unlocking valuable knowledge contained in millions of existing biomedical documents. Over the last two decades, the most dramatic advances in MR have followed in the wake of critical corpus development. Large, well-annotated corpora have been associated with punctuated advances in MR methodology and automated knowledge extraction systems in the same way that ImageNet was fundamental for developing machine vision techniques. This study contributes six components to an advanced, named entity analysis tool for biomedicine: (a) a new, Named Entity Recognition Ontology (NERO) developed specifically for describing textual entities in biomedical texts, which accounts for diverse levels of ambiguity, bridging the scientific sublanguages of molecular biology, genetics, biochemistry, and medicine; (b) detailed guidelines for human experts annotating hundreds of named entity classes; (c) pictographs for all named entities, to simplify the burden of annotation for curators; (d) an original, annotated corpus comprising 35,865 sentences, which encapsulate 190,679 named entities and 43,438 events connecting two or more entities; (e) validated, off-the-shelf, named entity recognition (NER) automated extraction, and; (f) embedding models that demonstrate the promise of biomedical associations embedded within this corpus.
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http://dx.doi.org/10.1038/s41540-021-00200-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528865PMC
October 2021

A comparison of two different surgical procedures in the treatment of isolated spinal metastasis patients with metastatic spinal cord compression: a case-control study.

Eur Spine J 2021 Oct 19. Epub 2021 Oct 19.

Department of Orthopedics, Orthopaedic Oncology Center, Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai, Huangpu District, China.

Objective: The aim of the study was to compare total en bloc spondylectomy (TES) and separation surgery with postoperative stereotactic radiosurgery (SSRS) for isolated metastatic patients with spinal cord compression by assessing recurrence-free survival (RFS), overall survival (OS), postoperative complications, and quality of life scores (QoL).

Methods: From October 2013 to December 2020, 52 isolated spinal metastasis patients with cord compression were selected and separated into two groups based on the surgical method used (TES group, n = 26; and SSRS group, n = 26). Indexes for evaluation included postoperative Frankel grade, postoperative ECOG-PS, RFS, OS, postoperative complications, operation time, intraoperative blood loss, and QoL.

Results: The average follow-up duration was 31.44 months. There was no significant difference (P > 0.05) in postoperative complications and OS between the two groups. However, a significant difference in operation time, intraoperative blood loss, postoperative ECOG-PS, RFS, and mental health domain (6 months after surgery) was found between the two groups (P < 0.05). According to The Spine Oncology Study Group Outcomes Questionnaire assessment, the total pain and physical function domains scores were also elevated after surgery in both groups. However, no significant difference was observed between groups A and B (p = 0.450 and 0.446, respectively).

Conclusions: TES and SSRS were efficient methods for treating solitary spinal metastasis patients with metastatic spinal cord compression. Better local tumor control and mental health were found in the TES group, and most patients felt as if they were free of spinal tumors. Compared with TES, the SSRS caused less operation-related trauma. However, there was no significant difference in OS between the two groups.
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http://dx.doi.org/10.1007/s00586-021-07032-7DOI Listing
October 2021

Two new dinor-eudesmane sesquiterpenoids from the roots of .

J Asian Nat Prod Res 2021 Oct 19:1-7. Epub 2021 Oct 19.

School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China.

Two new dinor-eudesmane sesquiterpenoids, named multistalin A (), and multistalin B (), together with three sesquiterpene glycosides (-), and a norlabdane-type diterpene () were isolated from the root extract of Pei. Their structures were elucidated on the basis of spectroscopic analysis including 1D, 2D NMR techniques and HR-ESI-MS. In addition, the cytotoxicity activities of the isolated compounds against selected cancer cells (Hela and A-549) were evaluated by MTT assay.
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http://dx.doi.org/10.1080/10286020.2021.1981873DOI Listing
October 2021

The prevalence and prognosis of hyponatraemia in non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis.

Leuk Lymphoma 2021 Oct 18:1-8. Epub 2021 Oct 18.

Department of Geriatric Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.

Non-Hodgkin lymphoma associated hemophagocytic lymphohistiocytosis (NHL-HLH) in adult secondary HLH is a common and universally highly lethal critical disorder. Hyponatraemia is the most common electrolyte disorder in the critical illness setting and acts as a negative prognostic factor. The aim of our study was to evaluate the prognostic role of hyponatraemia among patients with NHL-HLH. The results showed that 81 (52.9%) patients had hyponatraemia. After a median follow up 47 (range 14-180) days, there were 72 (88.9%) cumulative deaths in hyponatraemia group while 50 (69.4%) in normonatremia group. After adjustment for confounders, multivariate analysis revealed that hyponatraemia was an independent prognostic factor for OS (HR:1.51, 95% CI: 1.03-2.20;  = 0.033). Restricted cubic spline confirmed a linear and positive association between serum sodium and the risk of mortality. Hyponatraemia is relatively frequent in NHL-HLH. As a readily available biomarker in clinical routine, it was a promising prognostic predictor for NHL-HLH.
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http://dx.doi.org/10.1080/10428194.2021.1992623DOI Listing
October 2021

LGR6 promotes glioblastoma malignancy and chemoresistance by activating the Akt signaling pathway.

Exp Ther Med 2021 Dec 27;22(6):1364. Epub 2021 Sep 27.

Department of Neurosurgery, The Second Affiliated Hospital of Shandong First Medical University and Shandong Academy of Medical Sciences, Tai'an, Shandong 270000, P.R. China.

Chemoresistance is the primary cause of the poor outcome of glioblastoma multiforme (GBM) therapy. Leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) is involved in the growth and proliferation of several types of cancer, including gastric cancer and ovarian cancer. Therefore, the aim of the present study was to investigate the role of LGR6 in GBM malignancy and chemoresistance. Cell counting kit-8 and Matrigel-Transwell assays were conducted to assess GBM cell viability and invasion. The effect of LGR6 on cell cycle progression and activation of Akt signaling was analyzed by performing propidium iodide staining and western blotting, respectively. The results demonstrated that LGR6, a microRNA-1236-3p target candidate, promoted GBM cell viability and invasion, and mediated temozolomide sensitivity in SHG-44 and U251 GBM cells. In addition, LGR6 triggered the activation of the Akt signaling pathway during GBM progression. Collectively, the results of the present study suggested that LGR6 promoted GBM malignancy and chemoresistance, at least in part, by activating the Akt signaling pathway. The results may aid with the identification of a novel therapeutic target and strategy for GBM.
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http://dx.doi.org/10.3892/etm.2021.10798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515564PMC
December 2021

Mitochondria-targeted phosphorescent cyclometalated iridium(III) complex for bioimaging of HS.

J Inorg Biochem 2021 Oct 7;226:111626. Epub 2021 Oct 7.

Centre for Translational Medicine Research & Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address:

The selective visualization of HS in mitochondria is still a challenge, but it correlates closely with mitochondrial damage and some related diseases. In this work, a cyclometalated iridium complex Ir-DNB, [Ir(ppy)(N^N)](PF) (ppy = 2-phenylpyridine, N^N = (4'-methyl-[2,2'-bipyridin]-4-yl)methyl 2-((2,4-dinitrophenyl) thio)benzoate) has been explored for the detection of mitochondrial HS. Adding HS to a solution of complex Ir-DNB results in a clearly luminescence enhancement, and displays high selectivity and sensitivity. Moreover, this complex displays negligible toxicity and good mitochondrial localization to HeLa cells, and has also been successfully used for endogenous and exogenous HS imaging in vitro and in vivo.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111626DOI Listing
October 2021

Transfer-Enabled Fabrication of Graphene Wrinkle Arrays for Epitaxial Growth of AlN Films.

Adv Mater 2021 Oct 13:e2105851. Epub 2021 Oct 13.

Beijing Graphene Institute (BGI), Beijing, 100095, P. R. China.

Formation of graphene wrinkle arrays can periodically alter the electrical properties and chemical reactivity of graphene, which is promising for numerous applications. However, large-area fabrication of graphene wrinkle arrays remains unachievable with a high density and defined orientations, especially on rigid substrates. Herein, relying on the understanding of the formation mechanism of transfer-related graphene wrinkles, the graphene wrinkle arrays are fabricated without altering the crystalline orientation of entire graphene films. The choice of the transfer medium that has poor wettability on the corrugated surface of graphene is proven to be the key for the formation of wrinkles. This work provides a deep understanding of formation process of transfer-related graphene wrinkles and opens up a new way for periodically modifying the surface properties of graphene for potential applications, including direct growth of AlN epilayers and deep ultraviolet light emitting diodes.
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http://dx.doi.org/10.1002/adma.202105851DOI Listing
October 2021

Lethal variants in humans: lessons learned from a large molecular autopsy cohort.

Genome Med 2021 Oct 13;13(1):161. Epub 2021 Oct 13.

Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background: Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans.

Methods: We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels.

Results: The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results.

Conclusions: Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.
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http://dx.doi.org/10.1186/s13073-021-00973-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511862PMC
October 2021

BlockPolish: accurate polishing of long-read assembly via block divide-and-conquer.

Brief Bioinform 2021 Oct 8. Epub 2021 Oct 8.

School of Computer Science and Engineering, Central South University, China.

Long-read sequencing technology enables significant progress in de novo genome assembly. However, the high error rate and the wide error distribution of raw reads result in a large number of errors in the assembly. Polishing is a procedure to fix errors in the draft assembly and improve the reliability of genomic analysis. However, existing methods treat all the regions of the assembly equally while there are fundamental differences between the error distributions of these regions. How to achieve very high accuracy in genome assembly is still a challenging problem. Motivated by the uneven errors in different regions of the assembly, we propose a novel polishing workflow named BlockPolish. In this method, we divide contigs into blocks with low complexity and high complexity according to statistics of aligned nucleotide bases. Multiple sequence alignment is applied to realign raw reads in complex blocks and optimize the alignment result. Due to the different distributions of error rates in trivial and complex blocks, two multitask bidirectional Long short-term memory (LSTM) networks are proposed to predict the consensus sequences. In the whole-genome assemblies of NA12878 assembled by Wtdbg2 and Flye using Nanopore data, BlockPolish has a higher polishing accuracy than other state-of-the-arts including Racon, Medaka and MarginPolish & HELEN. In all assemblies, errors are predominantly indels and BlockPolish has a good performance in correcting them. In addition to the Nanopore assemblies, we further demonstrate that BlockPolish can also reduce the errors in the PacBio assemblies. The source code of BlockPolish is freely available on Github (https://github.com/huangnengCSU/BlockPolish).
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http://dx.doi.org/10.1093/bib/bbab405DOI Listing
October 2021

Reference values of urine protein/creatinine ratio in healthy Dalian adults.

J Clin Lab Anal 2021 Oct 7:e24043. Epub 2021 Oct 7.

Department of Laboratory Medicine, Dalian Municipal Central Hospital, Liaoning, China.

Background: The urine protein/creatinine ratio (UPCR) is commonly used in current clinical practice. However, there are only few published clinical data on UPCR from large cohorts of Chinese adults. This study aimed to determine the overall and age- and sex-specific UPCR reference values for healthy Dalian adults.

Methods: According to the Clinical & Laboratory Standards Institute EP28-A3c guidelines, 1321 healthy Dalian adults (646 men and 675 women) aged 20-69 years were enrolled. Urine protein and creatinine levels were analyzed in the random morning spot urine samples, and UPCR was calculated. The 95th percentile of the UPCR was used as the normal upper limit. The Mann-Whitney U test was used to test differences among groups.

Results: The UPCR reference value was 141.7 mg/g for the entire cohort, 128.7 mg/g for men, and 150.8 mg/g for women. In addition, women had relatively higher UPCR values than men in the same age group. We also compared the UPCR reference values between different estimated glomerular filtration rate (eGFR) groups and found that women had significantly higher UPCR values than men in the normal eGFR groups.

Conclusions: This study provides the overall and age- and sex-specific UPCR reference values for healthy Dalian adults.
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http://dx.doi.org/10.1002/jcla.24043DOI Listing
October 2021

An Isolation System to Collect High Quality and Purity Extracellular Vesicles from Serum.

Int J Nanomedicine 2021 29;16:6681-6692. Epub 2021 Sep 29.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.

Purpose: Extracellular vesicles (EVs) are membrane-encapsulated nanoparticles that function as carriers and play a role in intercellular communication. There are a large number of EVs in the blood and serve as an indicator of pathophysiological conditions. Studies on the basics and application of EVs are hampered by the limitations of current protocols to isolate EVs from blood. However, current isolation methods are difficult to achieve a balance between yield and purity.

Methods: Firstly, we use Sepharose-4B to build a self-made size exclusion chromatography (SEC) column and perform separation and characteristics. Then, we use the SEC column to systematically compare the efficiency with the most common EV isolation methods: Ultracentrifugation (UC) and total exosomes isolation commercial kit (TEI). The EVs isolated through different methods were characterized the yield and size of EVs, analyzed their protein profiles, the morphology and purity were observed under the transmission electron microscope. To further improve the quality and purity, we combined SEC and UC methods and established a two-steps method to isolated EVs from serum.

Results: Self-made SEC column can well separate EVs from complex serum protein, and EVs enriched in the 8-13 fractions with good morphology and yield. By systematically compare SEC with the commonly used UC and TEI kit, SEC is outstanding in all aspects and balances both isolation purity and yield. However, using the SEC method alone still has certain limitations and residual impurities. The SEC+UC combined method can cleverly solve the shortcomings of SEC and optimize the quality and purity of EVs from serum, which is much better than using one method alone.

Conclusion: Our study presents the combination of size-exclusion chromatography and ultracentrifugation as a feasible and time-saving method to isolate high-quality and purity extracellular vesicles from serum.
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http://dx.doi.org/10.2147/IJN.S328325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487857PMC
September 2021

DRAK2 aggravates nonalcoholic fatty liver disease progression through SRSF6-associated RNA alternative splicing.

Cell Metab 2021 Oct;33(10):2004-2020.e9

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address:

Nonalcoholic steatohepatitis (NASH) is an advanced stage of nonalcoholic fatty liver disease (NAFLD) with serious consequences that currently lacks approved pharmacological therapies. Recent studies suggest the close relationship between the pathogenesis of NAFLD and the dysregulation of RNA splicing machinery. Here, we reveal death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is markedly upregulated in the livers of both NAFLD/NASH patients and NAFLD/NASH diet-fed mice. Hepatic deletion of DRAK2 suppresses the progression of hepatic steatosis to NASH. Comprehensive analyses of the phosphoproteome and transcriptome indicated a crucial role of DRAK2 in RNA splicing and identified the splicing factor SRSF6 as a direct binding protein of DRAK2. Further studies demonstrated that binding to DRAK2 inhibits SRSF6 phosphorylation by the SRSF kinase SRPK1 and regulates alternative splicing of mitochondrial function-related genes. In conclusion, our findings reveal an indispensable role of DRAK2 in NAFLD/NASH and offer a potential therapeutic target for this disease.
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http://dx.doi.org/10.1016/j.cmet.2021.09.008DOI Listing
October 2021

3D multi-scale, multi-task, and multi-label deep learning for prediction of lymph node metastasis in T1 lung adenocarcinoma patients' CT images.

Comput Med Imaging Graph 2021 Sep 30;93:101987. Epub 2021 Sep 30.

Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China; Jinan Guoke Medical Engineering and Technology Development Co., Ltd., Jinan, Shandong 250101, China. Electronic address:

The diagnosis of preoperative lymph node (LN) metastasis is crucial to evaluate possible therapy options for T1 lung adenocarcinoma patients. Radiologists preoperatively diagnose LN metastasis by evaluating signs related to LN metastasis, like spiculation or lobulation of pulmonary nodules in CT images. However, this type of evaluation is subjective and time-consuming, which may result in poor consistency and low efficiency of diagnoses. In this study, a 3D Multi-scale, Multi-task, and Multi-label classification network (3M-CN) was proposed to predict LN metastasis, as well as evaluate multiple related signs of pulmonary nodules in order to improve the accuracy of LN metastasis prediction. The following key approaches were adapted for this method. First, a multi-scale feature fusion module was proposed to aggregate the features from different levels for which different labels be best modeled at different levels; second, an auxiliary segmentation task was applied to force the model to focus more on the nodule region and less on surrounding unrelated structures; and third, a cross-modal integration module called the refine layer was designed to integrate the related risk factors into the model to further improve its confidence level. The 3M-CN was trained using data from 401 cases and then validated on both internal and external datasets, which consisted of 100 cases and 53 cases, respectively. The proposed 3M-CN model was then compared with existing state-of-the-art methods for prediction of LN metastasis. The proposed model outperformed other methods, achieving the best performance with AUCs of 0.945 and 0.948 in the internal and external test datasets, respectively. The proposed model not only obtain strong generalization, but greatly enhance the interpretability of the deep learning model, increase doctors' confidence in the model results, conform to doctors' diagnostic process, and may also be transferable to the diagnosis of other diseases.
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http://dx.doi.org/10.1016/j.compmedimag.2021.101987DOI Listing
September 2021

Prevalence and Correlates of Healthy Aging Among Elderly Aged 65 Years and Over - 6 PLADs, China, 2019.

China CDC Wkly 2021 Jan;3(4):69-73

Shandong Center for Disease Control and Prevention, Jinan, Shandong, China.

Summary:

Healthy aging among Chinese older people has low prevalence. Some sociodemographic and lifestyle factors were shown to be associated with healthy aging.



The age-adjusted prevalence of healthy aging in the 6 provincial-level administrative divisions (PLADs) of China is 15.8 % in 2019. County-level factors, such as the prevalence of healthy communities in a county, as well as some sociodemographic variables and physical exercise, are potential factors of healthy aging.



These findings showed that more targeted actions, including generalizing healthy communities and individual-level interventions, may be of great importance for healthy aging.
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http://dx.doi.org/10.46234/ccdcw2021.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393085PMC
January 2021

Machine learning and deep learning methods that use omics data for metastasis prediction.

Comput Struct Biotechnol J 2021 4;19:5008-5018. Epub 2021 Sep 4.

Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.

Knowing metastasis is the primary cause of cancer-related deaths, incentivized research directed towards unraveling the complex cellular processes that drive the metastasis. Advancement in technology and specifically the advent of high-throughput sequencing provides knowledge of such processes. This knowledge led to the development of therapeutic and clinical applications, and is now being used to predict the onset of metastasis to improve diagnostics and disease therapies. In this regard, predicting metastasis onset has also been explored using artificial intelligence approaches that are machine learning, and more recently, deep learning-based. This review summarizes the different machine learning and deep learning-based metastasis prediction methods developed to date. We also detail the different types of molecular data used to build the models and the critical signatures derived from the different methods. We further highlight the challenges associated with using machine learning and deep learning methods, and provide suggestions to improve the predictive performance of such methods.
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http://dx.doi.org/10.1016/j.csbj.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450182PMC
September 2021

Change in urea to creatinine ratio is associated with postoperative complications and skeletal muscle wasting in pancreatic cancer patients following pancreatoduodenectomy.

Asia Pac J Clin Nutr 2021 Sep;30(3):374-382

Department of General Surgery, The First Affiliated Hospital of Soochow University, Jiangsu, P.R. China. Email:

Background And Objectives: Surgical patients with depleted skeletal muscle mass tend to have a worse outcome. Whether perioperative change of urea to creatinine ratio (CUCR) can reflect muscle wasting and predict postoperative complications have not been investigated. This study aimed to evaluate the relationship of perioperative CUCR with postoperative complications and skeletal muscle wasting in pancreatic cancer patients undergoing pancreatoduodenectomy (PD).

Methods And Study Design: Pancreatic cancer patients undergoing PD were included retrospectively. The association between postoperative complications and perioperative CUCR as well as other nutritional biomarkers was analyzed. In a subset of patients with serial CT scans, the correlation of the CUCR and the changes of CT-derived skeletal muscle area (SMA) were tested. Furthermore, the capacity of complication prediction of CUCR and CT-derived parameter were compared in these patients.

Results: A total of 321 surgical patients were included. Univariable and multivariable logistic regression demonstrated CUCR was a strong predictor for complications in these patients, independent of age, BMI and comorbidity. Patients with CUCR above the median have higher complication rate (p=0.007) and longer postoperative days to discharge (p=0.017). In a subset patients with both pre- and postoperative digital abdominal CT scans, spearman correlation analysis shown both L3 muscle area and L4-psoas area were significantly correlated with CUCR (R2=0.64, p<0.05; R2=0.62, p<0.05, respectively).

Conclusions: Perioperative CUCR is an independent predictor for postoperative complications in pancreatic cancer patients undergoing PD. Elevated CUCR is a reflection of skeletal muscle wasting in postoperative surgical patients.
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http://dx.doi.org/10.6133/apjcn.202109_30(3).0004DOI Listing
September 2021

Unique Tubulin-Based Structures in the Zoonotic Apicomplexan Parasite .

Microorganisms 2021 Sep 10;9(9). Epub 2021 Sep 10.

Key Laboratory for Zoonoses Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China.

parasites are known to be highly divergent from other apicomplexan species at evolutionary and biological levels. Here we provide evidence showing that the zoonotic also differs from other apicomplexans, such as , by possessing only two tubulin-based filamentous structures, rather than an array of subpellicular microtubules. Using an affinity-purified polyclonal antibody against β-tubulin (CpTubB), we observed a long and a short microtubule that are rigid and stable in the sporozoites and restructured during the intracellular parasite development. In asexual development (merogony), the two restructuring microtubules are present in pairs (one pair per nucleus or merozoites). In sexual developmental stages, tubulin-based structures are detectable only in microgametes, but undetectable in macrogametes. These observations indicate that parasites use unique microtubule structures that differ from other apicomplexans as part of their cytoskeletal elements.
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http://dx.doi.org/10.3390/microorganisms9091921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464796PMC
September 2021

Continuous Spectrophotometric Assay for High-Throughput Screening of Predominant d-Allulose 3-Epimerases.

J Agric Food Chem 2021 Oct 26;69(39):11637-11645. Epub 2021 Sep 26.

Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education; Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology; National Engineering Laboratory for Industrial Enzymes, Tianjin 300457, P. R. China.

d-Allulose is an attractive noncaloric sugar substitute with numerous health benefits, which can be biosynthesized by d-allulose 3-epimerases (DAEases). However, enzyme instability under harsh industrial reaction conditions hampered its practical applications. Here, we developed a continuous spectrophotometric assay (CSA) for the efficient analysis of d-allulose in a mixture. Furthermore, a high-throughput screening strategy for DAEases was developed using CSA by coupling DAEase with a NADH-dependent ribitol dehydrogenase, enabling high-throughput screening of DAEase variants with desired properties. The variant M15S/P40N/S209N exhibited a half-life of 22 h at 60 °C and an 8.7 °C increase of the value, with a 1.2-fold increase of activity. Structural modeling and molecular dynamics simulations indicated that the improvement of thermostability and activity was due to some new hydrogen bonds between chains at the dimer interface and between the residue and the substrate d-fructose. This work offers a robust tool and theoretical basis for the improvement of DAEases, which will benefit the enzymatic biosynthesis of d-allulose and promote its industrial application.
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http://dx.doi.org/10.1021/acs.jafc.1c04716DOI Listing
October 2021

Construction of Interferon-Gamma-Related Gene Signature to Characterize the Immune-Inflamed Phenotype of Glioblastoma and Predict Prognosis, Efficacy of Immunotherapy and Radiotherapy.

Front Immunol 2021 10;12:729359. Epub 2021 Sep 10.

Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Interferon-gamma (IFNG) has profound impacts on tumor-immune interaction and is of great clinical significance for multiple cancers. Exploring the role of IFNG in glioblastoma (GBM) may optimize the current treatment paradigm of this disease. Here, multi-dimensional data of 429 GBM samples were collected. Various bioinformatics algorithms were employed to establish a gene signature that characterizes immunological features, genomic alterations, and clinical characteristics associated with the IFNG response. In this way, a novel IFNG-related gene signature (IFNGrGS, including TGFBI, IL4I1, ACP5, and LUM) has been constructed and validated. Samples with increased IFNGrGS scores were characterized by increased neutrophil and macrophage infiltration and exuberant innate immune responses, while the activated adaptive immune response may be frustrated by multiple immunosuppressive mechanisms. Notably, the IFNG pathway as well as its antagonistic pathways including IL4, IL10, TGF-beta, and VEGF converged on the expression of immune checkpoints. Besides, gene mutations involved in the microenvironment were associated with the IFNGrGS-based stratification, where the heterogeneous prognostic significance of EGFR mutation may be related to the different degrees of IFNG response. Moreover, the IFNGrGS score had solid prognostic value and the potential to screen ICB and radiotherapy sensitive populations. Collectively, our study provided insights into the role of IFNG on the GBM immune microenvironment and offered feasible information for optimizing the treatment of GBM.
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http://dx.doi.org/10.3389/fimmu.2021.729359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461254PMC
September 2021

CT-based radiomics signatures can predict the tumor response of non-small cell lung cancer patients treated with first-line chemotherapy and targeted therapy.

Eur Radiol 2021 Sep 26. Epub 2021 Sep 26.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, No.440 Jiyan Road, Huaiyin District, Jinan, 250100, Shandong, China.

Objectives: The goal of this study was to evaluate the effectiveness of radiomics signatures on pre-treatment computed tomography (CT) images of lungs to predict the tumor responses of non-small cell lung cancer (NSCLC) patients treated with first-line chemotherapy, targeted therapy, or a combination of both.

Materials And Methods: This retrospective study included 322 NSCLC patients who were treated with first-line chemotherapy, targeted therapy, or a combination of both. Of these patients, 224 were randomly assigned to a cohort to help develop the radiomics signature. A total of 1946 radiomics features were obtained from each patient's CT scan. The top-ranked features were selected by the Minimum Redundancy Maximum Relevance (MRMR) feature-ranking method and used to build a lightweight radiomics signature with the Random Forest (RF) classifier. The independent predictive (IP) features (AUC > 0.6, p value < 0.05) were further identified from the top-ranked features and used to build a refined radiomics signature by the RF classifier. Its prediction performance was tested on the validation cohort, which consisted of the remaining 98 patients.

Results: The initial lightweight radiomics signature constructed from 15 top-ranked features had an AUC of 0.721 (95% CI, 0.619-0.823). After six IP features were further identified and a refined radiomics signature was built, it had an AUC of 0.746 (95% CI, 0.646-0.846).

Conclusions: Radiomics signatures based on pre-treatment CT scans can accurately predict tumor response in NSCLC patients after first-line chemotherapy or targeted therapy treatments. Radiomics features could be used as promising prognostic imaging biomarkers in the future.

Key Points: The radiomics signature extracted from baseline CT images in patients with NSCLC can predict response to first-line chemotherapy, targeted therapy, or both treatments with an AUC = 0.746 (95% CI, 0.646-0.846). The radiomics signature could be used as a new biomarker for quantitative analysis in radiology, which might provide value in decision-making and to define personalized treatments for cancer patients.
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http://dx.doi.org/10.1007/s00330-021-08277-yDOI Listing
September 2021

Quantitative proteomics reveals tissue-specific toxic mechanisms for acute hydrogen sulfide-induced injury of diverse organs in pig.

Sci Total Environ 2021 Sep 16;806(Pt 1):150365. Epub 2021 Sep 16.

Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, TERRA Teaching and Research Centre, University of Liège, Passage des Déportés 2, Gembloux 5030, Belgium.

Hydrogen sulfide (HS) is a highly toxic gas in many environmental and occupational places. It can induce multiple organ injuries particularly in lung, trachea and liver, but the relevant mechanisms remain poorly understood. In this study, we used a TMT-based discovery proteomics to identify key proteins and correlated molecular pathways involved in the pathogenesis of acute HS-induced toxicity in porcine lung, trachea and liver tissues. Pigs were subjected to acute inhalation exposure of up to 250 ppm of HS for 5 h for the first time. Changes in hematology and biochemical indexes, serum inflammatory cytokines and histopathology demonstrated that acute HS exposure induced organs inflammatory injury and dysfunction in the porcine lung, trachea and liver. The proteomic data showed 51, 99 and 84 proteins that were significantly altered in lung, trachea and liver, respectively. Gene ontology (GO) annotation, KEGG pathway and protein-protein interaction (PPI) network analysis revealed that acute HS exposure affected the three organs via different mechanisms that were relatively similar between lung and trachea. Further analysis showed that acute HS exposure caused inflammatory damages in the porcine lung and trachea through activating complement and coagulation cascades, and regulating the hyaluronan metabolic process. Whereas antigen presentation was found in the lung but oxidative stress and cell apoptosis was observed exclusively in the trachea. In the liver, an induced dysfunction was associated with protein processing in the endoplasmic reticulum and lipid metabolism. Further validation of some HS responsive proteins using western blotting indicated that our proteomics data were highly reliable. Collectively, these findings provide insight into toxic molecular mechanisms that could potentially be targeted for therapeutic intervention for acute HS intoxication.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150365DOI Listing
September 2021

Structural Basis of Salicylic Acid Decarboxylase Reveals a Unique Substrate Recognition Mode and Access Channel.

J Agric Food Chem 2021 Oct 23;69(39):11616-11625. Epub 2021 Sep 23.

Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, No. 29, 13th Avenue, Tianjin 300457, China.

Salicylic acid (SA) decarboxylase from (TmSdc), which reversibly catalyses the decarboxylation of SA to yield phenol, is of significant interest because of its potential for the production of benzoic acid derivatives under environmentally friendly reaction conditions. TmSdc showed a preference for C2 hydroxybenzoate derivatives, with / of SA being 3.2 × 10 M s. Here, we presented the first crystal structures of TmSdc, including a complex with SA. The three conserved residues of Glu8, His169, and Asp298 are the catalytic residues within the TIM-barrel domain of TmSdc. Trp239 forms a unique hydrophobic recognition site by interacting with the phenyl ring of SA, while Arg235 is responsible for recognizing the hydroxyl group at the C2 of SA via hydrogen bond interactions. Using a semi-rational combinatorial active-site saturation test, we obtained the TmSdc mutant MT3 (Y64T/P191G/F195V/E302D), which exhibited a 26.4-fold increase in / with SA, reaching 8.4 × 10 M s. Steered molecular dynamics simulations suggested that the structural changes in MT3 relieved the steric hindrance within the substrate access channel and enlarged the substrate-binding pocket, leading to the increased activity by improving substrate access. Our data elucidate the unique substrate recognition mode and the substrate entrance tunnel of SA decarboxylase.
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http://dx.doi.org/10.1021/acs.jafc.1c04091DOI Listing
October 2021

Tunable plasmonic gallium nano liquid metal from facile and controllable synthesis.

Mater Horiz 2021 Sep 23. Epub 2021 Sep 23.

School of Chemistry and Chemical Engineering, Jiangsu Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, P. R. China.

Liquid metal (LM) gallium (Ga) is famous for its metallic properties with unique fluidity and has been extensively utilized in modern technologies. However, chemical strategies towards nanostructured Ga are extremely challenging, which severely limits further advanced applications of Ga. This work reports a facile method, the classical galvanic replacement reaction (GRR), to readily realize the synthesis of uniform Ga nano LM through sacrificial seeds (zinc) and gallium ions (Ga). Different from the previous tedious Ga nanoparticle synthesis, the GRR can be achieved under mild conditions without involving any highly active reagents or special equipment. Surprisingly, the temperature heavily influences the results of GRR due to the unique solid-liquid phase transition of Ga LM. This work figures out the critical issues of temperature, oxygen and solvent in the GRR to successfully prepare Ga nanodroplets. Interestingly, the GRR provides a convenient strategy to control the size of Ga nano LM to mediate localized surface plasmon resonance (LSPR) in the ultraviolet region, which is hardly observed in noble metals. Besides, the nano Ga from GRR exhibits remarkable SERS detection capability with an extremely low limit of detection (10 M), which ranks as the highest enhancement factor with an average value exceeding 10 among Ga materials. Moreover, the SERS activity of the nano Ga shows no obvious decrease within 60 days, verifying its excellent storage stability. This work demonstrates a facile "bottom-up" chemistry for Ga LM, which could greatly benefit its potential applications in the future.
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http://dx.doi.org/10.1039/d1mh01101dDOI Listing
September 2021

DTi2Vec: Drug-target interaction prediction using network embedding and ensemble learning.

J Cheminform 2021 Sep 22;13(1):71. Epub 2021 Sep 22.

Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), Computational Bioscience Research Center, Computer (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Kingdom of Saudi Arabia.

Drug-target interaction (DTI) prediction is a crucial step in drug discovery and repositioning as it reduces experimental validation costs if done right. Thus, developing in-silico methods to predict potential DTI has become a competitive research niche, with one of its main focuses being improving the prediction accuracy. Using machine learning (ML) models for this task, specifically network-based approaches, is effective and has shown great advantages over the other computational methods. However, ML model development involves upstream hand-crafted feature extraction and other processes that impact prediction accuracy. Thus, network-based representation learning techniques that provide automated feature extraction combined with traditional ML classifiers dealing with downstream link prediction tasks may be better-suited paradigms. Here, we present such a method, DTi2Vec, which identifies DTIs using network representation learning and ensemble learning techniques. DTi2Vec constructs the heterogeneous network, and then it automatically generates features for each drug and target using the nodes embedding technique. DTi2Vec demonstrated its ability in drug-target link prediction compared to several state-of-the-art network-based methods, using four benchmark datasets and large-scale data compiled from DrugBank. DTi2Vec showed a statistically significant increase in the prediction performances in terms of AUPR. We verified the "novel" predicted DTIs using several databases and scientific literature. DTi2Vec is a simple yet effective method that provides high DTI prediction performance while being scalable and efficient in computation, translating into a powerful drug repositioning tool.
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http://dx.doi.org/10.1186/s13321-021-00552-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459562PMC
September 2021

Gene Cloning, Functional Expression, and Characterization of a Novel GH46 Chitosanase from Streptomyces avermitilis (SaCsn46A).

Appl Biochem Biotechnol 2021 Sep 20. Epub 2021 Sep 20.

Laboratory of Applied Microbiology, School of Pharmaceutical, Changzhou University, Changzhou, China.

A n ovel glycoside hydrolase (GH) family 46 chitosanase (SaCsn46A) from Streptomyces avermitilis was cloned and functionally expressed in Escherichia coli Rosetta (DE3) strains. SaCsn46A consists of 271 amino acids, which includes a 34-amino acid signal peptide. The protein sequence of SaCsn46A shows maximum identity (83.5%) to chitosanase from Streptomyces sp. SirexAA-E. Then, the mature enzyme was purified to homogeneity through Ni-chelating affinity chromatography with a recovery yield of 78% and the molecular mass of purified enzyme was estimated to be 29 kDa by SDS-PAGE. The recombinant enzyme possessed a temperature optimum of 45 °C and a pH optimum of 6.2, and it was stable at pH ranging from 4.0 to 9.0 and below 30 °C. The K and V values of this enzyme were 1.32 mg/mL, 526.32 U/mg/min, respectively (chitosan as substrate). The enzyme activity can be enhanced by Mg and especially Mn, which could enhance the activity about 3.62-fold at a 3-mM concentration. The enzyme can hydrolyze a variety of polysaccharides which are linked by β-1,4-glycosidic bonds such as chitin, xylan, and cellulose, but it could not hydrolyze polysaccharides linked by α-1,4-glycosidic bonds. The results of thin-layer chromatography and HPLC showed that the enzyme exhibited an endo-type cleavage pattern and could hydrolyze chitosan to glucosamine (GlcN) and (GlcN). This study demonstrated that SaCsn46A is a promising enzyme to produce glucosamine and chitooligosaccharides (COS) from chitosan.
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http://dx.doi.org/10.1007/s12010-021-03687-6DOI Listing
September 2021

Iodide-Induced Fragmentation of Polymerized Hydrophilic Carbon Nitride for High-Performance Quasi-Homogeneous Photocatalytic H O Production.

Angew Chem Int Ed Engl 2021 Sep 17. Epub 2021 Sep 17.

Key Laboratory of Integrated Regulation and Resource Development on Shallow Lakes, Ministry of Education, College of Environment, Hohai University, No.1, Xikang road, Nanjing, 210098, China.

Polymeric carbon nitride (PCN) as a class of two-electron oxygen reduction reaction (2 e ORR) photocatalyst has attracted much attention for H O production. However, the low activity and inferior selectivity of 2 e ORR greatly restrict the H O production efficiency. Herein, we develop a new strategy to synthesize hydrophilic, fragmented PCN photocatalyst by the terminating polymerization (TP-PCN) effect of iodide ions. The obtained TP-PCN with abundant edge active sites (AEASs), which can form quasi-homogeneous photocatalytic system, exhibits superior H O generation rate (3265.4 μM h ), far surpassing PCN and other PCN-based photocatalysts. DFT calculations further indicate that TP-PCN is more favorable for electron transiting from β spin-orbital to the π* orbitals of O , which optimizes O activation and reduces the energy barrier of H O formation. This work provides a new concept for designing functional photocatalysts and understanding the mechanism of O activation in ORR for H O production.
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http://dx.doi.org/10.1002/anie.202111769DOI Listing
September 2021

Identification of circulating sphingosine kinase-related metabolites for prediction of type 2 diabetes.

J Transl Med 2021 Sep 16;19(1):393. Epub 2021 Sep 16.

Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Background: Sphingosine Kinase (SphK) that catalyzes sphingosine (Sph) to sphingosine 1-phosphate (S1P), plays a key role in both sphingolipid metabolism and cellular signaling. While SphK has been implicated in type 2 diabetes mellitus (T2DM), it is unexplored in humans. Herein, we investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort.

Methods: Levels of SphK-related sphingolipid metabolites, including Sph, S1P, dihydrosphingosine (dhSph) and dihydro-S1P (dhS1P) in serum were measured by targeted-lipidomic analyses. By accessing to an established prospective cohort that involves a total of 2486 non-diabetic adults at baseline, 100 subjects who developed T2DM after a mean follow-up of 4.2-years, along with 100 control subjects matched strictly with age, sex, BMI and fasting glucose, were randomly enrolled for the present study.

Results: Comparison with the control group, medians of serum dhS1P and dhS1P/dhSph ratio at baseline were elevated significantly prior to the onset of T2DM. Each SD increment of dhS1P and dhS1P/dhSph ratio was associated with 53.5% and 54.1% increased risk of incident diabetes, respectively. The predictive effect of circulating dhS1P and dhS1P/dhSph ratio on T2DM incidence was independent of conventional risk factors in multivariate regression models. Furthermore, combination of serum dhS1P and dhS1P/dhSph ratio with conventional clinical indices significantly improved the accuracy of T2DM prediction (AUROC, 0.726), especially for normoglycemic subjects (AUROC, 0.859).

Conclusion: Circulating levels of dhS1P and dhS1P/dhSph ratio are strongly associated with increased risk of T2DM, and could serve as a useful biomarker for prediction of incident T2DM in normoglycemic populations.
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http://dx.doi.org/10.1186/s12967-021-03066-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447705PMC
September 2021
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