Publications by authors named "Donghui Li"

302 Publications

A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.

Am J Hum Genet 2021 Oct 23;108(10):1852-1865. Epub 2021 Sep 23.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10, OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (p = 1.40 × 10, β = 1.99; p = 1.02 × 10, β = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10, OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.
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http://dx.doi.org/10.1016/j.ajhg.2021.09.002DOI Listing
October 2021

Association of dietary fat intake and hepatocellular carcinoma among US adults.

Cancer Med 2021 Sep 18. Epub 2021 Sep 18.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background And Aims: The role of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) remains unclear. We investigated the associations of total fat and fatty acids with risk of HCC among US adults in a hospital-based case-control study.

Methods: We analyzed data from 641 cases and 1034 controls recruited at MD Anderson Cancer Center during 2001-2018. Cases were new patients with a pathologically or radiologically confirmed diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck. Cases and controls were frequency-matched by age and sex. Dietary intake was assessed using a validated food frequency questionnaire. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection.

Results: Monounsaturated fatty acid (MUFA) intake was inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.49; 95% CI, 0.33-0.72). Total polyunsaturated fatty acid (PUFA) intake was directly associated with HCC risk (highest vs. lowest tertile: OR, 1.82; 95% CI, 1.23-2.70). Omega-6 PUFA was directly associated with HCC risk (highest vs. lowest tertile: OR 2.29; 95% CI, 1.52-3.44). Long-chain omega-3 PUFA (eicosapentaenoic acid and docosahexaenoic acid) intake was also inversely associated with HCC risk (highest vs. lowest tertile: OR, 0.50; 95% CI, 0.33-0.70). No association was observed for saturated fat and HCC risk.

Conclusion: Our findings support a direct association of omega-6 PUFA intake with HCC and an inverse association of MUFA and long-chain omega-3 PUFA intake with HCC.
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http://dx.doi.org/10.1002/cam4.4256DOI Listing
September 2021

Tuning of the Interconnecting Layer for Monolithic Perovskite/Organic Tandem Solar Cells with Record Efficiency Exceeding 21.

Nano Lett 2021 Sep 10;21(18):7845-7854. Epub 2021 Sep 10.

School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China.

The photovoltaic performance of inorganic perovskite solar cells (PSCs) still lags behind the organic-inorganic hybrid PSCs due to limited light absorption of wide bandgap CsPbIBr under solar illumination. Constructing tandem devices with organic solar cells can effectively extend light absorption toward the long-wavelength region and reduce radiative photovoltage loss. Herein, we utilize wide-bandgap CsPbIBr semiconductor and narrow-bandgap PM6:Y6-BO blend to fabricate perovskite/organic tandem solar cells with an efficiency of 21.1% and a very small tandem open-circuit voltage loss of 0.06 V. We demonstrate that the hole transport material of the interconnecting layers plays a critical role in determining efficiency, with polyTPD being superior to PBDB-T-Si and D18 due to its low parasitic absorption, sufficient hole mobility and quasi-Ohmic contact to suppress charge accumulation and voltage loss within the tandem device. These perovskite/organic tandem devices also display superior storage, thermal and ultraviolet stabilities.
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http://dx.doi.org/10.1021/acs.nanolett.1c02897DOI Listing
September 2021

A [email protected] quantum dots based electrochemiluminescence aptasensor for sensitive detection of ochratoxin A.

Chemosphere 2021 Aug 27;287(Pt 1):131994. Epub 2021 Aug 27.

Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China. Electronic address:

In this work, a [email protected] quantum dots (QDs) based label-free electrochemiluminescence (ECL) aptasensor was developed for the specific and sensitive detection of ochratoxin A (OTA). Chitosan (CHI) could immobilize abundant QDs on the surface of an Au electrode as the luminescent nanomaterials. Glutaraldehyde was used as the crosslinking agent for coupling a large number of OTA aptamers. Thanks to the excellent stability, good biocompatibility, and strong ECL intensity of [email protected] QDs, as well as the quick reactions of the generated SO•- in the electrolyte, strong ECL signals were measured. Because of the specific recognition of aptamer toward OTA, the reduced ECL signals caused by OTA in the samples were recorded for quantify the content of OTA. After optimizing a series of crucial conditions, the ECL aptasensor displayed superior sensitivity for OTA with a detection limit of 0.89 ng/mL and a wide linear concentration range of 1-100 ng/mL. The practicability and viability were verified through the rapid and facile analysis of OTA in real Lily and Rhubarb samples with recovery rates (n = 3) of 98.1-105.6% and 97.3-101.5%, respectively. The newly-developed QDs-based ECL aptasensor provided a new universal analytical tool for more mycotoxins in safety assessment of foods and feeds, environmental monitoring, and clinical diagnostics.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131994DOI Listing
August 2021

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the and genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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http://dx.doi.org/10.1016/j.xhgg.2021.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336922PMC
July 2021

Simultaneously Enhanced Efficiency and Operational Stability of Nonfullerene Organic Solar Cells via Solid-Additive-Mediated Aggregation Control.

Small 2021 Sep 22;17(35):e2102558. Epub 2021 Jul 22.

School of Materials Science and Engineering, Wuhan University of Technology, Wuhan, 430070, China.

The additive strategy is widely used in optimizing the morphology of organic solar cells (OSCs). The majority of additives are liquid with high boiling points, which will be trapped within device and consequently deteriorate performance during operation. In this work, solid but volatile additives 2-(4-fluorobenzylidene)-1H-indene-1,3(2H)-dione (INB-F) and 2-(4-chlorobenzylidene)-1H-indene-1,3(2H)-dione (INB-Cl) are designed to replace the common 1,8-diiodooctane (DIO) in nonfullerene OSCs. These additives present during solution casting but evaporate after moderate heating. Molecular dynamics simulations show that they can reduce the adsorption energy to improve π-π stacking among nonfullerene acceptor (NFA) molecules, an effect that enhances light absorption and electron mobility. Both INB-F and INB-Cl enhance efficiency, with INB-F achieving a maximum efficiency of 16.7% from 15.1% of the reference PBDB-T-2F (PM6):BTP-BO-4F (Y6-BO) cell, and outperforming DIO. Remarkably, they can simultaneously enhance the operational stability, with the INB-F-treated OSC maintaining over 60% of the initial efficiency after 1000 h operation, demonstrating a T lifetime of 523 h, which is a significant improvement over T values of 66.2 h for the reference and 6.6 h for DIO-treated OSC. The simultaneously enhanced efficiency and operational lifetime are also effective in PM6:BTP-BO-4Cl (Y7-BO) OSCs, demonstrating a universal strategy to improve the performance of OSCs.
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http://dx.doi.org/10.1002/smll.202102558DOI Listing
September 2021

Sedimentary organic carbon and nutrient distributions in an endorheic lake in semiarid area of the Mongolian Plateau.

J Environ Manage 2021 Oct 6;296:113184. Epub 2021 Jul 6.

Chinese Research Academy of Environmental Sciences, Beijing, 100012, PR China; School of Municipal and Environmental Engineering, Shenyang Jianzhu University, Shenyang, 110168, PR China.

Due to the lack of outlets, inflowing pollutants are often deposited in an endorheic lake, posing potential pressure on the environment. With climate change, extreme weather is expected to be more frequent and will contribute to the release of carbon and nutrients buried in the lakebeds. However, the distribution of sedimentary organic carbon and nutrients and the mechanisms that control the distribution are not fully understood, despite their significance to environmental development in endorheic lakes being widely recognized. In this study, the mechanisms controlling the sedimentary organic carbon and nutrient distributions in endorheic lakes were examined based on the analysis of an endorheic lake in the semiarid area of the Mongolian Plateau. The field survey results indicate that the concentrations of sedimentary organic carbon (TOC) and nutrients (NH-N and TP) on the lakebed have significant correlations and present spatial heterogeneities. To further study the distribution mechanisms, numerical models were established to calculate the age of the water discharged from the rivers around the lake, and satellite remote sensing data were applied to examine the external source of organic carbon and nutrients and the factors influencing their movements to the lake. Based on the distribution of the water age, the water flow and mass transport trends in Lake Hulun were determined, and the time scales of the environmental processes were compared with those of water circulation. Further analysis indicates that the water circulation in the lake favors the accumulation of sedimentary organic carbon and nutrients in the northwestern part of the lake, and the organic carbon produced in the lake is transported to this region within an ice-free period. Satellite remote sensing data indicate that the region on the northwest bank of the lake experiences a larger terrestrial slope and better vegetation coverage than that on the southeast bank, which corresponds to a higher concentration of sedimentary organic carbon and nutrients in the northwest of the lake. This suggests that the sediment quality is closely related to the environment around the endorheic lake, and the larger slope and better vegetation coverage are significant factors for the high concentration of sedimentary organic carbon and nutrients on the lakebed under the conditions of scarce precipitation and low temperature. This study provides a theoretical basis and direction for further protection and management of the ecological environment of endorheic lakes.
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http://dx.doi.org/10.1016/j.jenvman.2021.113184DOI Listing
October 2021

Dietary N-Nitroso Compounds and Risk of Hepatocellular Carcinoma: A USA-Based Study.

Hepatology 2021 Jul 7. Epub 2021 Jul 7.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Background And Aims: N-nitroso compounds (NOCs) are among the most potent dietary carcinogens. N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), and N-nitrosopiperidine (NPIP) are abundant in foods and carcinogenic to the liver. We investigated the relationship between dietary NOCs and HCC risk.

Approach And Results: In this large, hospital-based, case-control study of 827 pathologically or radiologically confirmed HCC cases and 1,013 controls, NOC intake was calculated by linking food frequency questionnaire-derived dietary data with a comprehensive NOC concentration database. Multivariable-adjusted ORs and 95% CIs of HCC by quartiles of NOC consumption were estimated using logistic regression models, with the lowest quartile as the referent. We further investigated joint effects of consuming the highest quartile of NOCs that were associated with increased HCC risk and hepatitis, diabetes, or alcohol drinking on HCC risk. After adjustment for confounding factors, higher intake of NDEA from plant sources (OR  = 1.58; 95% CI = 1.03-2.41), NDMA from plant sources (OR  = 1.54; 95% CI = 1.01-2.34), and NPIP (OR  = 2.52; 95% CI = 1.62-3.94) was associated with increased HCC risk. No association was observed for nitrate or total NOC intake and HCC risk. Higher consumption of HCC-inducing NOCs and positive hepatitis virus status jointly increased the risk of developing HCC.

Conclusions: In conclusion, though some of our findings may indicate the presence of reverse causation owing to lower meat intake among cases with chronic liver diseases before HCC diagnosis, the potent dietary HCC carcinogens, NDEA, NDMA, and NPIP, and their enhanced carcinogenic effects among chronic carriers of hepatitis virus warrant further prospective investigation.
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http://dx.doi.org/10.1002/hep.32046DOI Listing
July 2021

Study on Cavitation and Tribological of TiO₂ Nano-Film on Bearing Pads Surface.

J Nanosci Nanotechnol 2021 12;21(12):5906-5911

School of Electrical Engineering, Xi'an Jiaotong University, Xi'an, 710049, China.

Bearings play a vital role in the operation of a two-axis system. Long-term bearing use inevitably produce bubbles and frictional damage. Therefore, the protection of bearings is critical for the stable operation of a two-axis system. In this study, a TiO₂ nanofilm is used to physically protect a bearing. The discretization method is used to analyse the cavitation process. Cavitation primarily occurs on the front surface of the pad during bearing operation. A finite element analysis of a bearing pad coated and not coated with TiO₂ nanofilms shows that TiO₂ nanofilms can effectively absorb the cavitation force exerted on pads, thereby reducing inflicted damage. Moreover, the TiO₂ nanofilm reduces the friction coefficient of the pad surface, promoting good bearing capacity of the bearing during rotation. The TiO₂ nanofilm serves as a protective layer that improves the anti-wear and bearing performance of a two-axis system.
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http://dx.doi.org/10.1166/jnn.2021.19506DOI Listing
December 2021

[Determination of 15 lipid regulators in fish meat by QuEChERS-ultra performance liquid chromatography-quadrupole/ electrostatic field orbitrap mass spectrometry].

Se Pu 2020 Jun;38(6):655-662

Institute of Food Safety, Chinese Academy of Inspection&Quarantine, Beijing 100176, China.

An analytical method was established for the determination of 15 lipid regulators in fish meat by QuEChERS combined with ultra performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry (UPLC-Q/Orbitrap-MS). The samples were purified by optimized QuEChERS methods. The amounts of the adsorbent materials (primary secondary amine (PSA) (20, 60, 100, 140 and 180 mg), C18 (40, 100, 160, 220 and 280 mg) and sodium acetate (0.2, 0.6, 1.0, 1.4 and 1.8 g)) were optimized by the response surface method to obtain the best purification effect. The target compounds were separated on an XBridge-C18 column (100 mm×2.1 mm, 3.5 μm) using acetonitrile-0.1% (v/v) formic acid aqueous solution (containing 1.5 mmol/L ammonium acetate) as the mobile phases by a gradient elution program. Qualitative and quantitative analysis of the target compounds were performed in the full scan and secondary mass spectrometry scan (dd-MS) modes with positive and negative ionization. The target compounds showed good linear relationships in their respective ranges, with correlation coefficients () greater than 0.99. The limits of detection (LOD, =3) and limits of quantification (LOQ, =10) were in the range of 0.2-1.0 μg/kg and 0.3-3.1 μg/kg, respectively. The average recoveries were 76.4%-116.0% at LOQ, 2-fold LOQ, and 10-fold LOQ levels. The intra-day relative standard deviations (RSDs) were 1.0%-7.9%, and the inter-day RSDs were 1.7%-18.4%. The method is simple, sensitive and accurate, and it is suitable for the determination and quantification of lipid regulators in fish meat.
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http://dx.doi.org/10.3724/SP.J.1123.2019.10011DOI Listing
June 2020

Dietary Patterns and Hepatocellular Carcinoma Risk among US Adults.

Nutrients 2021 Jun 11;13(6). Epub 2021 Jun 11.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The objective of this study was to assess the association between dietary patterns and risk of hepatocellular carcinoma (HCC) among US adults in a hospital-based case-control study. We analyzed data from 641 cases and 1002 controls recruited at The University of Texas MD Anderson Cancer Center during 2001-2018. Cases were patients with a pathologically or radiologically confirmed new diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck cancer. Cases and controls were frequency-matched by age and sex. Dietary patterns were identified by principal component analysis. Odds ratios (ORs) and corresponding confidence intervals (CIs) were computed using unconditional logistic regression with adjustment for major HCC risk factors, including hepatitis B virus and hepatitis C virus infection. A vegetable-based dietary pattern was inversely associated with HCC risk (highest compared with lowest tertile: OR 0.66, 95% CI 0.46-0.94). A Western diet pattern was directly associated with HCC risk (highest compared with lowest tertile: OR 1.79, 95% CI 1.19-2.69). These findings emphasize the potential role of dietary intake in HCC prevention and clinical management.
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http://dx.doi.org/10.3390/nu13062011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230753PMC
June 2021

Clinical characterization and the improved molecular diagnosis of autosomal dominant cone-rod dystrophy in patients with SCA7.

Mol Vis 2021 7;27:221-232. Epub 2021 May 7.

Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Purpose: To evaluate the retinal phenotype and genetic features of Chinese patients with spinocerebellar ataxia type 7 (SCA7).

Methods: Detailed ophthalmic examinations, including electroretinograms, fundus photography, fundus autofluorescence and optical coherence tomography, were performed to analyse the retinal lesions of patients with SCA7. A molecular genetic analysis was completed to confirm the number of CAG repeats in gene on the patients and their family members.

Results: Eight patients from three families with SCA7 were included in this study. Trinucleotide repeat was expanded from 43 to 113 in the affected patients. The affected patients were characterized by different degrees of cone-rod dystrophy, which is positively related to the number of CAG repeats and age. All patients complained of progressive bilateral visual loss, and most cases reported visual disturbance earlier than gait movement or dysarthria. A coarse granular appearance of the macular region on scanning laser ophthalmoscopy, hypofluorescence in the macula on autofluorescence, retinal atrophy on optic coherence tomography, depression of multifocal electroretinograms and prominent abnormalities in cone-mediated responses on electrograms are the general features of SCA7-related retinopathy. Hyperreflective dots in the outer retinal layers and choroidal vessel layers are a common sign in optic coherence tomography in the advanced stage.

Conclusions: SCA7 shows a cone-rod dystrophy phenotype. The multimodal imaging of the retina is beneficial to detect the early lesions of cone-rod dystrophy related to SCA7.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116265PMC
May 2021

Sensor drift fault diagnosis for chiller system using deep recurrent canonical correlation analysis and k-nearest neighbor classifier.

ISA Trans 2021 May 5. Epub 2021 May 5.

School of Electrical and Information Engineering, Tianjin University, Nankai District, Tianjin 300072, China. Electronic address:

Early detection and diagnosis of the chiller sensor drift fault are crucial to maintain normal operation for energy saving. Due to the complex physical structure and operation conditions, sensor drift fault in the chiller system is difficult to discover. To improve the energy efficiency and operation reliability of the chiller system, this paper proposes a novel chiller sensor drift fault diagnosis method using deep recurrent canonical correlation analysis and k-nearest neighbor (KNN) classifier. A deep bidirectional long short-term memory recurrent neural network-based deep recurrent canonical correlation analysis (BLCCA) model is developed, which can automatically extract the nonlinear and temporal features from raw operation data in the chiller system. Based on the proposed BLCCA model, a residual generator is designed to generate the directional residual vector. The cumulative residual vector method is employed to improve the detectability of the sensor drift fault. An efficient KNN-based method is applied to classify the residual vector and judge the faulty sensor. Different distance measures and neighbor numbers are further analyzed to optimize the fault diagnosis performance. The proposed fault detection and diagnosis (FDD) method is validated by using a data set which has been collected from an actual chiller system. Three different state-of-the-art fault diagnosis methods are used for comparison with the proposed method. The comparisons of the experimental results demonstrate that this method achieves significant fault diagnosis performance in terms of diagnosis accuracy, recall, and F measure (F1 score).
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http://dx.doi.org/10.1016/j.isatra.2021.04.037DOI Listing
May 2021

Assembling cyanidin-3-O-glucoside by using low-viscosity alginate to improve its in vitro bioaccessibility and in vivo bioavailability.

Food Chem 2021 Sep 25;355:129681. Epub 2021 Mar 25.

College of Food and Biological Engineering, Jimei University, Xiamen, Fujian 361021, China.

In this work, an enteric soluble alginate was proposed to improve the absorption efficiency of cyanidin-3-O-glucoside (C3G) through molecular self-assembly. Under the optimized conditions, the obtained low-viscosity alginate (LVA) was released completely during the simulated gastrointestinal digestion and an LVA-C3G complex with 84.2% binding efficiency was acquired. Fourier transform infrared spectroscopy displayed that the characteristic spectrum of C3G had disappeared after the LVA conjugation. Furthermore, based on the analysis of scanning electron microscopy and differential scanning calorimetry, a porous network structure and the shifted endothermic peak in the thermograms were observed, further confirming the formation of a complex between LVA and C3G. The results of simulated gastrointestinal digestion reveal that the LVA assembly significantly (p < 0.05) improved the bioaccessibility of C3G. Correspondingly, the C3G level in mouse plasma was increased by 27.4% in the C3G-LVA group. This suggests the suitability of LVA as an oral delivery vehicle for dietary anthocyanins.
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http://dx.doi.org/10.1016/j.foodchem.2021.129681DOI Listing
September 2021

Description of a new toad of Megophrys Kuhl amp; Van Hasselt, 1822 (Amphibia: Anura: Megophryidae) from western Yunnan Province, China.

Zootaxa 2021 Mar 15;4942(3):zootaxa.4942.3.3. Epub 2021 Mar 15.

CAS Key Laboratory of Mountain Ecological Restoration and Bioresource Utilization Ecological Restoration Biodiversity Conservation Key Laboratory of Sichuan Province, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China University of Chinese Academy of Sciences, Beijing 100049, China.

A new species of genus Megophrys from Gaoligong Mountains, Yunnan Province, China is described. Phylogenetic analyses based on mitochondrial DNA and nuclear DNA all clustered the new species as an independent clade nested into the subgenus Panophrys. The smallest genetic distance based on 16S rRNA gene between the new species and its congeners was 3.0%. The new species could be identified from its congeners by a combination of following characters: moderate body size (SVL 31.0-34.8 mm in males); vomerine ridge weak, vomerine teeth absent; dorsal skin relatively smooth; tongue slightly notched behind; tympanum rounded and relatively large, 0.54 times of eye length; a horn-like tubercle on edge of each upper eyelid small; tibio-tarsal articulation reaches middle eye when leg stretched forward; finger tips rounded, not expanded to small pad; toes with narrow fringes and rudimentary webbing; ventral hindlimbs semitransparent purplish with greyish white pigments; ventral body scattered with distinct dark patches in the middle.
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http://dx.doi.org/10.11646/zootaxa.4942.3.3DOI Listing
March 2021

Application of counter-selectable marker PIGA in engineering designer deletion cell lines and characterization of CRISPR deletion efficiency.

Nucleic Acids Res 2021 03;49(5):2642-2654

Institute for Systems Genetics and Department of Biochemistry & Molecular Pharmacology, NYU Langone Health, New York, NY 10016, USA.

The CRISPR/Cas9 system is a technology for genome engineering, which has been applied to indel mutations in genes as well as targeted gene deletion and replacement. Here, we describe paired gRNA deletions along the PIGA locus on the human X chromosome ranging from 17 kb to 2 Mb. We found no compelling linear correlation between deletion size and the deletion efficiency, and there is no substantial impact of topologically associating domains on deletion frequency. Using this precise deletion technique, we have engineered a series of designer deletion cell lines, including one with deletions of two X-chromosomal counterselectable (negative selection) markers, PIGA and HPRT1, and additional cell lines bearing each individual deletion. PIGA encodes a component of the glycosylphosphatidylinositol (GPI) anchor biosynthetic apparatus. The PIGA gene counterselectable marker has unique features, including existing single cell level assays for both function and loss of function of PIGA and the existence of a potent counterselectable agent, proaerolysin, which we use routinely for selection against cells expressing PIGA. These designer cell lines may serve as a general platform with multiple selection markers and may be particularly useful for large scale genome engineering projects such as Genome Project-Write (GP-write).
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http://dx.doi.org/10.1093/nar/gkab035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969003PMC
March 2021

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Cancer Res 2021 06 11;81(11):3134-3143. Epub 2021 Feb 11.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and < 5 × 10 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, = 3.08 × 10). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178175PMC
June 2021

Nitrate removal from low C/N wastewater at low temperature by immobilized Pseudomonas sp. Y39-6 with versatile nitrate metabolism pathways.

Bioresour Technol 2021 Apr 2;326:124794. Epub 2021 Feb 2.

Key Laboratory of Functional Inorganic Material Chemistry, Heilongjiang University, Harbin 150080, China.

For solving the challenge in nitrate removal from low C/N wastewater at low temperature, Pseudomonas sp. Y39-6 was isolated and used in nitrate removal. It showed aerobic-heterotrophic denitrification with rate of 1.77 ± 0.31 mg/L·h and unusual aerobic-autotrophic nitrate removal (rate of 0.324 mg/L·h). The aerobic-autotrophic nitrate removal mechanisms were deep investigated by analyzing the nitrate removal process and genomic information. At aerobic-autotrophic condition, the strain Y39-6 could assimilate nitrate to amino acid (NO + PHA + CO → CHON) with the carbon source from Polyhydroxyalkanoic acid (PHA) degradation and CO fixation. Flagella motivation, swarming activity and extracellular polymeric substances (EPS) production regulated Pseudomonas sp. Y39-6 forming biofilm. Carriers immobilized with Pseudomonas sp. Y39-6 were used in moving bed biofilm reactor (MBBR) and achieved 24.83% nitrate removal at C/N < 1 and 4 °C. Results of this study provided a practical way for nitrogen removal from low C/N wastewater in cold region.
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http://dx.doi.org/10.1016/j.biortech.2021.124794DOI Listing
April 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 02 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Eur Urol Oncol 2021 Aug 9;4(4):570-579. Epub 2021 Jan 9.

Institute of Biomedicine, University of Turku, Turku, Finland.

Background: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.

Objective: To precisely estimate the contribution of germline ATM mutations to PrCa risk.

Design, Setting, And Participants: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.

Outcome Measurements And Statistical Analysis: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.

Results And Limitations: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).

Conclusions: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.

Patient Summary: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
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http://dx.doi.org/10.1016/j.euo.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381233PMC
August 2021

Association of Serum Bile Acids Profile and Pathway Dysregulation With the Risk of Developing Diabetes Among Normoglycemic Chinese Adults: Findings From the 4C Study.

Diabetes Care 2021 02 18;44(2):499-510. Epub 2020 Dec 18.

The First Hospital of Jilin University, Changchun, China

Objective: Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults.

Research Design And Methods: We tested 23 serum BA species in subjects with incident diabetes ( = 1,707) and control subjects ( = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios (ORs) for associations of BAs with T2DM were estimated using conditional logistic regression.

Results: In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with an OR (95% CI) of 0.89 (0.83-0.96) for cholic acid, 0.90 (0.84-0.97) for chenodeoxycholic acid, and 0.90 (0.83-0.96) for deoxycholic acid ( < 0.05 and false discovery rate <0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19 (95% CIs ranging between 1.05 and 1.28). In a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset.

Conclusions: These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.
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http://dx.doi.org/10.2337/dc20-0884DOI Listing
February 2021

Coagulopathy of Patients with COVID-19 is Associated with Infectious and Inflammatory Markers.

Risk Manag Healthc Policy 2020 7;13:1965-1975. Epub 2020 Oct 7.

Department of Intensive Care Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.

Background: SARS-CoV-2 infection activates coagulation and stimulates innate immune system. Little is known about coagulopathy and response of inflammation and infection in ICU patients with COVID-19. Derangement of coagulation and markers of infection and inflammation induced by SARS-CoV-2 infection, as well as their correlations were elucidated.

Methods: One hundred eight ICU patients with COVID-19 (28 survivors and 80 non-survivors) in Tongji hospital and Wuhan Jinyintan hospital, in Wuhan, China were included. Coagulation parameters, infectious and inflammatory markers were dynamically analysed. The correlation between coagulopathy of patients and infectious and inflammatory markers was verified.

Results: SARS-CoV-2-associated coagulopathy occurred in most cases of critical illness. Raised values of d-dimer and FDP were measured in all patients, especially in non-survivors, who had longer PT, APTT, INR, as well as TT, and lower PTA and AT compared to survivors. SIC and DIC mostly occurred in non-survivors. CRP, ESR, serum ferritin, IL-8, and IL-2R increased in all patients, and were much higher in non-survivors who had significantly higher levels of IL-6 and IL-10. D-dimer was positively associated with CRP, serum ferritin ( = 0.02), PCT ( < 0.001), and IL-2R ( = 0.007). SIC scores were positively correlated with CRP ( = 0.006), PCT ( = 0.0007), IL-1β ( = 0.048), and IL-6 ( = 0.009). DIC scores were positively associated with CRP ( < 0.0001), ESR ( = 0.02), PCT ( < 0.0001), serum ferritin ( < 0.0001), IL-10 ( = 0.02), and IL-2R ( = 0.0005).

Conclusion: Prothrombotic state, SIC, and DIC are the characteristics of coagulation in ICU patients with COVID-19. CRP, ESR, serum ferritin, IL-8, IL-2R, IL-6, and PCT were stimulated by SARS-CoV-2 infection. CRP, PCT, serum ferritin, and IL-2R indicate the coagulopathy severity of patients with COVID-19.
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http://dx.doi.org/10.2147/RMHP.S268238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548327PMC
October 2020

Optical Coherence Tomography Parameters Related to Vision Impairment in Patients with Diabetic Macular Edema: A Quantitative Correlation Analysis.

J Ophthalmol 2020 27;2020:5639284. Epub 2020 Sep 27.

Department of Ophthalmology, Peking Union Medical College Hospital, Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences, Beijing, China.

Purpose: To quantitatively explore the correlation between optical coherence tomography (OCT) parameters and vision impairment in patients with diabetic macular edema (DME).

Methods: This study was a retrospective observational case series. One-hundred eyes from 66 patients with DME were retrospectively included. OCT parameters, including central macular thickness (CMT), height of intraretinal cystoid, subretinal fluid and sponge-like retinal swelling, density of hyperreflective foci (HRF), and integrity of the ellipsoidal zone (EZ), were assessed. Correlation analyses and multiple linear regression analysis were performed to quantitatively explore the relationship between best-corrected visual acuity (BCVA) and OCT parameters.

Results: Among all OCT parameters, CMT, height of intraretinal cystoid, height of sponge-like retinal swelling, and density of HRF and EZ integrity were significantly correlated with BCVA ( = -0.550, -0.526, -0.411, -0.277, and -0.501, respectively; < 0.01). In multiple linear regression analysis, CMT, density of HRF, and EZ integrity fit a significant linear equation ( = 0.482, 0.184, and 0.447, respectively), with the adjusted square reaching 0.522 ( < 0.001). In eyes without SRF, the height of intraretinal cystoid, density of HRF, and EZ integrity were included in the model and an adjusted square of 0.605 ( < 0.001) was obtained.

Conclusion: In DME eyes, OCT parameters, including the density of HRF, the EZ integrity together with CMT, or the height of intraretinal cystoid, could explain 52.2% to 60.5% of the variation in BCVA and were weighted approximately 2 : 1 : 2, respectively.
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http://dx.doi.org/10.1155/2020/5639284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537709PMC
September 2020

CircRNA ITCH increases bortezomib sensitivity through regulating the miR-615-3p/PRKCD axis in multiple myeloma.

Life Sci 2020 Dec 5;262:118506. Epub 2020 Oct 5.

Ultrasound Department, The First Affiliated Hospital of Henan University, Kaifeng, Henan, China. Electronic address:

Aims: Bortezomib (BTZ) is described as the first-line agent for multiple myeloma (MM) chemotherapy, but the emergence of BTZ resistance usually results in the failure of chemotherapy in MM. Circular RNA (circRNA) itchy E3 ubiquitin protein ligase (circITCH) is a novel identified circRNA that plays a vital role in the development of human cancers. However, the role of circITCH in the development of BTZ resistance in MM remains elusive.

Materials And Methods: The expression of circITCH, miR-615-3p, and protein kinase C, delta (PRKCD) was detected with quantitative reverse transcription PCR and western blot. The effects of circITCH on the sensitivity of MM cells to BTZ were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, flow cytometry, and xenograft tumor assay. The interaction of circITCH, microRNA-615-3p, and PRKCD was explored using luciferase reporter assay and RNA immunoprecipitation assay.

Key Findings: circITCH was downregulated in MM bone marrow specimens and cell lines, as well as BTZ-resistant MM cells. Reduced expression of circITCH was indicative of poor prognosis in MM patients. Upregulation of circITCH enhanced the sensitivity of BTZ-resistant MM cells to BTZ in vitro and in vivo. Furthermore, circITCH was identified as a sponge for miR-615-3p, and PRKCD is confirmed as a direct target of miR-615-3p. Besides, circITCH overexpression enhanced the sensitivity of MM cells to BTZ through miR-615-3p/PRKCD axis.

Significance: circITCH overexpression enhanced the sensitivity of MM cells to BTZ through miR-615-3p/PRKCD axis, providing a novel potential target for combating BTZ resistance in patients with MM.
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http://dx.doi.org/10.1016/j.lfs.2020.118506DOI Listing
December 2020

Mechanisms of M2 Macrophage-Derived Exosomal Long Non-coding RNA PVT1 in Regulating Th17 Cell Response in Experimental Autoimmune Encephalomyelitisa.

Front Immunol 2020 4;11:1934. Epub 2020 Sep 4.

School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei, China.

Long non-coding RNA (lncRNA) is pivotal for multiple sclerosis (MS), but the potential mechanism of lncRNA PVT1 in MS animal model, experimental autoimmune encephalomyelitis (EAE) still remains unclear. In this study, macrophages were firstly isolated and induced to polarize into M2 macrophages. M2 macrophage-derived exosomes (M2-exos) were extracted and identified, and EAE mouse model was established and treated with M2-exos. The effect of M2-exos on EAE mice was evaluated by clinical scores. The proportion of Treg and Th17 cells in spinal cord cells and splenocytes, and levels of inflammatory factors were measured. The targeting relationships among PVT1, miR-21-5p, and SOCS5 were verified. The expression of JAKs/STAT3 pathway-related proteins was measured. After M2-exo treatment, the clinical score of EAE mice decreased, and demyelination and inflammatory infiltration improved; Th17 cells decreased, Treg cells increased, and the levels of inflammatory factors decreased significantly. SOCS5 and PVT1 were downregulated and miR-21-5p was upregulated in EAE mice. PVT1 could sponge miR-21-5p to regulate SOCS5. SOCS5 alleviated EAE symptoms by repressing the JAKs/STAT3 pathway. Together, M2-exos-carried lncRNA PVT1 sponged miR-21-5p to upregulate SOCS5 and inactivate the JAKs/STAT3 pathway, thus reducing inflammation and protecting EAE mice. This study may offer novel treatments for MS.
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http://dx.doi.org/10.3389/fimmu.2020.01934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500097PMC
April 2021

Hydrolyzed peptides from purple perilla (Perilla frutescens L. Britt.) seeds improve muscle synthesis and exercise performance in mice.

J Food Biochem 2020 11 28;44(11):e13461. Epub 2020 Sep 28.

School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China.

The purple perilla (Perilla frutescens L. Britt.) seed peptides (PPSP) were obtained and their improvement of muscle synthesis and exercise performance was investigated in this work. Results showed that the weight-average molecular weight of the PPSP was 869 Dalton. The PPSP were rich in branched-chain amino acids (18.82 g/100 g) and anti-fatigue amino acids, including glutamate (Glu), aspartic acid (Asp), and arginine (Arg). After the administration of PPSP at 1.2 g kg  day for 4 weeks, the muscle coefficient and muscle fiber thickness in mice displayed a distinct (p < .05) increase via the upregulation of myogenic differentiation (MyoD) and myogenin (MyoG). The improved muscle strength and exercise tolerance were also observed. Simultaneously, the levels of the biochemical blood markers associated with fatigue and the glycogen degradation in liver and muscle were significantly (p < .05) suppressed. These results suggested that PPSP could effectively promote muscle synthesis and ameliorate exercise fatigue. PRACTICAL APPLICATIONS: Purple perilla is an annual herbal plant and widely grown in Asian countries as an important crop and food. It is believed that the protein content of purple perilla seeds can reach 23.7%, and the protein is rich in essential amino acids. However, the information about the beneficial effects of their proteins or peptides on muscle synthesis and anti-exercise fatigue were still limited. The present results discovered that the PPSP can effectively promote the growth of muscle tissue and improve exercise tolerance. It is indicated that PPSP may have a potential application value in partly or completely replacing animal proteins such as whey protein.
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http://dx.doi.org/10.1111/jfbc.13461DOI Listing
November 2020

HepatoScore-14: Measures of Biological Heterogeneity Significantly Improve Prediction of Hepatocellular Carcinoma Risk.

Hepatology 2021 Jun 15;73(6):2278-2292. Epub 2021 Jun 15.

Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX.

Background And Aims: Therapeutic, clinical trial entry and stratification decisions for hepatocellular carcinoma (HCC) are made based on prognostic assessments, using clinical staging systems based on small numbers of empirically selected variables that insufficiently account for differences in biological characteristics of individual patients' disease.

Approach And Results: We propose an approach for constructing risk scores from circulating biomarkers that produce a global biological characterization of individual patient's disease. Plasma samples were collected prospectively from 767 patients with HCC and 200 controls, and 317 proteins were quantified in a Clinical Laboratory Improvement Amendments-certified biomarker testing laboratory. We constructed a circulating biomarker aberration score for each patient, a score between 0 and 1 that measures the degree of aberration of his or her biomarker panel relative to normal, which we call HepatoScore. We used log-rank tests to assess its ability to substratify patients within existing staging systems/prognostic factors. To enhance clinical application, we constructed a single-sample score, HepatoScore-14, which requires only a subset of 14 representative proteins encompassing the global biological effects. Patients with HCC were split into three distinct groups (low, medium, and high HepatoScore) with vastly different prognoses (medial overall survival 38.2/18.3/7.1 months; P < 0.0001). Furthermore, HepatoScore accurately substratified patients within levels of existing prognostic factors and staging systems (P < 0.0001 for nearly all), providing substantial and sometimes dramatic refinement of expected patient outcomes with strong therapeutic implications. These results were recapitulated by HepatoScore-14, rigorously validated in repeated training/test splits, concordant across Myriad RBM (Austin, TX) and enzyme-linked immunosorbent assay kits, and established as an independent prognostic factor.

Conclusions: HepatoScore-14 augments existing HCC staging systems, dramatically refining patient prognostic assessments and therapeutic decision making and enrollment in clinical trials. The underlying strategy provides a global biological characterization of disease, and can be applied broadly to other disease settings and biological media.
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http://dx.doi.org/10.1002/hep.31555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956911PMC
June 2021

Bayesian copy number detection and association in large-scale studies.

BMC Cancer 2020 Sep 7;20(1):856. Epub 2020 Sep 7.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging due to biological and technical sources of heterogeneity that vary across the genome within and between samples.

Methods: We developed an approach called CNPBayes to identify latent batch effects in genome-wide association studies involving copy number, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease.

Results: Applying a hidden Markov model (HMM) to identify CNVs in a large multi-site Pancreatic Cancer Case Control study (PanC4) of 7598 participants, we found CNV inference was highly sensitive to technical noise that varied appreciably among participants. Applying CNPBayes to this dataset, we found that the major sources of technical variation were linked to sample processing by the centralized laboratory and not the individual study sites. Modeling the latent batch effects at each CNV region hierarchically, we developed probabilistic estimates of copy number that were directly incorporated in a Bayesian regression model for pancreatic cancer risk. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Suppressor Candidate 3 (TUSC3).

Conclusions: Laboratory effects may not account for the major sources of technical variation in genome-wide association studies. This study provides a robust Bayesian inferential framework for identifying latent batch effects, estimating copy number, and evaluating the role of copy number in heritable diseases.
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http://dx.doi.org/10.1186/s12885-020-07304-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487704PMC
September 2020

Incorporating multiple sets of eQTL weights into gene-by-environment interaction analysis identifies novel susceptibility loci for pancreatic cancer.

Genet Epidemiol 2020 11 10;44(8):880-892. Epub 2020 Aug 10.

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

It is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene-by-environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data-adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case-Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome-wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking-related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.
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http://dx.doi.org/10.1002/gepi.22348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657998PMC
November 2020

Antibacterial Activity of Sulfated Galactans from and against Diarrheagenic via the Disruption of the Cell Membrane Structure.

Mar Drugs 2020 Jul 29;18(8). Epub 2020 Jul 29.

School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, Zhejiang, China.

Seaweed sulfated polysaccharides have attracted significant attention due to their antibacterial activity. This work investigated the antibacterial activity and mechanism of depolymerized sulfated galactans from () and () against enterotoxigenic (ETEC) K88. The results show that removing the metal ions improves the anti-ETEC K88 activity of the galactans. The fluorescence labeling study confirmed that the sulfated galactans penetrated the cell walls and eventually reached the interior of the ETEC K88. Nucleic acid staining and intracellular protein leakage were also observed, indicating the destruction of permeability and integrity of the cell membrane. Interestingly, the two polysaccharides exhibited no effect on the proliferation of the selected Gram-positive bacteria and yeast. This indicates that the cell wall structure of the microorganisms could influence the bacteriostatic activity of the sulfated polysaccharides, as well. These results suggest that the sulfated seaweed polysaccharides might have potential application value in antibacterial diarrhea.
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http://dx.doi.org/10.3390/md18080397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459719PMC
July 2020
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