Publications by authors named "Yu Huang"

1,725 Publications

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EGR1 promoted anticancer effects of Scutellarin via regulating LINC00857/miR-150-5p/c-Myc in osteosarcoma.

J Cell Mol Med 2021 Aug 4. Epub 2021 Aug 4.

The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.

Scutellarin, an active flavone extracted from Erigeron breviscapus, is known to exhibit antitumour activity in many cancers. However, the effects of Scutellarin on osteosarcoma remain unclear. In this study, we found that Scutellarin suppressed osteosarcoma cell growth, induced cell apoptosis and inhibited tumorigenesis. Mechanistically, our data revealed that EGR1 was significantly increased under Scutellarin treatment. Increased EGR1 enhanced tumour-suppressive effects of Scutellarin on osteosarcoma cells via transcriptionally downregulating LINC00857 expression. Additionally, we found that LINC00857 acted as a competitive endogenous RNA of miR-150-5p and inhibited the activity of miR-150-5p, which resulted in c-Myc increase. Scutellarin could suppress c-Myc protein levels through decreasing LINC00857 expression in osteosarcoma. Thus, these findings demonstrate that EGR1/ LINC00857/miR-150-5p/c-Myc axis plays a key role in promoting anticancer effects of Scutellarin and Scutellarin might have potential clinical implication in osteosarcoma clinical treatment.
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http://dx.doi.org/10.1111/jcmm.16809DOI Listing
August 2021

Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis.

Redox Biol 2021 Jul 26;46:102082. Epub 2021 Jul 26.

Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address:

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where succinate dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of succinate dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and succinate dehydrogenase is an exciting new therapeutic target to treat IPF.
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http://dx.doi.org/10.1016/j.redox.2021.102082DOI Listing
July 2021

A chromosome-level genome assembly of the striped catfish (Pangasianodon hypophthalmus).

Genomics 2021 Jul 31. Epub 2021 Jul 31.

BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China; Shenzhen Key Lab of Marine Genomics, Guangdong Provincial Key Lab of Molecular Breeding in Marine Economic Animals, BGI Academy of Marine Sciences, BGI Marine, BGI, Shenzhen 518083, China. Electronic address:

Striped catfish (Pangasianodon hypophthalmus), belonging to the Pangasiidae family, has become an economically important fish with wide cultivation in Southeast Asia. Owing to the high-fat trait, it is always considered as an oily fish. In our present study, a high-quality genome assembly of the striped catfish was generated by integration of Illumina short reads, Nanopore long reads and Hi-C data. A 731.7-Mb genome assembly was finally obtained, with a contig N50 of 3.5 Mb, a scaffold N50 of 29.5 Mb, and anchoring of 98.46% of the assembly onto 30 pseudochromosomes. The genome contained 36.9% repeat sequences, and a total 18,895 protein-coding genes were predicted. Interestingly, we identified a tandem triplication of fatty acid binding protein 1 gene (fabp1; thereby named as fabp1-1, fabp1-2 and fabp1-3 respectively), which may be related to the high fat content in striped catfish. Meanwhile, the FABP1-2 and -3 isoforms differed from FABP1-1 by several missense mutations including R126T, which may affect the fatty acid binding properties. In summary, we report a high-quality chromosome-level genome assembly of the striped catfish, which provides a valuable genetic resource for biomedical studies on the high-fat trait, and lays a solid foundation for practical aquaculture and molecular breeding of this international teleost species.
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http://dx.doi.org/10.1016/j.ygeno.2021.07.026DOI Listing
July 2021

Triformyl cholic acid and folic acid functionalized magnetic graphene oxide nanocomposites: Multiple-targeted dual-modal synergistic chemotherapy/photothermal therapy for liver cancer.

J Inorg Biochem 2021 Jul 22;223:111558. Epub 2021 Jul 22.

Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China. Electronic address:

Photo-chemotherapy (PCT) reveals great potential in hepatocellular carcinoma (HCC) treatment, therefore the construct of smart PCT nano-agents with high photothermal conversion efficiency and accurate drug delivery is of great significant. Herein, a novel hybrid nanomaterial MGO-TCA-FA has been designed and constructed by grafting the triformyl cholic acid (TCA) and folic acid (FA) on the surface of FeO modified graphene oxide (MGO). The doxorubicin hydrochloride (DOX) as a model drug could be effectively loaded on the MGO-TCA-FA via hydrogen bonding and π-π stacking (the drug loading amount was 1040 mg/g). The formed [email protected] has been developed to be an effective PCT nanoplatform with the advantages of multiple-targeted drug delivery, near-infrared light (NIR) and pH triggered drug release, and photothermal conversion efficiency. In vitro experiments showed that compared with other cancer cells and normal liver cells, [email protected] could specifically target liver cancer cells and presented significant killing ability to liver cancer cells. More importantly, in vivo experiments indicated that PCT synergistic therapy ([email protected]) revealed the best tumor inhibition (the tumor inhibition rate was about 85%) compared with chemotherapy and photothermal therapy alone. Thus, this study supplied a viable multiple-targeted PCT nano-agent for chemo-photothermal combination therapy of liver cancer.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111558DOI Listing
July 2021

The mechanisms of renin-angiotensin system in hepatocellular carcinoma: From the perspective of liver fibrosis, HCC cell proliferation, metastasis and angiogenesis, and corresponding protection measures.

Biomed Pharmacother 2021 Jul 14;141:111868. Epub 2021 Jul 14.

Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China; Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui 230032, China. Electronic address:

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, of which the occurrence and development involve a variety of pathophysiological processes, such as liver fibrosis, hepatocellular malignant proliferation, metastasis, and tumor angiogenesis. Some important cytokines, such as TGF-β, PI3K, protein kinase B (Akt), VEGF and NF-κB, can regulate the growth, proliferation, diffusion, metastasis, and apoptosis of HCC cells by acting on the corresponding signaling pathways. Besides, many studies have shown that the formation of HCC is closely related to the main components of renin-angiotensin system (RAS), such as Ang II, ACE, ACE2, MasR, AT1R, and AT2R. Therefore, this review focused on liver fibrosis, HCC cell proliferation, metastasis, tumor angiogenesis, and corresponding protective measures. ACE-Ang II-AT1 axis and ACE2-Ang-(1-7)-MasR axis were taken as the main lines to introduce the mechanism of RAS in the occurrence and development of HCC, so as to provide references for future clinical work and scientific research.
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http://dx.doi.org/10.1016/j.biopha.2021.111868DOI Listing
July 2021

Berberine Reverses Nitroglycerin Tolerance through Suppressing Protein Kinase C Alpha Activity in Vascular Smooth Muscle Cells.

Cardiovasc Drugs Ther 2021 Jul 28. Epub 2021 Jul 28.

Shenzhen Research Institute, Heart and Vascular Institute, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, 999077, China.

Purpose: The aim of this study was to evaluate the effects of berberine on nitroglycerin (NTG) tolerance and explore the underlying mechanism involved.

Methods: NTG tolerance was induced by pre-exposure of Sprague-Dawley rat aortas to NTG in vitro or by pretreating Sprague-Dawley rats with an NTG patch in vivo. The aortas were pre-treated with berberine or PKC inhibitors for different durations of time before induction of NTG tolerance. NTG-induced vasorelaxations was measured on wire myograph. Primary vascular smooth cells (VSMCs) were used to dissect the underlying mechanism of berberine-induced inhibition of NTG tolerance.

Results: NTG tolerance induced by either prior exposure of rat aortas to NTG in vitro or pretreatment with an NTG patch in vivo was reversed by co-treatment with berberine, as well as the inhibitors of protein kinase C (PKC) and protein kinase C alpha (PKCα). The mechanistic study revealed that PKCα participated in the development of NTG tolerance as NTG increased the activity of PKCα with enriched PKCα membrane localization and elevated phosphorylation of PKCα in VSMCs, which was reversed by berberine or PKCα inhibitors.

Conclusion: This study is probably the first demonstration that berberine reverses NTG tolerance through inhibiting PKCα activity in VSMCs and PKCα is an important contributor to the development of NTG tolerance. These new findings suggest that berberine could become a promising drug for prevention of NTG tolerance and that targeting PKCα in VSMCs is likely to be a potential therapeutic strategy for reversal of NTG tolerance in blood vessels.
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http://dx.doi.org/10.1007/s10557-021-07193-zDOI Listing
July 2021

[Abdominal free flap carrying bilateral superficial circumflex iliac arteries for repairing large skin and soft tissue defects of foot and ankle].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2021 Jul;35(7):886-890

Department of Hand Surgery, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou Sichuan, 646000, P.R.China.

Objective: To investigate the effectiveness of abdominal free flap carrying bilateral superficial circumflex iliac arteries for repairing large skin and soft tissue defects of foot and ankle.

Methods: Between June 2016 and June 2019, 15 patients with large skin and soft tissue defects of foot and ankle were admitted, including 10 males and 5 females with an average age of 30 years (range, 10-60 years). The causes of injury included 6 cases of traffic accident, 3 cases of machine strangulation, 3 cases of heavy object injury, 2 cases of fall, and 1 case of electric shock. The time from injury to admission was 3 hours to 10 days, with an average of 2 days. The wound located at dorsal foot in 5 cases, ankle in 6 cases, dorsal foot and ankle in 3 cases, and dorsal foot and sole in 1 case. All wounds were contaminated to varying degrees and accompanied by tendon and bone exposure, including 5 cases of extensive necrosis of the dorsal skin with infection. The area of defects ranged from 18 cm×6 cm to 25 cm×8 cm. There were 9 cases of foot and ankle fractures and dislocations, and 2 cases of foot and ankle bone defects. The wound was repaired with abdominal free flap carrying bilateral superficial circumflex iliac arteries. The area of the flaps ranged from 20 cm×8 cm to 27 cm×10 cm; the skin flaps were thinned under the microscope to make the thickness of 0.5-1.0 cm, with an average of 0.7 cm. All incisions at the donor site were sutured directly.

Results: During the operation, 1 case was replaced with an abdominal free flap carrying the superficial abdominal artery because the superficial iliac circumflex artery was thin and the superficial abdominal artery was thicker. The skin flaps of 15 cases survived smoothly, and the wounds healed by first intention; the donor incisions all healed by first intention. All patients were followed up 8-36 months, with an average of 15 months. The flap shape was satisfactory, with good texture and mild pigmentation of the flap edge, without obvious bloating, effect on shoe wear, or secondary surgical thinning of the flap. The linear scar left in the donor site and had no effect on hip joint movement. All fractures healed well, and the healing time ranged from 3 to 8 months, with an average of 6 months.

Conclusion: The abdominal free flap carrying bilateral superficial iliac circumflex arteries has concealed donor site, with little damage, and can be sutured in one stage. The blood vessel is anatomically constant, with less variation, and reliable blood supply. It is one of the ideal flaps for repairing large skin and soft tissue defects of foot and ankle.
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http://dx.doi.org/10.7507/1002-1892.202103023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311202PMC
July 2021

Pilot-scale evaluation of partial denitrification/anammox on nitrogen removal from low COD/N real sewage based on a modified process.

Bioresour Technol 2021 Oct 16;338:125580. Epub 2021 Jul 16.

National Engineering Laboratory for Advanced Municipal Wastewater Treatment and Reuse Technology, Engineering Research Center of Beijing, Beijing University of Technology, Beijing 100124, PR China. Electronic address:

The nitrogen removal performance of a pilot-scale biosystem was significantly improved via partial denitrification/anammox (PD/A) in real sewage with low COD/N ratio. The modified pilot plant was designed as an anaerobic/anoxic/oxic (AAO) reactor combined with a biological aerated filter. The inoculation of biocarriers into anaerobic and anoxic zones enhanced anammox and the nitrogen removal performance. Despite a COD/N ratio of 3.1, effluent total inorganic nitrogen decreased from 17.1 to 9.8 mg N/L. The anoxic unit developed as the PD/A hotspot, which was associated with the enrichment of Ca. Brocadia (2.00%) and partial denitrification functional groups (OLB14, 13.50%; Thauera, 5.45%) in the anoxic-carrier biofilms and contributed 34.1% towards total nitrogen removal. Besides improving the PD/A process, enhanced denitrifying dephosphatation was simultaneously realized, suggesting that the integration of PD/A into this modified system is a promising approach to enhance nutrient removal of low COD/N wastewater.
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http://dx.doi.org/10.1016/j.biortech.2021.125580DOI Listing
October 2021

Advanced nitrogen removal from low C/N municipal wastewater by combining partial nitrification-anammox and endogenous partial denitrification-anammox (PN/A-EPD/A) process in a single-stage reactor.

Bioresour Technol 2021 Jul 5;339:125501. Epub 2021 Jul 5.

National Engineering Laboratory for Advanced Municipal Wastewater Treatment and Reuse Technology, Engineering Research Center of Beijing, Beijing University of Technology, Beijing 100124, China. Electronic address:

In this study, an innovative partial nitrification-anammox (PN/A) and endogenous partial denitrification-anammox (EPD/A) process was developed in a single-stage integrated fixed film activated sludge sequencing batch reactor (IFAS-SBR) treating real municipal wastewater with C/N ratio below 3.2. Enhanced efficiency of total nitrogen (TN) removal reached 90.1% with low HRT of 12 h and DO of 0.4 ± 0.1 mg/L. Detailed nitrogen removal mechanism analysis of typical cycle revealed that 89.9% of TN was eliminated through anammox pathway. Anammox bacteria (Candidatus Brocadia) and endogenous denitrifying bacteria (Candidatus Competibacter) were abundant both in biofilms and suspended sludge, meanwhile ammonium-oxidizing bacteria has outcompeted nitrite-oxidizing bacteria, which all favored the synergistic effect of anammox with PN and EPD and contributed to the improvement of nitrogen removal. Overall, the above results confirmed that combined PN/A and EPD/A process is a reliable and efficient alternative for mainstream anammox process.
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http://dx.doi.org/10.1016/j.biortech.2021.125501DOI Listing
July 2021

Hemopexin as an acute phase protein regulates the inflammatory response against bacterial infection of Nile tilapia (Oreochromis niloticus).

Int J Biol Macromol 2021 Jul 21;187:166-178. Epub 2021 Jul 21.

School of Life Sciences, South China Normal University, Institute of Modern Aquaculture Science and Engineering, Guangdong Provincial Key Laboratory for Healthy and Safe Aquaculture, Guangzhou 510631, PR China. Electronic address:

Hemopexin, a high affinity heme-binding protein is widely involved in variety physiological and pathological processes. It is an important acute phase response protein, and is important in regulating the inflammatory response. In this study, the open reading frame of Nile tilapia hemopexin (OnHpx) gene was amplified. The expression pattern of OnHpx in natural and bacterial challenged tilapia tissues were analyzed through RT-qPCR. The results indicated the OnHpx was most abundant in liver, and increased significantly in liver, spleen, head kidney and peripheral blood after bacterial challenge. Furthermore, the OnHpx mRNA was also significantly up-regulated in monocytes/macrophages and hepatocytes under the stimulation of S. agalactiae or A. hydrophila. In addition, the recombinant OnHpx protein could effectively reduce the bacteria proliferation and alleviate the inflammatory reaction caused by bacteria. Moreover, the (r)OnHpx also regulated the respiratory burst of monocytes/macrophages and played an important role in the antioxidant process. To our knowledge, these results provide the first evidence on the antibacterial and anti-inflammatory response mechanism of Hpx in early vertebrates. This brings new insights about the understanding of the evolutionary origins and ancient roles of the Hpx in the innate immune defense.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.07.109DOI Listing
July 2021

A Novel Luminescent "Nanochip" as a Tandem Catalytic System for Chemiluminescent Detection of Sweat Glucose.

Anal Chem 2021 Aug 22;93(30):10593-10600. Epub 2021 Jul 22.

National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, China.

Accurate sweat glucose detection is a promising alternative to invasive finger-prick blood tests, allowing for self-monitoring of blood glucose with good patient compliance. In this study, we have developed a tandem catalytic system, termed as a luminescent "nanochip" (LAON), which was composed of gold nanoparticles (AuNPs) and -(aminobutyl)--(ethylisoluminol) (ABEI)-engineered oxygen-doped carbon nitride (O-g-CN), for chemiluminescent detection of sweat glucose. The LAON exhibits dual catalytic activity of glucose oxidase and peroxidase and can not only oxidize glucose to generate HO but catalyze HO-mediated luminol chemiluminescence, resulting in sensitive detection of glucose. We identify that the LAON can precisely detect glucose with a detection limit of 0.1 μM, enabling us to measure glucose levels in different biological samples. Particularly, the LAON is capable of sensitively and accurately monitoring dynamic changes in sweat glucose during exercise. Therefore, the LAON provides an alternative approach to supersede invasive blood tests and may improve the management of diabetes mellitus.
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http://dx.doi.org/10.1021/acs.analchem.1c01798DOI Listing
August 2021

MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes.

Nat Commun 2021 07 20;12(1):4427. Epub 2021 Jul 20.

NHC Key Laboratory of Systems Biology of Pathogens and Center for AIDS Research, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

The membrane-associated RING-CH (MARCH) proteins are E3 ligases that regulate the stability of various cellular membrane proteins. MARCH8 has been reported to inhibit the infection of HIV-1 and a few other viruses, thus plays an important role in host antiviral defense. However, the antiviral spectrum and the underlying mechanisms of MARCH8 are incompletely defined. Here, we demonstrate that MARCH8 profoundly inhibits influenza A virus (IAV) replication both in vitro and in mice. Mechanistically, MARCH8 suppresses IAV release through redirecting viral M2 protein from the plasma membrane to lysosomes for degradation. Specifically, MARCH8 catalyzes the K63-linked polyubiquitination of M2 at lysine residue 78 (K78). A recombinant A/Puerto Rico/8/34 virus carrying the K78R M2 protein shows greater replication and more severe pathogenicity in cells and mice. More importantly, we found that the M2 protein of the H1N1 IAV has evolved to acquire non-lysine amino acids at positions 78/79 to resist MARCH8-mediated ubiquitination and degradation. Together, our data support the important role of MARCH8 in host anti-IAV intrinsic immune defense by targeting M2, and suggest the inhibitory pressure of MARCH8 on H1N1 IAV transmission in the human population.
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http://dx.doi.org/10.1038/s41467-021-24724-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292393PMC
July 2021

CAMK2/CaMKII activates MLKL in short-term starvation to facilitate autophagic flux.

Autophagy 2021 Jul 20:1-19. Epub 2021 Jul 20.

Department of Integrative Biology and Pharmacology, McGovern Medical School, the University of Texas Health Science Center at Houston, Houston, Texas, USA.

MLKL (mixed lineage kinase domain like pseudokinase) is a well-known core component of necrosome that executes necroptotic cell death upon phosphorylation by RIPK3 (receptor interacting serine/threonine kinase 3). Recent studies also implicate a role of MLKL in endosomal trafficking, which is not always dependent on RIPK3. Using mouse Neuro-2a and L929 as well as human HEK293 and HT29 cells, we show here that MLKL is phosphorylated in response to serum and amino acid deprivation from the culture medium, in a manner that depends on CAMK2/CaMKII (calcium/calmodulin dependent protein kinase II) but not RIPK3. The starvation-induced increase in MLKL phosphorylation was accompanied by decreases in levels of lipidated MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta; LC3-II) and SQSTM1/p62 (sequestosome 1), markers of autophagosomes. These changes were prevented by disrupting either MLKL or CAMK2 by pharmacology and genetic manipulations. Moreover, disrupting MLKL or CAMK2 also inhibited the incorporation of LC3-II into autolysosomes, demonstrating a role of the CAMK2-MLKL pathway in facilitating autophagic flux during short-term starvation, in contrast to necroptosis which suppressed autophagic flux. Furthermore, unlike the necroptotic pathway, the starvation-evoked CAMK2-mediated MLKL phosphorylation protected cells from starvation-induced death. We propose that upon nutrient deprivation, MLKL is activated by CAMK2, which in turn facilitates membrane scission needed for autophagosome maturation, allowing the proper fusion of the autophagosome with lysosome and the subsequent substance degradation. This novel function is independent of RIPK3 and is not involved in necroptosis, implicating new roles for this pseudokinase in cell survival, signaling and metabolism.
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http://dx.doi.org/10.1080/15548627.2021.1954348DOI Listing
July 2021

Tracking the Differentiation Status of Human Neural Stem Cells through Label-Free Raman Spectroscopy and Machine Learning-Based Analysis.

Anal Chem 2021 Aug 20;93(30):10453-10461. Epub 2021 Jul 20.

Department of Biological Engineering, Utah State University, 4105 Old Main Hill, ENGR 402, Logan, Utah 84322, United States.

The ability to noninvasively monitor stem cells' differentiation is important to stem cell studies. Raman spectroscopy is a non-harmful imaging approach that acquires the cellular biochemical signatures. Herein, we report the first use of label-free Raman spectroscopy to characterize the gradual change during the differentiation process of live human neural stem cells (NSCs) in the in vitro cultures. Raman spectra of 600-1800 cm were measured with human NSC cultures from the undifferentiated stage (NSC-predominant) to the highly differentiated one (neuron-predominant) and subsequently analyzed using various mathematical methods. Hierarchical cluster analysis distinguished two cell types (NSCs and neurons) through the spectra. The subsequently derived differentiation rate matched that measured by immunocytochemistry. The key spectral biomarkers were identified by time-dependent trend analysis and principal component analysis. Furthermore, through machine learning-based analysis, a set of eight spectral data points were found to be highly accurate in classifying cell types and predicting the differentiation rate. The predictive accuracy was the highest using the artificial neural network (ANN) and slightly lowered using the logistic regression model and linear discriminant analysis. In conclusion, label-free Raman spectroscopy with the aid of machine learning analysis can provide the noninvasive classification of cell types at the single-cell level and thus accurately track the human NSC differentiation. A set of eight spectral data points combined with the ANN method were found to be the most efficient and accurate. Establishing this non-harmful and efficient strategy will shed light on the in vivo and clinical studies of NSCs.
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http://dx.doi.org/10.1021/acs.analchem.0c04941DOI Listing
August 2021

Enhanced Electroplasticity through Room-Temperature Dynamic Recrystallization in a Mg-3Al-1Sn-1Zn Alloy.

Materials (Basel) 2021 Jul 3;14(13). Epub 2021 Jul 3.

State Key Laboratory of Automotive Simulation and Control, Nanling Campus, Jilin University, No. 5988 Renmin Street, Changchun 130025, China.

It has been well known that electric pulse can be utilized to enhance the plasticity of metals, which is attributed to the change of dislocation dynamics, e.g., localized planar slip to homogeneous wavy slip. Here, we show another effect of pulse current, which facilitates texture weakening through room-temperature dynamic recrystallization and additionally improve the plasticity of a polycrystalline Mg-3Al-1Sn-1Zn alloy. By conducting a tensile test under electrical pulse, we found that the peak flow stress and fracture strain depend strongly on current density. As peak current densities increases, the flow stress drops and the fracture strain increases. Our Electron Backscatter Diffraction results suggest that dynamic recrystallization occurs at room temperature, which develops a weakened texture. Our work provides a new insight into electroplasticity mechanism in Mg alloys.
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http://dx.doi.org/10.3390/ma14133739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269859PMC
July 2021

Protocol for nuclear export signal characterization of cGAS in mammalian cells.

STAR Protoc 2021 Sep 3;2(3):100649. Epub 2021 Jul 3.

NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Center for AIDS Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, P. R. China.

The cyclic GMP-AMP synthase (cGAS) is the principal DNA sensor, which binds DNA and triggers the type I interferon production. We used ISD45 or inactivated Vaccinia Virus (VACV) to stimulate cGAS and monitored cellular localization by immunofluorescence microscopy, Operetta high-content screening, and cytoplasmic/nuclear fractionation. LocNES server was used to predict cGAS nuclear export signal (NES) sequence and characterized the function by mutagenesis. This protocol provides a prototype of cGAS subcellular distribution or the identification of NES in other proteins. For complete details on the use and execution of this protocol, please refer to Sun et al. Sun et al. (2021).
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http://dx.doi.org/10.1016/j.xpro.2021.100649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261000PMC
September 2021

Effects of Soil Type on Trace Element Absorption and Fruit Quality of Pepper.

Front Plant Sci 2021 30;12:698796. Epub 2021 Jun 30.

College of Horticulture, Hunan Agricultural University, Changsha, China.

The inbred "SJ11-3" pepper was cultured in yellow brown soil, paddy soil, fluvo-aquic soil, and pastoral soil, and the factors affecting the absorption of trace elements and fruit quality were analyzed. The results showed that the physicochemical properties of the soils were significantly different, which led to differences in the nutritional quality of pepper fruits. The pH value had a significant effect on the absorption of trace elements in pepper. The increase of pH promoted the absorption of magnesium and molybdenum but inhibited the absorption of zinc, copper, manganese, and iron. The stepwise multivariable regression analysis showed that the amount of molybdenum in soil was the main factor affecting the total amino acid content of pepper. Total nitrogen, zinc, and copper were the main factors that contributed to the soluble sugar content of pepper, and the available potassium was the major determinant of the vitamin C content of pepper. This study provides new insight on the pepper fruit quality grown on different types of soil with varying levels of trace elements.
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http://dx.doi.org/10.3389/fpls.2021.698796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278326PMC
June 2021

High-speed secure key distribution based on chaos synchronization in optically pumped QD spin-polarized VCSELs.

Opt Express 2021 Jun;29(13):19675-19689

We propose and numerically demonstrate a high-speed secure key distribution (SKD) based on polarization-keying chaos synchronization in two quantum dot (QD) spin-polarized vertical-cavity surface-emitting lasers (VCSELs) without any external feedback. In this scheme, high-quality chaos synchronization can be obtained when the response lasers have the same polarization ellipticity. The proposed SKD scheme is benefited from the feasible tunability of the pump polarization ellipticity, and no other complex components are necessary. Moreover, the open-loop configuration is constructed in the commonly driven lasers and results in a short synchronization recovery time of hundreds of picoseconds, which is much shorter than that in most previous reports. Combined with these merits, a 1.34 Gb/s SKD with a bit error ratio lower than 3.8 × 10 can be achieved. The current study provides a new way to realize high-speed physical key distribution.
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http://dx.doi.org/10.1364/OE.426126DOI Listing
June 2021

Abatement technology of endocrine-disrupting chemicals (EDCs) by means of enhanced coagulation and ozonation for wastewater reuse.

Chemosphere 2021 Jul 10;285:131515. Epub 2021 Jul 10.

School of Environment and Sustainability, University of Saskatchewan, Saskatoon, SK, S7N 5B3, Canada.

In this study, we have investigated the purification efficiency during enhanced coagulation, ozone oxidation and their combined processes for the removal of trace amounts of EDCs in different DOM matrices. The results indicated that the maximum removal efficiency of EDCs occurred at or near pH 7.0 when measured over a pH range of 4.0-10.0. The addition of natural colloids had a two-part influence. While the floc generated by polyaluminium chloride (PAC) significantly increased in size from 198.0 μm to 290.4 μm with a simultaneous improvement in the removal efficiency of EDCs, the floc size generated by polyferric sulfate (PFS) had no worthwhile change except for a slight decrement. The removal efficiency of EDCs and the decrease in spectral parameters including UVA254, UVA280 and humic-like fluorescence during ozonation processes with and without pre-coagulation were investigated. During the ozonation process, efficient elimination of target EDCs are achieved at low O doses (O/dissolved organic carbon (DOC) < 0.2) in different water matrices. The pH-titration differential absorbance spectra technique further demonstrated that the high reactivity of O to EDCs is owing to their phenolic moieties. In addition, when mgO/mgDOC ratio reaches to ~0.40, >90% of estrogenic activity was eliminated. In a nutshell, ozonation with pre-coagulation together leads to considerably higher abatement of EDCs and estradiol (E2) equivalent values (EEQ) at the same ozone dosage than ozonation only process for wastewater treatment.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131515DOI Listing
July 2021

A Chromosome-Level Genome Assembly of the Mandarin Fish ().

Front Genet 2021 23;12:671650. Epub 2021 Jun 23.

Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China.

The mandarin fish, , is an economically important perciform species with widespread aquaculture practices in China. Its special feeding habit, acceptance of only live prey fishes, contributes to its delicious meat. However, little is currently known about related genetic mechanisms. Here, we performed whole-genome sequencing and assembled a 758.78 Mb genome assembly of the mandarin fish, with the scaffold and contig N50 values reaching 2.64 Mb and 46.11 Kb, respectively. Approximately 92.8% of the scaffolds were ordered onto 24 chromosomes (Chrs) with the assistance of a previously established genetic linkage map. The chromosome-level genome contained 19,904 protein-coding genes, of which 19,059 (95.75%) genes were functionally annotated. The special feeding behavior of mandarin fish could be attributable to the interaction of a variety of sense organs (such as vision, smell, and endocrine organs). Through comparative genomics analysis, some interesting results were found. For example, olfactory receptor (OR) genes (especially the beta and delta types) underwent a significant expansion, and endocrinology/vision related , , and genes presented various functional mutations. These may contribute to the special feeding habit of the mandarin fish by strengthening the olfactory and visual systems. Meanwhile, previously identified sex-related genes and quantitative trait locis (QTLs) were localized on the Chr14 and Chr17, respectively. 155 toxin proteins were predicted from mandarin fish genome. In summary, the high-quality genome assembly of the mandarin fish provides novel insights into the feeding habit of live prey and offers a valuable genetic resource for the quality improvement of this freshwater fish.
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http://dx.doi.org/10.3389/fgene.2021.671650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262678PMC
June 2021

Effects of non-surgical periodontal therapy on periodontal clinical data in periodontitis patients with rheumatoid arthritis: a meta-analysis.

BMC Oral Health 2021 07 10;21(1):340. Epub 2021 Jul 10.

Hospital of Stomatology, Jilin University, 1500th Qinghua Road, Changchun, 130021, Jilin, China.

Backgrounds: To date, there is still no consensus about the clinical efficacy of non-surgical periodontal therapy in rheumatoid arthritis (RA) patients with periodontitis. Therefore, the aim of this study was to summarize clinical data regarding the efficacy of scaling and root planing (SRP) in patients with RA and periodontitis compared to non-RA periodontitis patients.

Methods: We selected randomized controlled trials (RCTs) that compared periodontal clinical data in RA as compared to non-RA periodontitis patients by searching Embase, PubMed and Cochrane Central Register of Controlled Trials and by manually retrieving from the earliest records to March 8, 2021. The overall effect size of plaque index (PI), gingival index (GI), attachment loss (AL), probing depth (PD) and bleeding on probing (BOP) were calculated by either a fixed or random-effect model, and subgroup analyses were conducted according to the different time points of follow-up. Two investigators extracted the data and assess the accuracy of the obtained results with 95% of Confidence Intervals (CI). Cochrane Collaboration's tool was responsible for the evaluation of the literature quality and the inter-study heterogeneity was evaluated by Q test and I statistic. Sensitivity analyses were applied for results with heterogeneity. Publication bias was determined by Begg's test, Egger's test and the trim-and-fill method.

Results: Seven RCTs including 212 patients eventually met the inclusion criteria for the study. As the primary results, the change of PD was not statistically significant and in the secondary results changes of PI, GI, AL and BOP were also not statistically significant in RA patients with periodontitis compared to non-RA periodontitis patients. In subgroup analysis, a larger BOP reduction at 3 months, PI and AL reduction at 6 months were observed in patients with RA and periodontitis group. The results of sensitivity analyses had no significant effect. No evidence of potential publication bias was tested. There were some limitations due to the small number of eligible RCTs.

Conclusions: SRP is equally effective in RA as compared to non-RA periodontitis patients. It suggests RA does not affect the clinical efficacy of non-surgical periodontal therapy. These results could serve evidence-based practice.
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http://dx.doi.org/10.1186/s12903-021-01695-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272313PMC
July 2021

Evaluation of Burnout Among Anesthesiologists Working in Tibet, China: Altitude and Attitude.

Chin Med Sci J 2021 Jun;36(2):97-102

Department of Anesthesiology,Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730 China.

Objective Burnout is a triad of emotional exhaustion, depersonalization, and reduced personal accomplishment resulting from job stress. Although with distinct regional and cultural characteristics, burnout among anesthesiologists in the Tibet has not been described. This study aimed to explore the prevalence of burnout among anesthesiologists in Tibet and its associated factors. Methods A cross-sectional survey was conducted in Tibet, China, with an anonymous questionnaire. Social-demographic characteristics, work status, three dimensions of burnout assessed by the Maslach Burnout Inventory-Human Service Survey were collected and analyzed. Results A total of 133 individuals from 17 hospitals completed the survey from March to June 2018. The prevalence of moderate- to high-level of emotional exhaustion, depersonalization, and burnout in personal accomplishment was 65.4% (95%, 57.0%-72.9%), 66.9% (95%, 58.5%-74.3%), and 83.5% (95%, 76.2%-88.8%), respectively. An annual caseload ≥500, frequent overtime work and fair to poor sleep quality were significantly associated with a higher level of emotional exhaustion ( <0.001,=0.001, and <0.0001, respectively). 5-9 years in anesthesiology experience was significantly associated with a high level of emotional exhaustion and depersonalization (=0.002 and =0.003, respectively). Conclusions More than half of anesthesiologists working in Tibet experience a moderate- to high- level of burnout in at least one dimensional scale. Anesthesiologists having 5-9 years of experience are more prone to emotional exhaustion and depersonalization. Efforts to decrease burnout through reducing the working load and raising the social recognition of anesthesiologists in Tibet should be considered.
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http://dx.doi.org/10.24920/003800DOI Listing
June 2021

Assessing Empathy in Anesthesia Residents with the Chinese Version of the Consultation and Relational Empathy: A Pilot Standardized Patient Program.

Chin Med Sci J 2021 Jun;36(2):79-84

Department of Anesthesiology, Peking Union Medical College Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

Objectives To validate the reliability of the Chinese version of the Consultation and Relational Empathy (CARE) in physician-standardized patient (SP) encounter. We also tried to examine the agreement between video-based ratings and in-room ratings, as well as the agreement between the faculty ratings and SP ratings. Methods The CARE was translated into Chinese. Forty-eight anesthesia residents were recruited to make preoperative interview in SP-counter. Performance of each resident was graded by in-room raters, video raters and SP raters. Consistency between different raters was examined. Results The Chinese-CARE measure demonstrated high scale reliability with a Cronbach's alpha value of 0.95 and high consistency in the in-room ratings in intraclass correlation (coefficient=0.888,<0.001). Despite a good consistency in intraclass correlation, video ratings were significantly higher than in-room ratings (39.6±7.1. 24.0±10.0,<0.001), and Wilcoxon signed-rank test indicated that the pass/fail rate was significantly higher based on video ratings than based on in-room ratings (45/48. 22/48, <0.001). SP ratings had a moderate consistency with in-room faculty ratings (coefficient=0.568,<0.001), and there was no significant difference between the pass/fail rates based on the in-room ratings and SP ratings (22/48. 28/48, =0.12). Conclusions The Chinese-CARE measure is reliable in the assessment of empathy during preoperative anesthesia interview. In-room and video ratings are not equivalent, while SP may provide a feasible alternative for the faculty rater in the assessment of communication skills with an appropriate measure.
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http://dx.doi.org/10.24920/003741DOI Listing
June 2021

Characteristics and outcomes of COVID-19 infection in 45 patients with breast cancer: A multi-center retrospective study in Hubei, China.

Breast 2021 Jun 26;59:102-109. Epub 2021 Jun 26.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China. Electronic address:

Background: The COVID-19 pandemic is a significant worldwide health crisis. Breast cancer patients with COVID-19 are fragile and require particular clinical care. This study aimed to identify the clinical characteristics of breast cancer patients with COVID-19 and the risks associated with anti-cancer treatment.

Methods: The medical records of breast cancer patients with laboratory-confirmed COVID-19 were collected among 9559 COVID-19 patients from seven designated hospitals from 13th January to 18th March 2020 in Hubei, China. Univariate and multivariate analyses were performed to assess risk factors for COVID-19 severity.

Results: Of the 45 breast cancer patients with COVID-19, 33 (73.3%) developed non-severe COVID-19, while 12 (26.7%) developed severe COVID-19, of which 3 (6.7%) patients died. The median age was 62 years, and 3 (6.7%) patients had stage IV breast cancer. Univariate analysis showed that age over 75 and the Eastern Cooperative Oncology Group (ECOG) score were associated with COVID-19 disease severity (P < 0.05). Multivariate analysis showed that patients who received chemotherapy within 7 days had a significantly higher risk for severe COVID-19 (logistic regression model: RR = 13.886, 95% CI 1.014-190.243, P = 0.049; Cox proportional hazards model: HR = 13.909, 95% CI 1.086-178.150, P = 0.043), with more pronounced neutropenia and higher LDH, CRP and procalcitonin levels than other patients (P < 0.05).

Conclusions: In our breast cancer cohort, the severity of COVID-19 could be associated with baseline factors such as age over 75 and ECOG scores. Chemotherapy within 7 days before symptom onset could be a risk factor for severe COVID-19, reflected by neutropenia and elevated LDH, CRP and procalcitonin levels.
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http://dx.doi.org/10.1016/j.breast.2021.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233853PMC
June 2021

Broad tunable photonic microwave generation in an optically pumped spin-VCSEL with optical feedback stabilization.

Opt Lett 2021 Jul;46(13):3147-3150

We propose and numerically demonstrate a photonic microwave generation scheme based on the dynamic period-one oscillation of a solitary spin-polarized vertical-cavity surface-emitting laser (spin-VCSEL). The evolution of the oscillation amplitude, frequency, power, and linewidth of the generated microwave is systematically investigated by using two-dimensional maps. The results show that the generated microwave signals with a dominant linewidth of about 3 MHz have a broad tunable frequency (from several gigahertz to hundreds of gigahertz), which benefits from the birefringence-induced oscillation in spin-VCSELs. Moreover, with the help of optical feedback, the microwave linewidth can be effectively minimized (∼51) by increasing the feedback strength and feedback delay time. Importantly, this Letter offers prospects for applications requiring a feasible and resource-efficient microwave source in microwave photonic fields.
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http://dx.doi.org/10.1364/OL.431184DOI Listing
July 2021

The effect of selective serotonin reuptake inhibitors on cognitive impairment in patients with depression: A prospective, multicenter, observational study.

J Psychiatr Res 2021 Jun 15;141:26-33. Epub 2021 Jun 15.

Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China; NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China. Electronic address:

Whether selective serotonin reuptake inhibitors (SSRIs) can improve cognitive function in depressed patients remains unclear. We aimed to explore the effect of SSRIs on cognitive function and the influencing factors in patients with major depressive disorder (MDD) with impaired cognitive function. We used a neurocognitive test battery to assess five cognitive domains, namely, attention/vigilance, learning, memory, processing speed and executive functioning, and calculated the Global Deficit Score (GDS). A GDS≥0.5 indicated overall cognitive impairment. The changes in the cognitive domains and overall cognitive function were analyzed in MDD patients with a baseline GDS≥0.5 who completed 8 weeks of SSRI treatment. We divided the patients into the cognitive remission and nonremission groups to explore the associated factors. In total, 160 patients (mean age 37.6 ± 10.8 years, 30.6% male) were included in the final analysis. The median (quartiles) of baseline GDS and HRSD were 1.4 (0.8, 1.9) and 19.5 (17.0, 23.0), respectively. All five cognitive domains improved after the treatment, while only 41 (25.6%) patients achieved cognitive remission. Recurrence and a higher baseline GDS were risk factors for cognitive nonremission. More aggressive interventions may be needed to promote cognitive remission in clinical practice, especially for patients with severe cognitive impairment and recurrent episodes.
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http://dx.doi.org/10.1016/j.jpsychires.2021.06.020DOI Listing
June 2021

A transcriptional switch governs fibroblast activation in heart disease.

Nature 2021 Jul 23;595(7867):438-443. Epub 2021 Jun 23.

Gladstone Institutes, San Francisco, CA, USA.

In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.
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http://dx.doi.org/10.1038/s41586-021-03674-1DOI Listing
July 2021

N-Cadherin Nanoantagonist Driven Mesenchymal-to-Epithelial Transition in Fibroblasts for Improving Reprogramming Efficiency.

Nano Lett 2021 07 23;21(13):5540-5546. Epub 2021 Jun 23.

National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing 210093, China.

Induced pluripotent stem cells (iPSCs) hold promise in revolutionizing medicine; however, their application potential is limited because of low reprogramming efficiency. Mesenchymal-to-epithelial transition (MET) has been proved to involve reprogramming of somatic cells into iPSCs, making it a promising target for enhancing generation of iPSCs. Here, we nanoengineered N-cadherin-blocking peptide ADH-1 with gold nanoparticles, generating a multivalent N-cadherin antagonist (ADH-AuNPs), for improving reprogramming efficiency through driving cell MET. ADH-AuNPs exhibited good biocompatibility and showed higher N-cadherin inhibitory activity than ADH-1 due to multivalency, thereby enhancing cell-state reprogramming toward epithelial lineages. Particularly, ADH-AuNPs improved reprogramming efficiency by more than 7-fold after introduction of four Yamanaka factors. Importantly, ADH-AuNPs generated iPSCs displayed high stemness and pluripotency and . Therefore, we provide a cooperative strategy for promoting the iPSC generation efficacy.
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http://dx.doi.org/10.1021/acs.nanolett.1c00880DOI Listing
July 2021

Segmentation of MRI head anatomy using deep volumetric networks and multiple spatial priors.

J Med Imaging (Bellingham) 2021 May 17;8(3):034001. Epub 2021 Jun 17.

City College New York, Department of Biomedical Engineering, New York City, New York, United States.

Conventional automated segmentation of the head anatomy in magnetic resonance images distinguishes different brain and nonbrain tissues based on image intensities and prior tissue probability maps (TPMs). This works well for normal head anatomies but fails in the presence of unexpected lesions. Deep convolutional neural networks (CNNs) leverage instead spatial patterns and can learn to segment lesions but often ignore prior probabilities. We add three sources of prior information to a three-dimensional (3D) convolutional network, namely, spatial priors with a TPM, morphological priors with conditional random fields, and spatial context with a wider field-of-view at lower resolution. We train and test these networks on 3D images of 43 stroke patients and 4 healthy individuals which have been manually segmented. We demonstrate the benefits of each source of prior information, and we show that the new architecture, which we call Multiprior network, improves the performance of existing segmentation software, such as SPM, FSL, and DeepMedic for abnormal anatomies. The relevance of the different priors was compared, and the TPM was found to be most beneficial. The benefit of adding a TPM is generic in that it can boost the performance of established segmentation networks such as the DeepMedic and a UNet. We also provide an out-of-sample validation and clinical application of the approach on an additional 47 patients with disorders of consciousness. We make the code and trained networks freely available. Biomedical images follow imaging protocols that can be leveraged as prior information into deep CNNs to improve performance. The network segmentations match human manual corrections performed in 3D and are comparable in performance to human segmentations obtained from scratch in 2D for abnormal brain anatomies.
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http://dx.doi.org/10.1117/1.JMI.8.3.034001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209627PMC
May 2021

KLF2 Mediates the Suppressive Effect of Laminar Flow on Vascular Calcification by Inhibiting Endothelial BMP/SMAD1/5 Signaling.

Circ Res 2021 Jun 23. Epub 2021 Jun 23.

School of Biomedical Sciences, The Chinese University of Hong Kong, CHINA.

Vascular calcification in arterial intima is closely associated with atherosclerosis. Endothelial cells (ECs) sense blood flow and respond to the mechanical cues generated by different flow patterns. Laminar flow (LF) induces an anti-atherosclerotic EC phenotype whereas disturbed flow (DF) exerts an atheroprone effect. However, the contribution of blood flow to calcification in atherosclerotic arteries remains to be evaluated. We aim to investigate whether blood flow plays a determinant role in the distribution of vascular calcification and the underlying mechanisms involved. Computed tomography angiography analysis of human coronary arteries (n = 48) shows that calcification preferentially develops at flow perturbated sites. Similar phenomenon was observed in calcified human aortic valves and mouse arteries. Nonuniform shear stress produced in Y-shaped slide simulating live conditions in branched arteries promotes calcification in human umbilical vein ECs (HUVECs). The expression of Krüppel-like Factor 2 (KLF2), a transcription factor inducible by LF, is reduced in ECs of calcified human aortic valves and in endothelial calcification model, suggesting that KLF2 downregulation is likely involved in intimal calcification. Indeed, KLF2 silencing induces endothelial-to-mesenchymal transition and accelerates osteo-induction in both human aortic ECs and HUVECs. EC-specific KLF2 knockdown promotes whereas AAV9-mediated EC-KLF2 overexpression ameliorates vascular calcification in mice. Global mRNA profiling in HUVECs reveals that KLF2 inhibits BMP/SMAD1/5 pathway which is critical in vascular calcification. Furthermore, KLF2 mediates LF-induced inhibition of the BMP/SMAD1/5 pathway. By contrast, DF-induced activation of BMP/SMAD1/5 pathway is suppressed by KLF2 overexpression. Mechanistically, KLF2 binds to the promoters of BMP4, BMPER and SMAD1 to directly regulate their expression in ECs. Vascular calcification prefers to occur at branched or bifurcated areas of vasculature. LF inhibits vascular calcification through KLF2-mediated inhibition of endothelial BMP/SMAD1/5 signaling. Targeting KLF2 may represent a novel therapeutic approach against vascular calcification.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318690DOI Listing
June 2021
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