Publications by authors named "Yi Li"

4,850 Publications

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Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer.

Cell Death Differ 2021 May 10. Epub 2021 May 10.

Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.

Krüppel-like factor 5 (KLF5) is an oncogenic factor that is highly expressed in basal-like breast cancer (BLBC) and promotes cell proliferation, survival, migration, stemness, and tumor growth; however, its posttranslational modifications are poorly defined. Protein arginine methyltransferase 5 (PRMT5) is also an oncogene implicated in various carcinomas, including breast cancer. In this study, we found that PRMT5 interacts with KLF5 and catalyzes the di-methylation of KLF5 at Arginine 57 (R57) in a methyltransferase activity-dependent manner in BLBC cells. Depletion or pharmaceutical inhibition (using PJ-68) of PRMT5 decreased the expression of KLF5 and its downstream target genes in vitro and in vivo. PRMT5-induced KLF5R57me2 antagonizes GSK3β-mediated KLF5 phosphorylation and subsequently Fbw7-mediated KLF5 ubiquitination and coupled degradation. Functionally, PRMT5 promotes breast cancer stem cell maintenance and proliferation, at least partially, by stabilizing KLF5. PRMT5 and KLF5 protein levels were positively correlated in clinical BLBCs. Taken together, PRMT5 methylates KLF5 to prevent its phosphorylation, ubiquitination, and degradation, and thus promotes breast cancer stem cell maintenance and proliferation. These findings suggest that PRMT5 is a potential therapeutic target for BLBC.
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http://dx.doi.org/10.1038/s41418-021-00793-0DOI Listing
May 2021

Combined detection of circulating tumor cells, α-fetoprotein heterogene-3 and α-fetoprotein in the early diagnosis of HCC for the prediction of efficacy, prognosis, recurrence after microwave ablation.

Infect Agent Cancer 2021 May 10;16(1):28. Epub 2021 May 10.

Biological Cell Therapy Research Center, Puren Hospital Affiliated to Wuhan University of Science and Technology, 430081, Wuhan, China.

Background: Early diagnosis can significantly improve treatment outcomes for hepatocellular carcinoma (HCC) patients. Currently, the dosage of serum alpha fetoprotein (AFP) is widely used in the diagnosis of HCC, but this biomarker has low specificity and may cause false positive or false negative results. Thus, it's necessary to find and validate other serum tumor markers that in association for AFP would increase the sensitivity and the specificity in the HCC diagnosis. This study investigated the predictive value of combined of AFP, AFP-L3, and Circulating tumor cells (CTCs).

Methods: A total of 105 patients with HCC after microwave ablation (MWA) were divided into non recurrence group, recurrence group, good prognosis (CR + PR group, CR: Complete remission, PR: Partial remission) and poor prognosis (SD + PD group, SD: Stable, PD: Progression). ROC curve was used to analyze the short-term efficacy, prognosis and clinical value of combined detection of the three indicators in predicting postoperative recurrence of HCC patients with MWA.

Results: The positive rate of serum CTCs, AFP-L3 and AFP combined detection in the diagnosis of HCC is higher than that of single index and two index detection. The AUC, sensitivity and specificity of serum CTCs, AFP-L3 and AFP combined detection was better than that of single index and two indexes in patients with HCC after MWA.

Conclusions: Combined detection of AFP, AFP-L3, and CTCs can effectively make up for the shortcomings of the detection with single and pairwise indicators. It can't only diagnose HCC in early, but also has a high clinical value of predicting the short-term efficacy, prognosis and recurrence of HCC patients after MWA treatment.
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http://dx.doi.org/10.1186/s13027-021-00367-2DOI Listing
May 2021

Ventilation improvement after pneumonia treatment evaluated with electrical impedance tomography: an observational study.

Physiol Meas 2021 May 10. Epub 2021 May 10.

Department of Biomedical Engineering, Fourth Military Medical University, Xi'an, 710032, CHINA.

Objective: Due to radiation exposures, not all patients with pneumonia would receive chest x-ray or CT measurements to confirm treatment effectiveness. The aim of the study was to examine the ability of using electrical impedance tomography (EIT) to evaluate the treatment effectiveness in such patient group.

Methods: A total of 35 consecutive patients with non-severe pneumonia was included in this prospective study. The patients received standard treatment according to our internal protocol. EIT measurements were performed in supine position before the treatment start and on day 6 of the treatment period. EIT-based global inhomogeneity (GI) index and center of ventilation index (CoV) were calculated. Clinical pulmonary infection score (CPIS) was obtained at both time points.

Results: Clinically significant improvements in GI and CoV were found in patient group (ΔGI: -34%±17% and ΔCoV: -10%±11%; p<0.001). Although CPIS was also significantly improved (ΔCPIS -0.70±0.17, p<0.001), no correlations were demonstrated when it compared to ΔGI or ΔCoV.

Conclusion: EIT demonstrated individual improvement of ventilation heterogeneity after standard treatment in non-severe pneumonia, which provided different information compared to CPIS. EIT has the potential to become a routine non-invasive, non-radiative tool to assess pneumonia treatment effectiveness.
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http://dx.doi.org/10.1088/1361-6579/abffbfDOI Listing
May 2021

Better Together: Long-term Behaviors and Perspectives after a Practitioner-Family Writing Intervention in Clinical Practice.

Perm J 2021 May;25

Advocate Children's Hospital, Park Ridge, IL.

Background: An expressive writing intervention, the Three-minute Mental Makeover (3MMM), was previously associated with reduced stress for practitioners, patients, and families. The goal of this follow-up study was to evaluate long-term use of writing and perspectives after participation in the 3MMM.

Methods: The original study involved patients and families in the neonatal and pediatric Intensive Care Units, inpatient units, and outpatient clinics of a children's hospital. Health-care practitioners led the intervention, writing concurrently with patients and families using the 3MMM intervention. Follow-up contact by phone was attempted for all original patient/family participants 12 to 18 months after completing the exercise. Practitioners were contacted via email 24 months after the original study. Participants were surveyed about the 3MMM and continued use of writing to cope with stressful situations. Original and follow-up survey responses were compared using the Mann-Whitney test.

Results: Of the 96 original patient/family members, 61 individuals were reached, remembered the 3MMM, and agreed to participate in the follow-up study. Among the 61 participants, 52 (85%) agreed that the 3MMM had been helpful. Thirty-six (59%) reported using writing to help cope with stress at follow-up, compared to only 23 (38%) at baseline (P = 0.005). The majority of clinicians (87%) also continued to use the 3MMM in clinical practice following the original 3MMM study period and ranked it as both feasible (75%) and worth the time investment (75%).

Conclusion: The 3MMM demonstrated long-term perceived benefits and behavior changes. Findings provide preliminary support for using the 3MMM in routine clinical practice.
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http://dx.doi.org/10.7812/TPP/20.250DOI Listing
May 2021

Comparison of Pancreatic Damage in Rats for Two Methods of Paraquat Administration.

Front Pharmacol 2021 20;12:611433. Epub 2021 Apr 20.

Emergency Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

It is noted that elevated serum amylase levels suggesting pancreatic damage has an association with prognosis in PQ patients. This study aimed to determine whether PQ can cause pancreatic damage. The two conventional models (intragastric infusion (iG) and intraperitoneal injection (iP)) may exhibit different effects on the pancreas depending on whether or not they pass through the digestive tract. In this study, the rats were divided into four groups: the intragastric infusion group (PQ-iG, = 45), intraperitoneal injection group (PQ-iP, = 53), normal control group 1 (NC-iG, = 6) and normal control group 2 (NC-iP, = 6). Pancreatic damage was compared between groups using serum amylase activity assay, hematoxylin and eosin (H&E) staining, TUNEL assay, and transmission electron microscopy (TEM). Serum amylase levels in group PQ-iG were significantly higher than in group PQ-iP ( < 0.05). Examination of the H&E sections showed damage to the pancreas. Both experimental groups were displayed inflammatory infiltration within 9 h of PQ treatment. After 9 h, patchy necrosis was observed in group PQ-iP, when inflammatory infiltration was still the dominant pathology. Necrosis appeared and gradually worsened in group PQ-iG, in which necrosis was the dominant pathology. The TUNEL assay showed significantly higher numbers of apoptotic cells in the pancreas of PQ-groups than in the control NC- groups ( < 0.05). TEM showed expansive endoplasmic reticulum lumens and mitochondria swelling in the pancreas of the PQ-groups. It is concluded that both methods of modeling could cause pancreatic damage and the type and degree of damage would change over time. Note that pancreatic damage in group PQ-iG was more severe than that in group PQ-iP. Therefore, clinical practitioners should pay close attention to pancreatic damage caused by PQ, especially when the route of PQ administration was oral.
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http://dx.doi.org/10.3389/fphar.2021.611433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099104PMC
April 2021

A chromosome-level Amaranthus cruentus genome assembly highlights gene family evolution and biosynthetic gene clusters that may underpin the nutritional value of this traditional crop.

Plant J 2021 May 7. Epub 2021 May 7.

Centre for Novel Agricultural Products (CNAP), Department of Biology, University of York, Wentworth Way, York, YO10 5DD, UK.

Traditional crops historically provided accessible and affordable nutrition to millions of rural dwellers but have been neglected, with most modern agricultural systems over reliant on a small number of internationally-traded crops. Traditional crops are typically well-adapted to local agro-ecological conditions and many are nutrient-dense. They can play a vital role in local food systems through enhanced nutrition (especially where diets are dominated by starch crops), food security and livelihoods for smallholder farmers, and a climate-resilient and biodiverse agriculture. Using short-read, long-read and phased sequencing technologies we generated a high-quality chromosome-level genome assembly for Amaranthus cruentus, an under-researched crop with micronutrient- and protein-rich leaves and gluten-free seed, but lacking improved varieties, with respect to productivity and quality traits. The 370.9 MB genome demonstrates a shared whole genome duplication with a related species, Amaranthus hypochondriacus. Comparative genome analysis indicates chromosomal loss and fusion events following genome duplication that are common to both species, as well as fission of chromosome 2 in A. cruentus alone, giving rise to a haploid chromosome number of 17 (versus 16 in A. hypochondriacus). Genomic features potentially underlying the nutritional value of this crop include two A. cruentus-specific genes with a likely role in phytic acid synthesis (an anti-nutrient), expansion of ion transporter gene families, and identification of biosynthetic gene clusters conserved within the amaranth lineage. The A. cruentus genome assembly will underpin much-needed research and global breeding efforts to develop improved varieties for economically viable cultivation and realisation of the benefits to global nutrition security and agrobiodiversity.
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http://dx.doi.org/10.1111/tpj.15298DOI Listing
May 2021

Effects of doping high-valence transition metal (V, Nb and Zr) ions on the structure and electrochemical performance of LIB cathode material LiNiCoMnO.

Phys Chem Chem Phys 2021 May 7. Epub 2021 May 7.

College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, P. R. China. and State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou, Fujian, 350116, China and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry (FTCC), Xiamen University, Xiamen, Fujian, 61005, China.

Ni-rich layered oxides, like LiNi0.8Co0.1Mn0.1O2 (NCM811), have been widely investigated as cathodes due to their high energy density. However, gradual structural transformation during cycling can lead to capacity degradation and potential decay of cathode materials. Herein, we doped high-valence transition metal (TM) ions (V5+, Nb5+, and Zr4+) at the Ni site of NCM811 by first principles simulations and explored the mechanism of doping TMs in NCMs for enhancing the electrochemical performance. Analysis of the calculations shows that doping V, Nb and Zr has an efficient influence on alleviating the Ni oxidation, reducing the loss of oxygen, and facilitating Li+ migration. Moreover, V doping can further suppress the lattice distortion due to the radius of V5+ being close to the radius of Mn4+. In particular, compared with the barrier of the pristine NCM in Li divacancy, the barrier of V-doped NCM reaches the lowest. In conclusion, V is the most favorable dopant for NCM811 to improve the electrochemical properties and achieve both high capacity and cycling stability.
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http://dx.doi.org/10.1039/d1cp00426cDOI Listing
May 2021

Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression.

Cell Commun Signal 2021 May 6;19(1):50. Epub 2021 May 6.

Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China.

Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed the tumor microenvironment (TME) immune cells to functionally affect the development and progression of breast cancer. However, insufficient evidence of TME immune modulators limit the clinical application of immunotherapy for advanced and metastatic breast cancers. Intercellular STAT3 activation of immune cells plays a central role in breast cancer TME immunosuppression and distant metastasis. Accumulating evidence suggests that targeting STAT3 and/or in combination with radiotherapy may enhance anti-cancer immune responses and rescue the systemic immunologic microenvironment in breast cancer. Indeed, apart from its oncogenic role in tumor cells, the functions of STAT3 in TME of breast cancer involve multiple types of immunosuppression and is associated with tumor cell metastasis. In this review, we summarize the available information on the functions of STAT3-related immune cells in TME of breast cancer, as well as the specific upstream and downstream targets. Additionally, we provide insights about the potential immunosuppression mechanisms of each type of evaluated immune cells. Video abstract.
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http://dx.doi.org/10.1186/s12964-021-00705-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101191PMC
May 2021

Correlationship between Ki67, VEGF, and p53 and Hepatocellular Carcinoma Recurrence in Liver Transplant Patients.

Biomed Res Int 2021 15;2021:6651397. Epub 2021 Apr 15.

Department of Hepatobiliary Surgery, Xiang'an Hospital, Xiamen University, Xiamen, China.

Background And Aims: Patients with hepatocellular carcinoma (HCC) who undergo orthotopic liver transplantation (OLT) are at risk for posttransplant tumor recurrence. The aim of this study was to evaluate the correlation between the expression of Ki67, VEGF, and p53 in HCC and clinicopathological characteristics of HCC patients, as well as their predictive value for HCC recurrence after OLT.

Methods: 60 patients who underwent OLT and were found to have HCC in the liver explant. The expression of Ki67, VEGF, and p53 in HCC was detected by immunohistochemistry.

Results: Ki67 was associated with the tumor number and the grade of differentiation at baseline. VEGF was associated with the diameter and number of tumors, tumor differentiation, and lymph node metastasis. p53 was associated with the tumor diameter and tumor encapsulation. The expression of Ki67, VEGF, and p53 in HCC was correlated with the tumor recurrence after OLT, respectively. Among them, VEGF was an independent predictor for tumor recurrence after OLT.

Conclusion: Ki67, VEGF, and p53 are associated with the recurrence of HCC after OLT. VEGF independently predicts the recurrence of HCC.
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http://dx.doi.org/10.1155/2021/6651397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064788PMC
April 2021

Mutational Analysis of a Familial Adenomatous Polyposis Pedigree with Bile Duct Polyp Phenotype.

Can J Gastroenterol Hepatol 2021 12;2021:6610434. Epub 2021 Apr 12.

Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China.

A large number of colorectal cancers have a genetic background in China. However, due to insufficient awareness, the diagnostic rate remains low and merely 5-6% of colorectal cancer patients are diagnosed with hereditary colorectal cancer. Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disease caused by mutations in the adenomatous polyposis coli (APC) gene. Different mutation sites in APC are associated with the severity of FAP, risks of carcinogenesis, and extraintestinal manifestations. We used next-generation sequencing (NGS) and capture techniques to screen suspected mutation points in the proband in this pedigree. Using modified Sanger sequencing, we identified members of the family who were carriers of this variant and whether this segregated well with disease occurrence. FAP family members had multiple adenomatous polyps in their gastrointestinal tracts, some of which developed into cancer with age. Two subjects presented a rare common bile duct polyp phenotype. No extraintestinal manifestations were observed. A heterozygous frameshift mutation in APC exon 16 (NM_000038.6) was observed in the proband and in other patients: c.3260_3261del (p.Leu1087GlnQfs 31) (rs587782305); the variant call format was CCT/C. Due to the deletion of two bases, a stop codon appeared after 31 amino acids, and the protein was truncated prematurely, which affected the conformation of the protein. Pedigree genetic linkage analysis showed that the clinical phenotype cosegregated with the APC mutation p.L1087fs. This mutation may be the pathogenic in this FAP family and responsible for this rare common bile duct polyp.
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http://dx.doi.org/10.1155/2021/6610434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057911PMC
April 2021

The Predictive Value of Computed Tomography Enterography Index for Postoperative Intra-Abdominal Septic Complications in Patients with Crohn's Disease: Implications for Surgical Decision Making.

Dis Colon Rectum 2021 Apr 26. Epub 2021 Apr 26.

Department of General Surgery, Jinling Medical School of Nanjing Medical University, No. 305 East Zhongshan Road, Nanjing, PR China Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, PR China Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, PR China Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 East Zhongshan Road, Nanjing, PR China.

Background: Postoperative intra-abdominal septic complications in patients with Crohn's Disease undergoing intestinal resection and anastomosis are frequent and difficult to manage.

Objective: This study sought to explore the value of preoperative computed tomography enterography to predict intra-abdominal septic complications.

Design: This was a retrospective and prospective observational study.

Settings: This study was conducted in a tertiary referral hospital.

Patients: Patients with Crohn's Disease undergoing primary intestinal resection were enrolled in our study.

Main Outcome Measures: The computed tomography enterography severity index was calculated and its ability to predict intra-abdominal septic complications evaluated by multivariate analyses. A prospective study was then performed to assess the reliability of this computed tomography enterography index.

Results: The incidence of postoperative intra-abdominal septic complications in patients undergoing a one-stage procedure was significantly higher than those undergoing a two-stage procedure (3/103 vs 24/241; 2.9% vs 10.0%; p=0.026). A multivariate analysis identified five computed tomography enterography parameters including mesenteric fibrofatty proliferation, intra-abdominal abscess or phlegmon, intestinal fistula, peritoneal effusion, and intestinal dilatation with stricture to be independent predictors of intra-abdominal septic complications (p<0.001). A Nomogram model based on these five parameters was constructed. A receiver operating characteristic analysis identified a computed tomography enterography nomogram score cutoff of 175 as a predictor of intra-abdominal septic complications with a sensitivity of 83.3%, a specificity of 85.3%. In the prospective study, those patients with computed tomography enterography nomogram score greater than 175 were assigned to the two-stage group, which resulted in a similar intra-abdominal septic complications incidence in those undergoing intestinal resection with or without anastomosis (2/82 vs 2/34; P= 0.355).

Limitations: This study was limited by its single-center scope.

Conclusion: Preoperative computed tomography enterography findings may predict postoperative outcomes and help determine surgical approach in Crohn's Disease. Patients with worse intra-abdominal findings confirmed by computed tomography enterography may benefit from stoma creation after intestinal resection. See Video Abstract at http://links.lww.com/DCR/B588 .
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http://dx.doi.org/10.1097/DCR.0000000000001796DOI Listing
April 2021

Limonin Enhances the Antifungal Activity of Eugenol Nanoemulsion against In Vitro and In Vivo Tests.

Microorganisms 2021 Apr 30;9(5). Epub 2021 Apr 30.

College of Horticulture and Landscape Architecture, Southwest University, Chongqing 400716, China.

, the cause of citrus blue mold, is a pathogenic fungus that seriously affects the postharvest quality of citrus fruit and causes serious economic loss. In this study, a eugenol nanoemulsion containing limonin, an antimicrobial component from citrus seeds, was prepared using a high-pressure microfluidizer and the antifungal activity of the nanoemulsions against was evaluated based on the conidial germination rate, mycelial growth, and scanning electron microscopy analysis. The results showed that the minimum inhibitory concentration and the inhibition rate of limonin-loaded eugenol nanoemulsion was 160 μg/mL and 59.21%, respectively, which was more potent than that of the limonin-free eugenol emulsion. After treatment with the nanoemulsions, the integrity of the cell membrane was disrupted, the cell morphology was abnormal, and the leakage of nucleic acid and protein was observed. In addition, the challenge test on citrus fruits revealed that the limonin-loaded eugenol emulsion inhibited citrus infection for longer periods, with an infection rate of 29.2% after 5 days. The current research shows that nanoemulsions containing limonin and eugenol have effective antifungal activity against , and may be used as a substitute for inhibiting blue mold in citrus fruits.
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http://dx.doi.org/10.3390/microorganisms9050969DOI Listing
April 2021

Oxymatrine Extends Survival by Attenuating Neuroinflammation in a Mouse Model of Amyotrophic Lateral Sclerosis.

Neuroscience 2021 May 1;465:11-22. Epub 2021 May 1.

Department of Neurology, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China; Beijing Geriatric Healthcare Center, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Beijing 100053, China. Electronic address:

Amyotrophic lateral sclerosis (ALS) is one of the leading causes of death associated with neurodegenerative diseases worldwide, and the progression of the disease is characteristically accompanied by severe neuroinflammation. Neuroprotective effects of oxymatrine (OMT) were shown to be due to reduced neuroinflammation in the mouse models of Alzheimer's disease and Parkinson's disease. The present study investigated whether OMT has a therapeutic potential in transgenic SOD1-G93A (TgSOD1-G93A) mice. Daily OMT treatment started at the age of 55 days until the end stage of the disease. Body weight and rotarod motor performance were assessed every 3 days starting from 70 days of age. Footprints were recorded to measure the stride length 40 days and 60 days after the initiation of the treatment. Some animals were sacrificed at the age of 115 days, and the lumbar spinal cord was harvested for immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR) to evaluate the neuroinflammatory responses. The results indicated that treatment with OMT delayed body weight loss, improved motor performance, and prolonged the survival of SOD1-G93A mice. Mechanistically, OMT treatment enhanced motor neuronal survival and alleviated the activation of microglia and astrocytes compared with those in the vehicle-treated group. Furthermore, the expression of the proinflammatory mediators was downregulated, and the expression of the anti-inflammatory factors was upregulated in the OMT-treated group compared with those in the vehicle-treated group (P < 0.05). Thus, the treatment with OMT had neuroprotective effects, promoting neuronal survival and extending the lifetime of SOD1-G93A mice by suppressing neuroinflammation.
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http://dx.doi.org/10.1016/j.neuroscience.2021.04.019DOI Listing
May 2021

Establish a Real-time Responsible Home Quarantine and Monitoring Management mHealth Platform.

AMIA Annu Symp Proc 2020 25;2020:697-706. Epub 2021 Jan 25.

Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.

Due to the global spreading of the COVID-19 virus, countries all over the world are faced with the need to conduct centralized quarantine or home quarantine for "persons who have been in contact with individuals diagnosed with the COVID-19 virus" and "visitors who have travel histories via COVID-19 hot zones". We have presented the community home quarantine service platform design that was utilized in Nanjing, China when the first wave of citizens returns to work after the Chinese New Year holidays on 10th Feb 2020. The main functions of the home quarantine monitoring system include (1) community grid management,(2) GPS positioning application in home isolation movement management,(3) Bluetooth body temperature patch data transmission integration, (4) health assessment scale (physical and mental health state) and (5) multilingual language options.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075449PMC
May 2021

Neuromodulation Effect of Very Low Intensity Transcranial Ultrasound Stimulation on Multiple Nuclei in Rat Brain.

Front Aging Neurosci 2021 15;13:656430. Epub 2021 Apr 15.

Weill Cornell Medicine, New York, NY, United States.

Objective: Low-intensity transcranial ultrasound stimulation (TUS) is a non-invasive neuromodulation technique with high spatial resolution and feasible penetration depth. To date, the mechanisms of TUS modulated neural oscillations are not fully understood. This study designed a very low acoustic intensity (AI) TUS system that produces considerably reduced AI Ultrasound pulses ( < 0.5 W/cm2) when compared to previous methods used to measure regional neural oscillation patterns under different TUS parameters.

Methods: We recorded the local field potential (LFP) of five brain nuclei under TUS with three groups of simulating parameters. Spectrum estimation, time-frequency analysis (TFA), and relative power analysis methods have been applied to investigate neural oscillation patterns under different stimulation parameters.

Results: Under PRF, 500 Hz and 1 kHz TUS, high-amplitude LFP activity with the auto-rhythmic pattern appeared in selected nuclei when I exceeded 12 mW/cm. With TFA, high-frequency energy (slow gamma and high gamma) was significantly increased during the auto-rhythmic patterns. We observed an initial plateau in nuclei response when I reached 16.4 mW/cm for RPF 500 Hz and 20.8 mW/cm for RPF 1 kHz. The number of responding nuclei started decreasing while I continued increasing. Under 1.5 kHz TUS, no auto-rhythmic patterns have been observed, but slow frequency power was increased during TUS. TUS inhibited most of the frequency band and generated obvious slow waves (theta and delta band) when stimulated at RPF = 1.5 kHz, = 8.8 mW/cm.

Conclusion: These results demonstrate that very low intensity Transcranial Ultrasound Stimulation (VLTUS) exerts significant neuromodulator effects under specific parameters in rat models and may be a valid tool to study neuronal physiology.
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http://dx.doi.org/10.3389/fnagi.2021.656430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081960PMC
April 2021

Amyloid-β Protein Precursor Deficiency Changes Neuronal Electrical Activity and Levels of Mitochondrial Proteins in the Medial Prefrontal Cortex.

J Alzheimers Dis 2021 Apr 28. Epub 2021 Apr 28.

Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou, China.

Background: Neuropathological features of Alzheimer's disease are characterized by the deposition of amyloid-β (Aβ) plaques and impairments in synaptic activity and memory. However, we know little about the physiological role of amyloid-β protein precursor (AβPP) from which Aβ derives.

Objective: Evaluate APP deficiency induced alterations in neuronal electrical activity and mitochondrial protein expression.

Methods: Utilizing electrophysiological, biochemical, pharmacological, and behavioral tests, we revealed aberrant local field potential (LFP), extracellular neuronal firing and levels of mitochondrial proteins.

Result: We show that APP knockout (APP -/- ) leads to increased gamma oscillations in the medial prefrontal cortex (mPFC) at 1-2 months old, which can be restored by baclofen (Bac), a γ-aminobutyric acid type B receptor (GABABR) agonist. A higher dose and longer exposure time is required for Bac to suppress neuronal firing in APP -/-  mice than in wild type animals, indicating enhanced GABABR mediated activity in the mPFC of APP -/-  mice. In line with increased GABABR function, the glutamine synthetase inhibitor, L-methionine sulfonate, significantly increases GABABR levels in the mPFC of APP -/-  mice and this is associated with a significantly lower incidence of death. The results suggest that APP -/-  mice developed stronger GABABR mediated inhibition. Using HEK 293 as an expression system, we uncover that AβPP functions to suppress GABABR expression. Furthermore, APP -/-  mice show abnormal expression of several mitochondrial proteins.

Conclusion: APP deficiency leads to both abnormal network activity involving defected GABABR and mitochondrial dysfunction, suggesting critical role of AβPP in synaptic and network function.
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http://dx.doi.org/10.3233/JAD-201557DOI Listing
April 2021

Variation, distribution, and diversity of canonical ammonia-oxidizing microorganisms and complete-nitrifying bacteria in highly contaminated ecological restoration regions in the Siding mine area.

Ecotoxicol Environ Saf 2021 Jul 27;217:112274. Epub 2021 Apr 27.

Key Laboratory of Ecology of Rare and Endangered Species and Environmental Protection (Guangxi Normal University), Ministry of Education, China; College of Environment and Resources, Guangxi Normal University, 541004 Guilin, China; Innovation Institute of Sustainable Development, Guangxi Normal University, 541004 Guilin, China. Electronic address:

Canonical ammonia-oxidizing archaea (AOA), ammonia-oxidizing bacteria (AOB) and complete-nitrifying bacteria (comammox) exist in a variety of ecosystems. However, little is known about AOA, AOB and comammox or their contributions to nitrification in the soils of heavily degraded and acidic mine regions. In the present study, the activity, richness, diversity and distribution patterns of AOA, AOB and comammox in the Siding mine area were investigated. Nemerow's multifactor pollution index (P) values indicated that the soil in all three areas in the Siding mine area was highly contaminated by Cd, Pb, Zn, Mn and Cu. The AOA, AOB and comammox amoA gene copy numbers exhibited significant positive correlations with Pb and Zn levels and P values, which indicated that the populations of AOA, AOB and comammox underwent adaptation and reproduction in response to pollution from multiple metals in the Siding mine area. Among them, the abundance of AOA was the highest, and AOA may survive better than AOB and comammox under such severely pollution-stressed and ammonia-limited conditions. The phyla Thaumarchaeota and Crenarchaeota may play vital roles in the soil ammonia oxidation process. Unlike AOA, AOB may use soil available phosphorus to help them compete for NH and other limiting nutrients with AOA and heterotrophs. Moreover, soil organic matter was the main factor influencing the species diversity of AOB, the β-diversity of AOB and comammox, and the community composition of AOA, AOB and comammox. Our research will help to explain the role and importance of AOA, AOB and comammox in the different ecological restoration regions in the Siding mine area.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112274DOI Listing
July 2021

One-Dimensional Superlattice Heterostructure Library.

J Am Chem Soc 2021 May 30;143(18):7013-7020. Epub 2021 Apr 30.

Division of Nanomaterials and Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, Institute of Energy, Hefei Comprehensive National Science Center, CAS Center for Excellence in Nanoscience, Department of Chemistry, Institute of Biomimetic Materials and Chemistry, Anhui Engineering Laboratory of Biomimetic Materials, University of Science and Technology of China, Hefei, Anhui 230026, China.

Axially, epitaxially organizing nano-objects of distinct compositions and structures into superlattice nanowires enables full utilization of sunlight, readily engineered band structures, and tunable geometric parameters to fit carrier transport, thus holding great promise for optoelectronics and solar-to-fuel conversion. To maximize their efficiency, the general and high-precision synthesis of colloidal axial superlattice nanowires (ASLNWs) with programmable compositions and structures is the prerequisite; however, it remains challenging. Here, we report an axial encoding methodology toward the ASLNW library with precise control over their compositions, dimensions, crystal phases, interfaces, and periodicity. Using a predesigned, editable nanoparticle framework that offers the synthetic selectivity, we are able to chemically decouple adjacent sub-objects in ASLNWs and thus craft them in a controlled approach, yielding a library of distinct ASLNWs. We integrate therein plasmonic, metallic, or near-infrared-active chalcogenides, which hold great potential in solar energy conversion. Such synthetic capability enables a performance boost in target applications, as we report order-of-magnitude enhanced photocatalytic hydrogen production rates using optimized ASLNWs compared to corresponding solo objects. Furthermore, it is expected that such unique superlattice nanowires could bring out new phenomena.
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http://dx.doi.org/10.1021/jacs.1c01514DOI Listing
May 2021

CD8 T cells actively penetrate into hepatocytes via CD44/p-ERM/F-actin pathway in autoimmune hepatitis.

J Dig Dis 2021 Apr 29. Epub 2021 Apr 29.

Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Institute of Digestive Disease, Shanghai, China.

Aim: Emperipolesis, the cell-in-cell structure, is one of the pathological diagnostic standard of AIH. We have already identified that CD8+ T cells participated in the emperipolesis process in liver tissue of AIH patients. In this study, we aimed to clarify the characteristics and molecular mechanisms of emperipolesis in the patients with AIH in vitro and in mice with α-GalCer-induced acute hepatitis.

Methods: Peripheral blood mononuclear cell (PBMC) of patients with variant chronic liver diseases and healthy controls were co-cultured with hepatic cell line to induce emperipolesis in vitro. Confocal staining was performed to illustrate the cellular types and potential mechanisms of emperipolesis in AIH. In addition, the mouse model of α-GalCer-induced acute hepatitis which mimics human AIH in several features, was used to confirm the role of CD44/p-ERM/F-actin in the emperipolesis process in vivo.

Results: In co-culture system with PBMC and hepatic cell line, emperipolesis was observed most common in the patients with AIH. CD8+ T cells were the major cells participated in the emperipolesis process, and penetrated into hepatocytes actively via CD44/p-ERM/F-actin pathway. As a result, most CD8+ T cells engulfed in hepatocytes undergo self-apoptosis. In α-GalCer-induced acute hepatitis model, emperipolesis was observed around the inflammatory foci, and was inhibited by Ezrin phosphorylation inhibitor NSC668394. Similarly, activated murine CD8+ T cells penetrated into primary hepatocytes via CD44/p-ERM/F-actin pathway in vitro.

Conclusions: CD8+ T cells penetrated into hepatocytes actively via CD44/p-ERM/F-actin signaling pathway and undergo apoptosis, may be a compensative mechanism to attenuate overwhelming immune attack in AIH. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/1751-2980.12995DOI Listing
April 2021

Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis.

Br J Clin Pharmacol 2021 Apr 30. Epub 2021 Apr 30.

Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis.

Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 72 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation.

Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC = 1 mg/L.

Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.
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http://dx.doi.org/10.1111/bcp.14881DOI Listing
April 2021

Design Overview of the MIT 1.3-GHz LTS/HTS NMR Magnet with a New REBCO Insert.

IEEE Trans Appl Supercond 2021 Aug 4;31(5). Epub 2021 Mar 4.

Francis Bitter Magnet Laboratory/Plasma Science and Fusion Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

We present a design overview of the MIT 1.3-GHz LTS/HTS NMR magnet (1.3G) with a newly designed 835-MHz REBCO insert (H835) as a replacement for the 800-MHz REBCO insert (H800) that was damaged when it quenched during operation in 2018. The new H835 is designed to contribute 19.6 T in a background field of 10.93 T by an LTS NMR magnet that normally rated at 11.74 T (500 MHz): combined, 1.3G generates a total field of 30.53 T corresponding to a proton resonance frequency of 1.3 GHz. H835 is designed to operate stably while meeting 1.3G design constraints. We have also designed H835 to protect it from permanent damage in an improbable event like a quench. Key design features are: 1) a single-coil formation, composed of 38 stacked metal-co-wound no-insulation and 2 stacked no-insulation double-pancake coils, all with mechanically improved cross-over sections; 2) enhanced thermal stability; and 3) reduced current margin with a detect-and-heat method. This paper includes: 1) electromagnetic and mechanical design of H835; 2) cryogenics overview; 3) quench protection strategy; and 3) discussion on the next steps to successfully complete 1.3G.
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http://dx.doi.org/10.1109/tasc.2021.3064006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078478PMC
August 2021

A Novel Multi-Sensor Fusion Algorithm Based on Uncertainty Analysis.

Sensors (Basel) 2021 Apr 12;21(8). Epub 2021 Apr 12.

Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.

During the research and development of multiphase flowmeters, errors are often used to evaluate the advantages and disadvantages of different devices and algorithms, whilst an in-depth uncertainty analysis is seldom carried out. However, limited information is sometimes revealed from the errors, especially when the test data are scant, and this makes an in-depth comparison of different algorithms impossible. In response to this problem, three combinations of sensing methods are implemented, which are the "capacitance and cross-correlation", the "cross-correlation and differential pressure" and the "differential pressure and capacitance" respectively. The analytical expressions of the gas/liquid flowrate and the associated standard uncertainty have been derived, and Monte Carlo simulations are carried out to determine the desired probability density function. The results obtained through these two approaches are basically the same. Thereafter, the sources of uncertainty for each combination are traced and their respective variations with flowrates are analyzed. Further, the relationship between errors and uncertainty is studied, which demonstrates that the two uncertainty analysis approaches can be a powerful tool for error prediction. Finally, a novel multi-sensor fusion algorithm based on the uncertainty analysis is proposed. This algorithm can minimize the standard uncertainty over the whole flowrate range and thus reduces the measurement error.
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http://dx.doi.org/10.3390/s21082713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069628PMC
April 2021

A multi-omics approach to lignocellulolytic enzyme discovery reveals a new ligninase activity from NO1.

Proc Natl Acad Sci U S A 2021 May;118(18)

Centre for Novel Agricultural Products, Department of Biology, University of York, York YO10 5DD, United Kingdom;

Lignocellulose, the structural component of plant cells, is a major agricultural byproduct and the most abundant terrestrial source of biopolymers on Earth. The complex and insoluble nature of lignocellulose limits its conversion into value-added commodities, and currently, efficient transformation requires expensive pretreatments and high loadings of enzymes. Here, we report on a fungus from the genus, isolated from a wheat-straw composting community, that secretes a large and diverse array of carbohydrate-active enzymes (CAZymes) when grown on lignocellulosic substrates. We describe an oxidase activity that cleaves the major β-ether units in lignin, thereby releasing the flavonoid tricin from monocot lignin and enhancing the digestion of lignocellulose by polysaccharidase mixtures. We show that the enzyme, which holds potential for the biorefining industry, is widely distributed among lignocellulose-degrading fungi from the Sordariomycetes phylum.
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http://dx.doi.org/10.1073/pnas.2008888118DOI Listing
May 2021

Cardiovascular disease and cumulative incidence of cognitive impairment in the Health and Retirement Study.

BMC Geriatr 2021 Apr 26;21(1):274. Epub 2021 Apr 26.

Division of Healthcare Delivery Science, Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.

Background: We sought to examine whether people with a diagnosis of cardiovascular disease (CVD) experienced a greater incidence of subsequent cognitive impairment (CI) compared to people without CVD, as suggested by prior studies, using a large longitudinal cohort.

Methods: We employed Health and Retirement Study (HRS) data collected biennially from 1998 to 2014 in 1305 U.S. adults age ≥ 65 newly diagnosed with CVD vs. 2610 age- and gender-matched controls. Diagnosis of CVD was adjudicated with an established HRS methodology and included self-reported coronary heart disease, angina, heart failure, myocardial infarction, or other heart conditions. CI was defined as a score < 11 on the 27-point modified Telephone Interview for Cognitive Status. We examined incidence of CI over an 8-year period using a cumulative incidence function accounting for the competing risk of death.

Results: Mean age at study entry was 73 years, 55% were female, and 13% were non-white. Cognitive impairment developed in 1029 participants over 8 years. The probability of death over the study period was greater in the CVD group (19.8% vs. 13.8%, absolute difference 6.0, 95% confidence interval 2.2 to 9.7%). The cumulative incidence analysis, which adjusted for the competing risk of death, showed no significant difference in likelihood of cognitive impairment between the CVD and control groups (29.7% vs. 30.6%, absolute difference - 0.9, 95% confidence interval - 5.6 to 3.7%). This finding did not change after adjusting for relevant demographic and clinical characteristics using a proportional subdistribution hazard regression model.

Conclusions: Overall, we found no increased risk of subsequent CI among participants with CVD (compared with no CVD), despite previous studies indicating that incident CVD accelerates cognitive decline.
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http://dx.doi.org/10.1186/s12877-021-02191-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074515PMC
April 2021

A case of Pseudoparalysis of parrot - Re-emergence of the great mimicker.

Am J Emerg Med 2021 Apr 17. Epub 2021 Apr 17.

Department of Emergency Medicine, University of North Carolina, 170 Manning Dr., CB# 7594, Chapel Hill, NC 27599-7594, United States; WakeMed Health and Hospitals, Children's Emergency Department, 3000 New Bern Ave., Raleigh, NC 27610, United States. Electronic address:

We present the case of a 2-month-old adopted female seeking evaluation in the pediatric emergency department due to a one-day history of decreased right arm movement and fussiness. The physical exam was largely unremarkable with the exception of decreased spontaneous movement of the right upper extremity, obvious discomfort with passive movement and subtle edema of the forearm. Because of concern for non-accidental trauma, plain films were obtained which revealed no signs of traumatic injury. Subsequently, a broader investigation ensued with infectious etiologies in mind. Laboratory evaluation demonstrated anemia, transaminitis, and elevated inflammatory markers. These abnormalities led to the consideration of congenitally acquired infections, specifically syphilis, and serologies were confirmatory. Ultimately, the infant was diagnosed with Pseudoparalysis of Parrot - a rare musculoskeletal manifestation secondary to painful syphilitic periostitis. As Emergency Medicine physicians, it is important to be aware of the growing burden of syphilis infection and reacquaint ourselves with its numerous presentations in the young infant.
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http://dx.doi.org/10.1016/j.ajem.2021.04.038DOI Listing
April 2021

Machine Learning Models to Improve the Differentiation Between Benign and Malignant Breast Lesions on Ultrasound: A Multicenter External Validation Study.

Cancer Manag Res 2021 16;13:3367-3379. Epub 2021 Apr 16.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Breast Center, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China.

Purpose: This study aimed to establish and evaluate the usefulness of a simple, practical, and easy-to-promote machine learning model based on ultrasound imaging features for diagnosing breast cancer (BC).

Materials And Methods: Logistic regression, random forest, extra trees, support vector, multilayer perceptron, and XG Boost models were developed. The modeling data set of 1345 cases was from a tertiary class A hospital in China. The external validation data set of 1965 cases were from 3 tertiary class A hospitals and 2 primary hospitals. The area under the receiver operating characteristic curve (AUC) was used as the main evaluation index, and pathological biopsy was used as the gold standard for evaluating each model. Diagnostic capability was also compared with that of clinicians.

Results: Among the six models, the logistic model showed superior diagnostic efficiency, with an AUC of 0.771 and 0.906 and Brier scores of 0.181 and 0.165 in the test and validation sets, respectively. The AUCs of the clinician diagnosis and the logistic model were 0.913 and 0.906. Their AUCs in the tertiary class A hospitals were 0.915 and 0.915, respectively, and were 0.894 and 0.873 in primary hospitals, respectively.

Conclusion: The externally validated logical model can be used to distinguish between malignant and benign breast lesions in ultrasound images. Compared with clinician diagnosis, the logistic model has better diagnostic efficiency, making it potentially useful to assist in screening, particularly in lower level medical institutions.

Trial Registration: http://www.clinicaltrials.gov. ClinicalTrials.gov ID: NCT03080623.
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http://dx.doi.org/10.2147/CMAR.S297794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057795PMC
April 2021

Anthropogenic-Driven Alterations in Black Carbon Sequestration and the Structure in a Deep Plateau Lake.

Environ Sci Technol 2021 05 22;55(9):6467-6475. Epub 2021 Apr 22.

Yunnan Research Academy of Eco-environmental Science, Kunming 650034, China.

The continuous flux of organic carbon (OC) from terrestrial ecosystems into inland water is an important component of the global carbon cycle. The buried OC pool in inland water sediments is considerable, and black carbon (BC) is a significant contributor to this OC pool because of the continuous growth in BC emissions. Therefore, determining the effect of BC on total OC burial and variations in the structure of BC during the burial process will contribute significantly to our understanding of lacustrine carbon cycling. This study investigated BC burial and its structural variations in response to anthropogenic drivers using four dated sedimentary cores from a deep plateau lake in China. The BC burial rate rose from 0.96 ± 0.64 g·m·y (mean of sedimentary cores pre-1960s) to 4.83 ± 1.25 g·m·y (after 2000), which is a 5.48 ± 2.12-fold rise. The increase of char was similar to those of BC. The growth rate of soot was 7.20 ± 4.30 times, which is higher than that of BC and char, increasing from 0.12 ± 0.08 to 0.64 ± 0.23 g·m·y. There was a decreasing trend in the ratio of char and soot at a mean rate of 62.8 ± 6.46% (excluding core 3) in relation to increased fossil fuel consumption. The contribution of BC to OC burial showed a significant increasing trend from the past to the present, particularly in cores 3 and 4, and the mean contribution of the four cores was 11.78 ± 2.84%. Source tracer results from positive matrix factorization confirmed that the substantial use of fossil fuels has promoted BC burial and altered the BC structure. This has resulted in BC with a higher aromatic content in the lake sediment, which exhibits reduced reactivity and increased stability. The strong correlation between BC and allochthonous total OC indicates that the input pathways of the buried BC in this plateau lake sediment were terrestrial surface processes and not atmospheric deposition.
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http://dx.doi.org/10.1021/acs.est.1c00106DOI Listing
May 2021

The Big Five Inventory-2 in China: A Comprehensive Psychometric Evaluation in Four Diverse Samples.

Assessment 2021 Apr 22:10731911211008245. Epub 2021 Apr 22.

University of California, Berkeley, CA, USA.

The Big Five Inventory-2 (BFI-2) has received wide recognition since its publication because it strikes a good balance between content coverage and brevity. The current study translated the BFI-2 into Chinese, evaluated its psychometric properties in four diverse Chinese samples (college students, adult employees, adults treated for substance use, and adolescents), and compared its factor structure with those obtained from two U.S. samples. Across two studies, the Chinese BFI-2 demonstrated good reliability (Cronbach's α and test-retest reliability), structural validity, convergent/discriminant validity, and criterion-related validity at the domain level. At lower levels of analyses, some facets and negatively worded items functioned better among participants with higher than those with lower education levels. Implications, limitations, and future directions are discussed.
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http://dx.doi.org/10.1177/10731911211008245DOI Listing
April 2021

The bone microenvironment invigorates metastatic seeds for further dissemination.

Cell 2021 Apr 19;184(9):2471-2486.e20. Epub 2021 Apr 19.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.
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http://dx.doi.org/10.1016/j.cell.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087656PMC
April 2021

Measuring nonhomologous end-joining, homologous recombination and alternative end-joining simultaneously at an endogenous locus in any transfectable human cell.

Nucleic Acids Res 2021 Apr 20. Epub 2021 Apr 20.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Double strand break (DSB) repair primarily occurs through 3 pathways: non-homologous end-joining (NHEJ), alternative end-joining (Alt-EJ), and homologous recombination (HR). Typical methods to measure pathway usage include integrated cassette reporter assays or visualization of DNA damage induced nuclear foci. It is now well understood that repair of Cas9-induced breaks also involves NHEJ, Alt-EJ, and HR pathways, providing a new format to measure pathway usage. Here, we have developed a simple Cas9-based system with validated repair outcomes that accurately represent each pathway and then converted it to a droplet digital PCR (ddPCR) readout, thus obviating the need for Next Generation Sequencing and bioinformatic analysis with the goal to make Cas9-based system accessible to more laboratories. The assay system has reproduced several important insights. First, absence of the key Alt-EJ factor Pol θ only abrogates ∼50% of total Alt-EJ. Second, single-strand templated repair (SSTR) requires BRCA1 and MRE11 activity, but not BRCA2, establishing that SSTR commonly used in genome editing is not conventional HR. Third, BRCA1 promotes Alt-EJ usage at two-ended DSBs in contrast to BRCA2. This assay can be used in any system, which permits Cas9 delivery and, importantly, allows rapid genotype-to-phenotype correlation in isogenic cell line pairs.
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http://dx.doi.org/10.1093/nar/gkab262DOI Listing
April 2021