Publications by authors named "Peng Liu"

3,132 Publications

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New insights into the functional role of retrotransposon dynamics in mammalian somatic cells.

Cell Mol Life Sci 2021 May 14. Epub 2021 May 14.

Biological Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Retrotransposons are genetic elements present across all eukaryotic genomes. While their role in evolution is considered as a potentially beneficial natural source of genetic variation, their activity is classically considered detrimental due to their potentially harmful effects on genome stability. However, studies are increasingly shedding light on the regulatory function and beneficial role of somatic retroelement reactivation in non-pathological contexts. Here, we review recent findings unveiling the regulatory potential of retrotransposons, including their role in noncoding RNA transcription, as modulators of mammalian transcriptional and epigenome landscapes. We also discuss technical challenges in deciphering the multifaceted activity of retrotransposable elements, highlighting an unforeseen central role of this neglected portion of the genome both in early development and in adult life.
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http://dx.doi.org/10.1007/s00018-021-03851-5DOI Listing
May 2021

Pyrite/HO/hydroxylamine system for efficient decolorization of rhodamine B.

Water Sci Technol 2021 May;83(9):2218-2231

School of Chemical Engineering, Chongqing University of Technology, Chongqing 400054, China E-mail:

To improve the efficiency of the Fe(II)/Fe(III) cycle and continuous reactivity of pyrite, a pyrite/HO/hydroxylamine (HA) system was proposed to treat rhodamine B (RhB). The results showed that near-complete decolorization and 52.8% mineralization 50 mg L RhB were achieved under its optimum conditions: HA 0.8 mM, HO 1.6 mM, pyrite 0.4 g L, and initial pH 4.0. The degradation reaction was dominated by an •OH radical produced by the reaction of Fe with HO in solution. HA primarily had two roles: in solution, HA could accelerate the Fe(II)/Fe(III) cycle through its strong reducibility to enhance RhB decolorization; on the pyrite surface, HA could improve the continuous reactivity of pyrite by inhibiting the oxidation of pyrite. In addition, the dosing manner of HA had a significant effect on RhB decolorization. In addition, the high decolorization and mineralization efficiency of other dye pollutants suggested that the pyrite/HO/HA system might be widely used in textile wastewater treatment.
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http://dx.doi.org/10.2166/wst.2021.135DOI Listing
May 2021

Separation of Rare-Earth Ions from Mine Wastewater Using BS Nanoflakes as a Capacitive Deionization Electrode Material.

J Nanosci Nanotechnol 2021 Nov;21(11):5459-5476

College of Materials and Chemistry & Chemical Engineering, Chengdu University of Technology Chengdu 610059, China.

In this study, nanoflakes of BS were fabricated by plasma-assisted reaction of sulfur dichloride in an ionic liquid at room temperature using europium boride as a hard template. The nanoflakes had an average width and thickness of about 3 urn and 9.6 nm, respectively, and a large specific surface area of 1197.2 m² g . They behaved like typical electric double-layer capacitors with a capacitance of 201.2 F g at 0.2 mA cm ² During capacitive deionization to recover rare-earth ions, the nanoflakes had higher adsorption selectivity for Sm than for other competing ions present in real mine waste water. This is due to the strong interaction of the electron-concentered S-groups (S''') of the nanoflakes with S m. This provides an alternative to construct efficient systems to specifically remove Sm from aqueous solution using BS nanoflakes. This process demonstrates that other boron sulfide compounds can be used to recover valuable ions by capacitive deionization.
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http://dx.doi.org/10.1166/jnn.2021.19466DOI Listing
November 2021

Identification of prognosis-related molecular subgroups based on DNA methylation in pancreatic cancer.

Clin Epigenetics 2021 May 12;13(1):109. Epub 2021 May 12.

Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.

Background: Pancreatic cancer (PC) is one of the most lethal and aggressive cancer malignancies. The lethality of PC is associated with delayed diagnosis, presence of distant metastasis, and its easy relapse. It is known that clinical treatment decisions are still mainly based on the clinical stage and pathological grade, which are insufficient to determine an appropriate treatment. Considering the significant heterogeneity of PC biological characteristics, the current clinical classificatory pattern relying solely on classical clinicopathological features identification needs to be urgently improved. In this study, we conducted in-depth analyses to establish prognosis-related molecular subgroups based on DNA methylation signature.

Results: DNA methylation, RNA sequencing, somatic mutation, copy number variation, and clinicopathological data of PC patients were obtained from The Cancer Genome Atlas (TCGA) dataset. A total of 178 PC samples were used to develop distinct molecular subgroups based on the 4227 prognosis-related CpG sites. By using consensus clustering analysis, four prognosis-related molecular subgroups were identified based on DNA methylation. The molecular characteristics and clinical features analyses based on the subgroups offered novel insights into the development of PC. Furthermore, we built a risk score model based on the expression data of five CpG sites to predict the prognosis of PC patients by using Lasso regression. Finally, the risk score model and other independent prognostic clinicopathological information were integrative utilised to construct a nomogram model.

Conclusion: Novel prognosis-related molecular subgroups based on the DNA methylation signature were established. The specific five CpG sites model for PC prognostic prediction and the derived nomogram model are effective and intuitive tools. Moreover, the construction of molecular subgroups based on the DNA methylation data is an innovative complement to the traditional classification of PC and may contribute to precision medicine development, therapeutic efficacy prediction, and clinical decision guidance.
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http://dx.doi.org/10.1186/s13148-021-01090-wDOI Listing
May 2021

Subaxial Cervical Pedicular Screw Insertion via the Nonanatomic Axis: Technical Notes and Preliminary Clinical Report.

Global Spine J 2021 May 12:21925682211015649. Epub 2021 May 12.

Division of Spine surgery, Center for Orthopedics, Daping Hospital, Army Medical University, Chongqing, China.

Study Design: Retrospective study.

Objective: To report the technical details of subaxial cervical pedicular screw insertion via the nonanatomic axis (nAA-CPS) and evaluate its clinical safety and accuracy.

Methods: The nAA-CPS technique was performed in 21 patients. Preoperative and intraoperative management-related details are described, and a manipulation protocol is presented. Clinical outcomes were used to assess the safety and accuracy of screws was evaluated using postoperative computed tomography (CT) according to the pedicle perforation grading system, and the nonanatomic pedicle transverse angle (nPTA) and nonanatomic pedicle axis length (nPAL) were assessed based on pre- and postoperative CT images.

Results: According to "one constant entry point (EP) and two perpendicular trajectory angles" protocol, nAA-CPS was performed without much interference from the muscles. No intraoperative or postoperative neurovascular complications related to the technique were observed. Of the 112 inserted screws, 78 (69.64%) were assessed as grade 0, 24 (21.43%) as grade 1, 4 (3.57%) as grade 2 and 6 (5.36%) as grade 3. The overall rate of correct position (grades 0 and 1) was 91.07% (102/112), and the rate of malposition was 8.93% (10/112), including five screws implanted medially and the other five laterally. The nPTA was highly consistent on pre- and postoperative CT ( < .05), while postoperative nPAL was significantly shorter than preoperative nPAL ( > .05).

Conclusions: Clinically, the accuracy and safety of nAA-CPS was similar to the traditional CPS technique. The protocol, derived from previous radiological studies and workshops, greatly helped standardize clinical manipulation; thus, nAA-CPS is a promising alternative to the traditional CPS.
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http://dx.doi.org/10.1177/21925682211015649DOI Listing
May 2021

Proteome-Wide Chromatin Interactomics to Study Plant Epigenetics.

Trends Plant Sci 2021 May 8. Epub 2021 May 8.

KAUST Environmental Epigenetics Program, Division of Biological Environmental Sciences and Engineering, King Abdullah University of Science and Technology, 23955-6900, Thuwal, Saudi Arabia. Electronic address:

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http://dx.doi.org/10.1016/j.tplants.2021.04.002DOI Listing
May 2021

Anionic Polysaccharide-Modified Filter Papers for Rapid Isolation of Extracellular Vesicles from Diverse Samples in a Simple Bind-Wash-Elute Manner.

Anal Chem 2021 May 11. Epub 2021 May 11.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China.

Extracellular vesicles (EVs) play a significant role in the pathophysiological process of many diseases, highlighting their values in medical diagnosis and disease monitoring. However, the current EV isolation methods are time-consuming, inconvenient to operate, and incompatible with downstream analyses. Here, we present a novel isolation method employing anionic polysaccharide-modified filter papers for the isolation of EVs (AppiEV) via electrostatic adsorption. A disc of glass fiber-based filter modified with sodium alginate was assembled into a spin column to function as the solid capture phase. In the acidic condition, EVs were induced to carry more positively charged ions, which enable the capture of EVs by the negatively charged filter paper. After a wash, the EVs were released from the spin column using an alkaline elution buffer, which induces the EVs to carry more negative charges. The EVs isolated by AppiEV from cell culture supernatants, plasma, and urine are similar to or even better than those isolated by ultracentrifugation in terms of EV size distribution, protein distribution, and nucleic acid contents. Due to the interference removal of the EV-free RNA and DNA attributed to the negatively charged capture medium, the eluate of AppiEV could be directly used for genetic analysis, including the stem-loop RT-PCR analysis of miR-21 and the allele-specific PCR analysis of mutation genes of p.L858R and p.T790M. We believe that AppiEV offers a simple and efficient approach for the isolation of high-quality EVs from various liquid specimens.
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http://dx.doi.org/10.1021/acs.analchem.0c02107DOI Listing
May 2021

Lung cancer organoids analyzed on microwell arrays predict drug responses of patients within a week.

Nat Commun 2021 May 10;12(1):2581. Epub 2021 May 10.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.

While the potential of patient-derived organoids (PDOs) to predict patients' responses to anti-cancer treatments has been well recognized, the lengthy time and the low efficiency in establishing PDOs hamper the implementation of PDO-based drug sensitivity tests in clinics. We first adapt a mechanical sample processing method to generate lung cancer organoids (LCOs) from surgically resected and biopsy tumor tissues. The LCOs recapitulate the histological and genetic features of the parental tumors and have the potential to expand indefinitely. By employing an integrated superhydrophobic microwell array chip (InSMAR-chip), we demonstrate hundreds of LCOs, a number that can be generated from most of the samples at passage 0, are sufficient to produce clinically meaningful drug responses within a week. The results prove our one-week drug tests are in good agreement with patient-derived xenografts, genetic mutations of tumors, and clinical outcomes. The LCO model coupled with the microwell device provides a technically feasible means for predicting patient-specific drug responses in clinical settings.
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http://dx.doi.org/10.1038/s41467-021-22676-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110811PMC
May 2021

Survival and pretreatment prognostic factors for extensive-stage small cell lung cancer: A comprehensive analysis of 358 patients.

Thorac Cancer 2021 May 9. Epub 2021 May 9.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.

Background: Extensive-stage small cell lung cancer (ES-SCLC) is deemed as a fatal malignancy with a poor prognosis. Although immunotherapy has gradually played an important role in the treatment of ES-SCLC since 2018, ES-SCLC treatment data and patient outcome before 2018, when chemotherapy served as a fundamental therapeutic strategy, is still meaningful as a summary of the situation regarding previous medical treatment and is a baseline for comparative data. In addition, the prognostic factors of ES-SCLC have failed to reach a consensus until now. Therefore, this study aimed to evaluate survival and identify the prognostic factors in an ES-SCLC population.

Methods: We retrospectively collected the detailed medical records of 358 patients with ES-SCLC from January 1, 2011 to December 31, 2018 in a Chinese top-level cancer hospital. The prognostic factors were evaluated by Cox univariate and multivariate analysis.

Results: The median overall survival (OS) of ES-SCLC patients (N = 358) was 14.0 months, the one- and two-year OS rates were 56.2% and 21.7%, respectively. Moreover, we identified two demographic characters (age ≥ 70, smoking index ≥ 400), one tumor burden factor (bone multimetastasis), two tumor biomarkers (cyfra211, CA125) and two laboratory indexes (decreased Na, PLR < 76) as independent prognostic factors for OS in this patient population. Progression-free survival (PFS) data of 238 patients was obtained for further analysis, and the median PFS was 6.2 months, and six-month and one-year PFS rates were 51.7% and 14.3%, respectively. Elevated cyfra211, decreased Hb and Na were identified as independent prognostic factors for PFS.

Conclusions: This study provides real-world evidence of the survival and prognosis of ES-SCLC patients which will enable better evaluation and clinical decision-making in the future.
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http://dx.doi.org/10.1111/1759-7714.13977DOI Listing
May 2021

Case Report: Vertebral Artery Dissection After Intravascular Stenting of the Contralateral Unruptured Vertebral Artery Aneurysm.

Front Neurol 2021 23;12:599197. Epub 2021 Apr 23.

Department of Interventional Neuroradiology, Beijing Neurosurgical Institute, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China.

Spontaneous vertebral artery dissecting aneurysm has been increasingly attributed as a major cause of focal neurological deficits due to vertebrobasilar artery ischemia or subarachnoid hemorrhage (SAH). Although the development of spontaneous vertebral artery dissecting aneurysm (VADA) is rare, VADA after treatment of contralateral vertebral artery (VA) is more less frequently observed. There are only a few reports related to VADA after treatment of the contralateral VA in the medical literature. The mechanisms responsible for dissection after treatment of unilateral VADA are still not clearly understood. In this manuscript, we report an unusual case of a patient with a VADA after placement of a pipeline embolization device (PED) stent on the contralateral VA along with a thorough review of the literature. A 42-years old male patient was referred to the hospital with sudden onset of dizziness, nausea, and vomiting. Initial digital subtraction angiography (DSA) images demonstrated a VADA in the fourth segment of the left VA without the involvement of the posterior inferior cerebellar artery (PICA). There were no significant abnormalities found in the right vertebral artery. He underwent an endovascular pipeline embolization to treat the dissecting aneurysm (DA). Surprisingly, follow-up DSA imaging 14 months after the initial treatment showed a segmental dilatation and narrowing of the right VA, which suggested a VADA on the right side that had occurred postoperatively. This was followed by a tent-assisted coil embolization therapy for occluding this VADA. This patient showed an uneventful postoperative course with no neurological abnormalities. In addition to hemodynamic stress changes, the unique clinicopathological features of dissecting aneurysms may contribute significantly to the pathogenesis of VA dissection. Given that VA in VADA patients may be vulnerable on both sides, it is important to consider the risk of dissection after initial aneurysm treatment. The bilateral vertebral artery has to be carefully observed when treating any VADA patient to prevent any complications.
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http://dx.doi.org/10.3389/fneur.2021.599197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102744PMC
April 2021

Altered fractional amplitude of low-frequency fluctuation in women with premenstrual syndrome via acupuncture at Sanyinjiao (SP6).

Ann Gen Psychiatry 2021 May 8;20(1):29. Epub 2021 May 8.

Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China.

Background: Premenstrual syndrome (PMS) is a prevalent gynecological disease and is significantly associated with abnormal neural activity. Acupuncture is an effective treatment on PMS in clinical practice. However, few studies have been performed to investigate whether acupuncture might modulate the abnormal neural activity in patients with PMS. Thereby, the aim of the study was to assess alterations of the brain activity induced by acupuncture stimulation in PMS patients.

Methods: Twenty PMS patients were enrolled in this study. All patients received a 6-min resting-state functional magnetic resonance imaging (rs-fMRI) scan before and after electro-acupuncturing stimulation (EAS) at Sanyinjiao (SP6) acupoint in the late luteal phase of menstrual. Fractional amplitude of low-frequency fluctuation (fALFF) method was applied to examine the EAS-related brain changes in PMS patients.

Results: Compared with pre-EAS at SP6, increased fALFF value in several brain regions induced by SP6, including brainstem, right thalamus, bilateral insula, right paracentral lobule, bilateral cerebellum, meanwhile, decreased fALFF in the left cuneus, right precuneus, left inferior temporal cortex.

Conclusions: Our findings provide imaging evidence to support that SP6-related acupuncture stimulation may modulate the neural activity in patients with PMS. This study may partly interpret the neural mechanisms of acupuncture at SP6 which is used to treat PMS patients in clinical.

Trial Registration: The study was registered on http://www.chictr.org.cn . The Clinical Trial Registration Number is ChiCTR-OPC-15005918, registry in 29/01/2015.
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http://dx.doi.org/10.1186/s12991-021-00349-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106846PMC
May 2021

Ruthenabenzene: A Robust Precatalyst.

J Am Chem Soc 2021 May 7. Epub 2021 May 7.

Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, Illinois 60607, United States.

Metallaaromatics constitute a unique class of aromatic compounds where one or more transition metal elements are incorporated into the aromatic system, the parent of which is metallabenzene. One of the main concerns about metallabenzenes generally deals with the structural characterization related to their relative aromaticity compared to the carbon archetype. Transition metal-containing metallabenzenes are also implicated in certain catalytic processes such as alkyne metathesis polymerization; however, these transition metal-based metallaaromatic compounds have not been developed as a catalyst. Herein, we describe an effective strategy to generate diverse arrays of ruthenabenzenes and demonstrated them as an aromatic equivalent of the Grubbs-type ruthenium alkylidene catalysts. These ruthenabenzenes can be prepared via an enyne metathesis and metallotropic [1,3]-shift cascade process to form alkyne-chelated ruthenium alkylidene intermediates followed by spontaneous cycloaromatization. The aromatic nature of these complexes was confirmed by spectroscopic and X-ray crystallographic data, and the mechanistic pathways for the cycloaromatization process were studied by DFT calculations. These ruthenabenzenes display robust catalytic activity for metathesis and other transformations, which illustrates that metallabenzenes are not only compounds of structural and theoretical interests but also are a novel platform for new catalyst development.
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http://dx.doi.org/10.1021/jacs.1c02237DOI Listing
May 2021

Predictive Value of Blood Ammonia in the Prognosis of Acute Liver Failure Evaluated by Receiver Operating Characteristic Curves.

Turk J Gastroenterol 2021 Feb;32(2):164-168

Critical Care Center, Fifth Medical Center of Chinese PLA Hospital, Beijing, China.

Background: To investigate the predictive value of blood ammonia (BLA) quantification in the prognosis of acute liver failure (ALF).

Methods: Seventy-one patients with ALF were enrolled and BLA concentration was measured in all patients. After following up for 28 days, patients were divided into two groups: the surviving group (n = 21) and the deceased group (n = 50). An independent-samples t-test was used to compare BLA concentrations between the two groups, and receiver operating characteristic curves were used to ¬evaluate the predictive value of BLA in the prognosis of ALF. A fourfold table analysis was performed with the determined BLA cutoff value.

Results: The average concentration of BLA in the deceased group was significantly higher compared with the surviving group (144.50 µmol/L vs. 106 µmol/L, respectively; P = .035). The cutoff BLA concentration for a good ALF prognosis was 122.5 µmol/L. The area under the curve was 0.659. Both the sensitivity and specificity were >0.6. The 95% CIs for sensitivity and specificity were 0.452-0.733 and 0.477-0.878, respectively. The fourfold table analysis revealed a positive predictive value of 83.3%, a negative predictive value of 42.9%, a misdiagnosis rate of 28.6%, and an accuracy of 63.4%.

Conclusion: With a cutoff BLA concentration of 122.5 µmol/L, the prognosis of ALF could be predicted with high sensitivity and specificity, a positive predictive value, a low misdiagnosis rate, and good accuracy.
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http://dx.doi.org/10.5152/tjg.2021.19663DOI Listing
February 2021

Three-dimensional cell printed lock-key structure for oral soft and hard tissue regeneration.

Tissue Eng Part A 2021 May 6. Epub 2021 May 6.

University of Michigan School of Dentistry, 43800, Ann Arbor, Michigan, United States;

Alveolar ridge absorbs rapidly following tooth extraction. To promote implant rehabilitation, an adequate bone and soft tissue volume are required. Three-dimensional (3D) cell printing technique provides the advantages of precise spatial distribution and personalization. In this study, 3D cell printing was used to establish a soft-hard construct that is composed of alginate/gelatin (AG)/gingival fibroblast cells (GFs) and alginate/gelatin/nano-hydroxyapatite (AGH)/bone marrow-derived mesenchymal stem cells (BMSCs). Physicochemical results showed that nano-hydroxyapatite (nHA) added in the bioink maintained its crystalline phase. In addition, an increase of viscosity, the improvement of compressive modulus (P<0.01), and slow degradation rate (P<0.01) were found after adding nHA. SEM showed cell stretched and attached well on the surface of the 3D printed construct. At day 7 after printing, the viability of GFs in AG was 94.80%±1.14, while BMSCs viability in AGH was 86.59%±0.75. PCR results indicated that the expression levels of ALP, RUNX-2, and OCN in BMSCs were higher in AGH than AG bioink (P<0.01). After 8-week implantation into the dorsum of 6-8-week-old male BALB/c nude mice, the cellular printed construct displayed a more integrated structure and better healing of subcutaneous tissue compared with the acellular printed construct. In conclusion, this 3D cell printed soft-hard construct exhibits favorable biocompatibility and has potential for alveolar ridge preservation.
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http://dx.doi.org/10.1089/ten.TEA.2021.0022DOI Listing
May 2021

Electroacupuncture at GV20‑GB7 regulates mitophagy to protect against neurological deficits following intracerebral hemorrhage via inhibition of apoptosis.

Mol Med Rep 2021 Jul 6;24(1). Epub 2021 May 6.

Department of Clinical Medicine, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China.

The acupuncture penetrating line of Baihui (GV20) to Qubin (GB7) spans the parietal, frontal and temporal lobes. The present study aimed to elucidate the mechanism by which electroacupuncture (EA) at GV20‑GB7 regulates mitophagy in intracerebral hemorrhage (ICH) and whether it serves a neuroprotective role. A whole blood‑induced ICH model was used. Mitophagy‑regulating proteins, including BCL/adenovirus E1B 19 kDa‑interacting protein 3 (BNIP3), PTEN‑induced putative kinase 1 (PINK1), Parkin and apoptosis‑associated proteins were detected by western blotting; autophagy following ICH was evaluated by immunofluorescent techniques; morphological characteristics of mitophagy were observed using transmission electron microscopy; and TUNEL assay was performed to determine the number of apoptotic cells. Immunohistochemistry was used to detect p53 expression. The protective role of EA (GV20‑GB7) via enhanced mitophagy and suppressed apoptosis in ICH was further confirmed by decreased modified neurological severity score. The results showed that EA (GV20‑GB7) treatment upregulated mitochondrial autophagy following ICH and inhibited apoptotic cell death. The mechanism underlying EA (GV20‑GB7) treatment may involve inhibition of p53, an overlapping protein of autophagy and apoptosis. EA (GV20‑GB7) treatment decreased neurobehavioral deficits following ICH but pretreatment with 3‑methyladenine counteracted the beneficial effects of EA (GV20‑GB7) treatment. In conclusion, EA (GV20‑GB7) improved recovery from ICH by regulating the balance between mitophagy and apoptosis.
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http://dx.doi.org/10.3892/mmr.2021.12131DOI Listing
July 2021

Application of Enhanced Recovery after Surgical Treatment of the Occipitocervical Region.

Orthop Surg 2021 May 5. Epub 2021 May 5.

Department of Orthopaedic Surgery, Eastern Hospital, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.

Objective: The concept of enhanced recovery after surgery (ERAS) has been proposed to provide guidance for the improved postoperative rehabilitation of patients with occipitocervical region disease (ORD).

Methods: This study retrospectively investigated 208 consecutive patients (116 men and 92 women) ranging in age from 22 to 76 years with ORD between July 2014 and June 2017 in our medical center, who were divided into three groups that received different preoperative, intraoperative, and postoperative management plans: traditional group (n = 73), ameliorated group (n = 70), and ERAS group (n = 65). We compiled a range of data relating to demographics and postoperative changes in hemoglobin and albumin, surgery duration, intraoperative blood loss, number of postoperative hospitalization days and expenses, readmission rates, and visual analog scale pain symptoms. Data were statistically evaluated using one-way analysis of variance with Student-Newman-Keuls-q post hoc tests or chi-square tests.

Results: There were no significant differences in terms of age (P = 0.235), gender (P = 0.691), body mass index (P = 0.723), American Society of Anesthesiologists grade (0.747), lesion character (P = 0.337) and lesion site (P = 0.957) between the three groups. Within a 6 months follow-up period, there was no significant difference between the three groups in terms of surgery duration (P = 0.225), blood loss (P = 0.172), changes in hemoglobin (P = 0.255) and albumin (P = 0.178). However, postoperative hospitalization days (P = 0.000), postoperative costs (P = 0.019) and improvement of pain symptoms (P = 0.000) in ERAS group were significantly lower or higher than those in traditional group or ameliorated group, respectively. There were 29 (39.73%), 22 (31.43%), and 13 (20.00%), recorded cases of postoperative complications in traditional group, ameliorated group and ERAS group, respectively; complications in ERAS group were significantly lower than those in other two groups (P = 0.043). Moreover, all of the complications were mitigated effectively by the infusion of fluid, analgesia, treatment of infections, or antiemetic medications. There were 2 (2.74%), 3 (4.29%) and 2 (3.08%), recorded cases of re-admission in traditional group, ameliorated group and ERAS group, respectively, but there were no statistically significant differences when compared across the three groups (P = 0.866).

Conclusions: ERAS can provide benefits when it applied to patients undergoing ORD surgery mainly in terms of reducing postoperative complications, however, ERAS does not increase the economic burden of patients or decrease the risk of readmission.
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http://dx.doi.org/10.1111/os.13018DOI Listing
May 2021

MR1 overexpression correlates with poor clinical prognosis in glioma patients.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab034. Epub 2021 Feb 20.

Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Background: Glioblastoma is the most common adult primary brain tumor with near-universal fatality. Major histocompatibility complex (MHC) class I molecules are important mediators of CD8 activation and can be downregulated by cancer cells to escape immune surveillance. MR1 is a nonclassical MHC-I-like molecule responsible for the activation of a subset of T cells. Although high levels of MR1 expression should enhance cancer cell recognition, various tumors demonstrate MR1 overexpression with unknown implications. Here, we study the role of MR1 in glioma.

Methods: Using multi-omics data from the Cancer Genome Atlas (TCGA), we studied expression patterns and its impact on survival for various solid tumors. In glioma specifically, we validated expression by histology, elucidate transcriptomic profiles of high versus low gliomas. To understand expression, we analyzed the methylation status of the gene and gene-related transcription factor (TF) expression.

Results: is overexpressed in all grades of glioma and many other solid cancers. However, only in glioma, overexpression correlated with poor overall survival and demonstrated global dysregulation of many immune-related genes in an -dependent manner. MR1 overexpression correlated with decreased gene methylation and upregulation of predicted promoter binding TFs, implying gene methylation might regulate MR1 expression in glioma.

Conclusions: Our in silico analysis shows that expression is a predictor of clinical outcome in glioma patients and is potentially regulated at the epigenetic level, resulting in immune-related genes dysregulation. These findings need to be validated using independent in vitro and in vivo functional studies.
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http://dx.doi.org/10.1093/noajnl/vdab034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080245PMC
February 2021

Dietary Structure and Nutritional Status of Chinese Beekeepers: Demographic Health Survey.

JMIR Public Health Surveill 2021 May 3;7(5):e28726. Epub 2021 May 3.

Department of Clinical Nutrition, Peking University People's Hospital, Beijing, China.

Background: Beekeeping and honey gathering are traditional forms of agricultural farming in China. However, only few studies have focused on the nutritional status and health level of this special occupational group.

Objective: By comparing the health status of apiculturists (beekeepers) and vegetable farmers in plain areas of Hubei Province, and analyzing the influence of dietary structure and intake on their nutritional level, this paper provides a scientific theoretical basis for the further development of health education and disease prevention for beekeepers.

Methods: From February to April 2016, 191/236 beekeepers (80.9% of the total beekeepers) with large-scale breeding (300-500 colonies) and 182 vegetable farmers in the same area were sampled by the cluster sampling method. Their nutrient composition was analyzed using a human body composition analyzer, dietary structure information was collected using the dietary frequency query method, and cognitive function was investigated. In addition, blood samples of both groups were collected.

Results: A total of 362 valid questionnaires (beekeepers/vegetable farmers: 185/177) were collected, with an effective response rate of 97.1% (362/373). Both beekeepers and vegetable farmers were overweight, and the beekeepers' grip strength was much stronger than that of the vegetable farmers' regardless of gender. The dietary structure of beekeepers is very unique: 29.7% (55/185) of beekeepers indicated consuming royal jelly regularly for more than 10 years. Their main foods are grain, cereals, and fresh vegetables; 68.1% (126/185) of the beekeepers never drank milk and other dairy products, and their overall nutrient intake is unbalanced. The average intake of cellulose in this group was also significantly higher than that in the epidemiological survey in the same sex and age group. The intake of vitamin A and selenium in the beekeepers group was significantly higher than that in the vegetable-farmers group (all P<.001). The blood indices of creatinine (P=.03) and blood copper (P<.001) in the beekeepers group were significantly higher than those in the vegetable-farmers group, and the total protein, albumin, calcium, sodium, potassium, phosphorus, folic acid, and vitamin B12 in the beekeepers group were significantly lower than those in the vegetable-farmers group (P<.03 for potassium and P<.001 for others). The total Mini-Mental State Examination (MMSE) score of the beekeepers group was 28.1, significantly higher (P=.006) than that of the vegetable-farmers group (23.3).

Conclusions: The beekeepers in this area have their special dietary structure, body nutrient level, and disease characteristics. The cognitive level of the beekeepers who regularly consume royal jelly is significantly higher than that of their peers. The chronic diseases of this special occupational group are closely related to their lifestyle and nutritional status, so more attention and in-depth studies are needed to improve the quality of life of this population.
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http://dx.doi.org/10.2196/28726DOI Listing
May 2021

Administration Timing and Efficacy of Tocilizumab in Patients With COVID-19 and Elevated IL-6.

Front Mol Biosci 2021 15;8:651662. Epub 2021 Apr 15.

Department of Infection Diseases No. 1, The Maternal and Child Health Hospital of Hubei Province, Wuhan, China.

Background: Tocilizumab (TCZ), an interleukin-6 receptor antibody, has previously been used for treating patients with the coronavirus disease 2019 (COVID-19), but there is a lack of data regarding the administration timing of TCZ.

Objectives: This study aimed to evaluate the timing and efficacy of TCZ in the treatment of patients with COVID-19.

Methods: Laboratory-confirmed patients with COVID-19 with an elevated interleukin-6 (IL-6) level (>10 pg/ml) were offered TCZ intravenously for compassionate use. Clinical characteristics, laboratory tests, and chest imaging before and after the administration of TCZ were retrospectively analyzed.

Results: A total of 58 consecutive patients who met the inclusion criteria and with no compliance to the exclusion criteria were included. Of these 58 patients, 39 patients received TCZ treatment, and 19 patients who declined TCZ treatment were used as the control cohort. In the TCZ-treatment group, 6 patients (15.4%) were in mild condition, 16 (41.0%) were in severe condition, and 17 (43.6%) were in critical condition. After TCZ treatment, the condition of 27 patients (69.2%) improved and 12 (30.8%) died. Compared with the improvement group, patients in the death group had higher baseline levels of IL-6 ( = 0.0191) and procalcitonin (PCT) ( = 0.0003) and lower lymphocyte percentage (LYM) ( = 0.0059). Patients receiving TCZ treatment had better prognoses than those without TCZ treatment ( = 0.0273). Furthermore, patients with a baseline IL-6 level of ≥100 pg/ml in the TCZ-treatment group had poorer clinical outcomes than those with an IL-6 level of <100 pg/ml ( = 0.0051).

Conclusion: The administration of TCZ in an early stage of cytokine storm (IL-6 level < 100 pg/ml) may effectively improve the clinical prognosis of patients with COVID-19 by blocking the IL-6 signal pathway.
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http://dx.doi.org/10.3389/fmolb.2021.651662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084410PMC
April 2021

Identification and Characterization of an O-Succinyl-L-Homoserine Sulfhydrylase From .

Front Chem 2021 14;9:672414. Epub 2021 Apr 14.

The National and Local Joint Engineering Research Center for Biomanufacturing of Chiral Chemicals, Zhejiang University of Technology, Hangzhou, China.

L-methionine is an important natural amino acid with broad application prospects. A novel gene encoding the enzyme with the ability to catalyze O-succinyl-L-homoserine (OSH) to L-methionine was screened and characterized. The recombinant O-succinyl-L-homoserine sulfhydrylase from (OSHS) exhibited maximum activity at 35°C and pH 6.5. OSHS displayed an excellent thermostability with a half-life of 21.72 h at 30°C. Furthermore, the activity of OSHS increased 115% after Fe added. L-methionine was obtained with a total yield reaching 42.63 g/L under the concentration of O-succinyl-L-homoserine 400 mM (87.6 g/L). These results indicated that OSHS is a potential candidate for applying in the large-scale bioproduction of L-methionine.
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http://dx.doi.org/10.3389/fchem.2021.672414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080516PMC
April 2021

Hepatocellular-cholangiocarcinoma with sarcomatous change: Clinicopathological features and outcomes.

Hepatobiliary Pancreat Dis Int 2021 Apr 17. Epub 2021 Apr 17.

Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yan-ta Road, Xi'an 710061, China; National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. Electronic address:

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http://dx.doi.org/10.1016/j.hbpd.2021.03.011DOI Listing
April 2021

Simulation of natural aging property of microplastics in Yangtze River water samples via a rooftop exposure protocol.

Sci Total Environ 2021 Apr 23;785:147265. Epub 2021 Apr 23.

State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210093, China. Electronic address:

Due to low aging rate, the environmental behavior of naturally weathered microplastics (MPs) are not fully understood. Here, we systematically investigated the surface property and adsorption behavior of polypropylene (PP), polyethylene (PE) and polystyrene (PS) MPs during outdoor exposure in Yangtze River water for 18 months, and compared their difference from those in laboratory process. Results showed that compared to PE and PS MPs, PP underwent higher changes in surface aging properties such as rapid fragmentation and surface oxidation. Outdoor exposure exhibited different effects on adsorption property of MPs for metal ions, where adsorption capacities of PE and PS MPs for Co(II) were increased with aging degrees, while few change occurred on different aged PP MPs. As for Cr(VI), aging process further decreased the overall adsorption on PP, PE and PS MPs. The difference was mainly ascribed to the surface property (e.g. oxygen-containing groups and size) and the adhered biofilm and charged minerals. We further validated that similar types of oxidation products were formed between natural and laboratory aging of MPs, whereas the reaction order of these products, fragmentation rate and the change in adsorption property of aged MPs might be different in both processes. The findings provide essential information to assess real environmental behavior of MP samples.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147265DOI Listing
April 2021

Smaller volume and altered functional connectivity of the amygdala in patients with lifelong premature ejaculation.

Eur Radiol 2021 Apr 30. Epub 2021 Apr 30.

Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, Shaanxi, China.

Objectives: To analyze the abnormal amygdala structure and function in lifelong premature ejaculation (PE) patients compared with healthy controls (HCs).

Methods: Forty-four lifelong PE patients and thirty-one HCs were enrolled in this study. Each subject was diagnosed with PE using a Premature Ejaculation Diagnostic Tool (PEDT) and intravaginal ejaculation latency time (IELT) score. Based on t-tests and Pearson correlation analysis, the voxel-based morphometry and functional connectivity (FC) analyses were applied to evaluate brain structural and functional changes by using T1-weighted and resting-state functional magnetic resonance imaging scans.

Results: Lifelong PE patients had decreased gray matter volume in the bilateral amygdala and increased FC between the amygdala and precuneus, posterior cingulate cortex (PCC), and middle temporal cortex (MTC), as well as decreased FC between the amygdala and precentral gyrus, insula, and inferior frontal gyrus. Moreover, significantly negative correlations between the IELT score and the mean z-score from amygdala-MTC (r = -0.49) and amygdala-PCC (r = -0.48) FC were found in lifelong PE patients.

Conclusions: Our study investigated the abnormal amygdala-related structure and connectivity patterns in PE patients, which might provide novel perspective for understanding the crucial role of the amygdala in the neural mechanism of PE.

Key Points: • As one of the most common diseases in men, PE may be related to abnormal brain mechanisms. • Functional and structural magnetic resonance imaging used to explore amygdala abnormalities in PE patients. • The correlation between clinical scores and functional connectivity was used to assess the reasonability of the results.
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http://dx.doi.org/10.1007/s00330-021-08002-9DOI Listing
April 2021

Choriocapillaris Changes Are Correlated With Disease Duration and MoCA Score in Early-Onset Dementia.

Front Aging Neurosci 2021 13;13:656750. Epub 2021 Apr 13.

Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.

: Imaging of the choroid may detect the microvascular changes associated with early-onset dementia (EOD) and may represent an indicator for detection of the disease. We aimed to analyze the choriocapillaris (CC) flow density in EOD patients using optical coherence tomography angiography (OCTA) and evaluate the association with its clinical measures. : This cross-sectional study used the OCTA to image and analyze the choriocapillaris (CC) of 25 EOD patients and 20 healthy controls. Choriocapillaris flow density in the 3 mm area and 6 mm area was measured by an inbuilt algorithm in the OCT tool. Brain volume using magnetic resonance imaging and cognitive assessment was done and recorded. : Significantly reduced capillary flow density of the choriocapillaris was seen in EOD patients when compared to healthy controls in the 3.0 mm ( = 0.001) and 6.0 mm ( < 0.001) area respectively. Montreal Cognitive Assessment (MoCA) scores in EOD patients positively correlated with choriocapillaris flow density in the 3 mm area (Rho = 0.466, = 0.021). Disease duration of EOD patients also negatively correlated with choriocapillaris density in the 3 mm area (Rho = -0.497, = 0.008). : Our report suggests that choriocapillaris damage may be a potential indicator of early-onset dementia. Microvascular impairment may be involved in the early phase of dementia without aging playing a role in its impairment. : www.ClinicalTrials.gov, ChiCTR2000041386.
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http://dx.doi.org/10.3389/fnagi.2021.656750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076507PMC
April 2021

Treatment and mechanism of fecal microbiota transplantation in mice with experimentally induced ulcerative colitis.

Exp Biol Med (Maywood) 2021 Apr 29:15353702211006044. Epub 2021 Apr 29.

Department of Anorectal, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, P.R. China.

Restoring intestinal microbiota dysbiosis with fecal microbiota transplantation is considered as a promising treatment for ulcerative colitis. However, the mechanisms underlying its relieving effects remain unclear. Ulcerative colitis pathogenesis is associated with the involvement of immune cells and inflammatory cytokines. Here, we aimed to investigate the effect of fecal microbiota transplantation on T cell cytokines in a dextran sulfate sodium-induced ulcerative colitis mouse model. Five-aminosalicylic acid (5-ASA) was used as the positive control. Male C57BL/6 mice were randomly assigned to control, model (UC), UC + FMT, and UC + 5-ASA groups. Each group consisted of five mice. The establishment of the mouse model was verified by fecal occult-blood screening and hematoxylin-eosin staining. Results showed that fecal microbiota transplantation reduced colonic inflammation, significantly decreased T helper (Th)1 and Th17 cells, interferon-gamma, interleukin-2 and interleukin-17, as well as significantly increased Th2 and regulatory T (Treg) cells, interleukin-4, interleukin-10, and transforming growth factor-beta, and improved routine blood count. Furthermore, 16S rRNA gene-sequencing analysis showed a significant increase in the relative abundance of genus and a significant decrease in the relative abundance of genus in the ulcerative colitis group. Fecal microbiota transplantation restored the profile of the intestinal microbiota to that of the control group. These findings demonstrated the capability of fecal microbiota transplantation in controlling experimentally induced ulcerative colitis by improving Th1/Th2 and Th17/Treg imbalance through the regulation of intestinal microbiota.
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http://dx.doi.org/10.1177/15353702211006044DOI Listing
April 2021

Gene Coexpression Network Analysis Indicates that Hub Genes Related to Photosynthesis and Starch Synthesis Modulate Salt Stress Tolerance in .

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, Beijing 100083, China.

L. is an excellent afforestation and biofuel tree that produces high-quality wood, rich in starch. In addition, is highly adaptable to adverse environmental conditions, which is conducive to its utilization for vegetating saline soils. However, little is known about the physiological responses and transcriptional regulatory network of under salt stress. In this study, we exposed five main cultivars in saline-alkali land (Upu2, 5, 8, 11, and 12) to NaCl stress. Of the five cultivars assessed, Upu11 exhibited the highest salt resistance. Growth and biomass accumulation in Upu11 were promoted under low salt concentrations (<150 mM). However, after 3 months of continuous treatment with 150 mM NaCl, growth was inhibited, and photosynthesis declined. A transcriptome analysis conducted after 3 months of treatment detected 7009 differentially expressed unigenes (DEGs). The gene annotation indicated that these DEGs were mainly related to photosynthesis and carbon metabolism. Furthermore, PHOTOSYNTHETIC ELECTRON TRANSFERH (UpPETH), an important electron transporter in the photosynthetic electron transport chain, and UpWAXY, a key gene controlling amylose synthesis in the starch synthesis pathway, were identified as hub genes in the gene coexpression network. We identified 25 and 62 unigenes that may interact with PETH and WAXY, respectively. Overexpression of UpPETH and UpWAXY significantly increased the survival rates, net photosynthetic rates, biomass, and starch content of transgenic plants under salt stress. Our findings clarify the physiological and transcriptional regulators that promote or inhibit growth under environmental stress. The identification of salt-responsive hub genes directly responsible for photosynthesis and starch synthesis or metabolism will provide targets for future genetic improvements.
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http://dx.doi.org/10.3390/ijms22094410DOI Listing
April 2021

Causes and predictors of mortality from lupus nephritis in Southern Hunan, China.

Mod Rheumatol 2021 Apr 28:1-16. Epub 2021 Apr 28.

Department of Nephrology, The First Affiliated Hospital of University of South China, Hengyang, Hunan Province, China.

The objective of the study was to explore the causes and predictors of mortality in a cohort of LN with LN in southern Hunan, China. We analyzed 236 patients with biopsy-proven LN during 2010-2018. Demographic data, laboratory data, SLEDAI scores, treatment strategies, and comorbidity were collected. Cox regression analysis was carried out to determine the independent predictors of mortality. The patients had mean disease duration of 67.9 ± 28.2 months. Class IV LN was the predominant biopsy class within the cohort (38.1%). After 1 year therapy, the majority of patients achieved complete remission (72.9%) and 44 (18.6%) patients achieved partial remission. The 5- and 10-years survival rates for our cohort were 94.4% and 85.2%, respectively. There were 18 deaths (7.6%), of which the main causes were infection (50%) alone and cardiovascular diseases (27.8%). Independent predictors of mortality in our cohort were: platelet-to-neutrophil ratio (PNR) [hazard ratio (HR) 5.910; confidence interval (CI) 1.253-27.875], onset age (HR 1.090; CI 1.035-1.147), and SLEDAI scores (HR 1.258; CI 1.068-1.482). We firstly revealed that PNR might be a promising predictor of mortality and reported the causes and prognostic predictors of mortality in LN from southern Hunan, China.
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http://dx.doi.org/10.1080/14397595.2021.1920097DOI Listing
April 2021

Efficacy and safety of double-filtration plasmapheresis treatment of myasthenia gravis: A systematic review and meta-analysis.

Medicine (Baltimore) 2021 Apr;100(17):e25622

Hebei Key Laboratory of Myasthenia Gravis, Center of Treatment of Myasthenia Gravis Hebei Province, First Hospital of Shijiazhuang, Chang'an District, Shijiazhuang, Hebei Province, China.

Objectives: To evaluate the efficacy of double-filtration plasmapheresis (DFPP) treatment of myasthenia gravis (MG) through a systematic review and meta-analysis.

Methods: PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang databases were searched for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) on DFPP for MG from database establishment to June 2019. Two researchers independently screened the articles, extracted the data, and cross checked the results. RevMan 5.3 was used for statistical analyses.

Results: Seven RCTs and 2 CCTs were found comprising 329 patients. The results showed that clinical MG remission rate after DFPP treatment was significantly higher (OR = 4.33; 95% confidence interval [CI], 1.97-9.53; P < .001) and the serum levels of antititin antibody was significantly decreased (standardized mean difference [SMD] = 9.30; 95% CI, 7.51-11.08; P < .001). In addition, the quantitative MG (QMG) score, hospital stay and time to remission of MG symptoms, and acetylcholine receptor antibody (AchRAb) decreased in the DFPP treatment group; however, these outcomes had high heterogeneity among the studies. Only one study has reported on the adverse effects, including hypotension and hematoma.

Conclusion: This meta-analysis suggests that DFPP can be recommended for the short-term mitigation of MG. Because our review was limited by the quantity and quality of the included studies, the above conclusions should be verified by additional high-quality studies.
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http://dx.doi.org/10.1097/MD.0000000000025622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084046PMC
April 2021

Red blood cells serve as a vehicle for PEDV transmission.

Vet Microbiol 2021 Apr 20;257:109081. Epub 2021 Apr 20.

MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, PR China. Electronic address:

As the most abundant cell type in the blood, red blood cells (RBCs) are serving for transporting oxygen. However, the mechanism by which RBCs binding virus remains largely unknown. Here, we demonstrated that porcine epidemic diarrhea virus (PEDV), a kind of coronavirus, could hijack RBCs and cause typical diarrhea in neonatal piglets. In an epidemiology investigation of PEDV, the RBCs samples from diarrheic pigs in several pig farms were found to be PEDV-positive. PEDV could bind to neonatal RBCs through CD71 and clathrin-mediated endocytosis, and its viability was maintained for 12 h. PEDV-loaded RBCs could transfer the virus to CD3 T cells by conjugation and reach the intestine mucosa, where it caused infection. Finally, a further animal challenge revealed that transfusing with PEDV-loaded RBCs could cause intestinal epithelial cells (IECs) infection and typical diarrhea symptom. Therefore, our studies illustrated the mechanism by which PEDV could cause intestinal infection through hijacking RBCs, further providing a novel insight into the role of RBCs as potential cells for viral transmission in coronavirus pathogenesis.
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http://dx.doi.org/10.1016/j.vetmic.2021.109081DOI Listing
April 2021

Extranodal Rosai Dorfman disease mimicking multiple liver metastases.

Authors:
Che Liu Peng Liu

Hepatobiliary Surg Nutr 2021 Apr;10(2):297-298

Department of Hepatobiliary surgery, The Sixth Medical Center of PLA General Hospital, Beijing, China.

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http://dx.doi.org/10.21037/hbsn-20-642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050581PMC
April 2021