Characterization of Fluorescent Proteins with Intramolecular Photostabilization*

Chembiochem. 2021 Jul 22. doi: 10.1002/cbic.202100276. Online ahead of print.

ABSTRACT

Genetically encodable fluorescent proteins have revolutionized biological imaging in vivo and in vitro. Despite their importance, their photophysical properties, i. e., brightness, count-rate and photostability, are relatively poor compared to synthetic organic fluorophores or quantum dots. Intramolecular photostabilizers were recently rediscovered as an effective approach to improve photophysical properties of organic fluorophores. Here, direct conjugation of triplet-state quenchers or redox-active substances creates high local concentrations of photostabilizer around the fluorophore. In this paper, we screen for effects of covalently linked photostabilizers on fluorescent proteins. We produced a double cysteine mutant (A206C/L221C) of α-GFP for attachment of photostabilizer-maleimides on the β-barrel near the chromophore. Whereas labelling with photostabilizers such as trolox, a nitrophenyl group, and cyclooctatetraene, which are often used for organic fluorophores, had no effect on α-GFP-photostability, a substantial increase of photostability was found upon conjugation to azobenzene. Although the mechanism of the photostabilizing effects remains to be elucidated, we speculate that the higher triplet-energy of azobenzene might be crucial for triplet-quenching of fluorophores in the blue spectral range. Our study paves the way for the development of fluorescent proteins with photostabilizers in the protein barrel by methods such as unnatural amino acid incorporation.

PMID:34296494 | DOI:10.1002/cbic.202100276

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Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma

Br J Haematol. 2021 Jul 22. doi: 10.1111/bjh.17527. Online ahead of print.

ABSTRACT

ZUMA-1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous CD19-directed chimaeric antigen receptor (CAR)-T cell therapy, in refractory large B-cell lymphoma. To reduce treatment-related toxicity, several exploratory safety management cohorts were added to ZUMA-1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end-points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days -5 through -3), 2 × 106 CAR-T cells/kg (day 0) and once-daily oral dexamethasone [10 mg, day 0 (before axi-cel) through day 2]. Forty patients received axi-cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty-eight per cent of patients did not experience CRS or NEs within 72 h of axi-cel. With a median follow-up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.

PMID:34296427 | DOI:10.1111/bjh.17527

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Nutritional and ecological perspectives of the interrelationships between diet and the gut microbiome in multiple sclerosis: Insights from marmosets

iScience. 2021 Jun 10;24(7):102709. doi: 10.1016/j.isci.2021.102709. eCollection 2021 Jul 23.

ABSTRACT

Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, have shown potential links between diet components, microbiome composition, and modulation of immune responses. In this review, we reanalyze and discuss findings in an outbred marmoset EAE model in which a yogurt-based dietary supplement decreased disease frequency and severity. We show that although diet has detectable effects on the fecal microbiome, microbiome changes are more strongly associated with the EAE development. Using an ecological framework, we further show that the dominant factors influencing the gut microbiota were marmoset sibling pair and experimental time point. These findings emphasize challenges in assigning cause-and-effect relationships in studies of diet-microbiome-host interactions and differentiating the diet effects from other environmental, stochastic, and host-related factors. We advocate for animal experiments to be designed to allow causal inferences of the microbiota’s role in pathology while considering the complex ecological processes that shape microbial communities.

PMID:34296070 | PMC:PMC8282968 | DOI:10.1016/j.isci.2021.102709

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Performance of Basic Life Support by Lifeboat Crewmembers While Wearing a Survival Suit and Life Vest: A Randomized Controlled Trial

Front Public Health. 2021 Jul 6;9:666553. doi: 10.3389/fpubh.2021.666553. eCollection 2021.

ABSTRACT

Introduction: Crewmembers of the “Royal Netherlands Sea Rescue Institution” (KNRM) lifeboats must wear heavy survival suits with integrated lifejackets. This and the challenging environment onboard (boat movements, limited space) might influence Basic Life Support (BLS) performance. The primary objective of this study was to assess the impact of the protective gear on single-rescuer BLS-quality. Material and Methods: Sixty-five active KNRM crewmembers who had recently undergone a BLS-refresher course were randomized to wear either their protective gear (n = 32) or their civilian clothes (n = 33; control group) and performed five 2-min sessions of single rescuer BLS on a mannequin on dry land. BLS-quality was assessed according to Dutch and European Resuscitation guidelines. A between group analysis (Mann-Whitney U) and a repeated within group analysis of both groups (Friedman test) were performed. Results: There were no major demographic differences between the groups. The protective gear did not significant impair BLS-quality. It was also not associated with a significant increase in the perceived exertion of BLS (Borg’s Rating scale). Compression depth, compression frequency, the percentage of correct compression depth and of not leaning on the thorax, and ventilation volumes in both groups were suboptimal when evaluated according to the BLS-guidelines. Conclusions: The protective gear worn by KNRM lifeboat-crewmembers does not have a significant influence on BLS-quality under controlled study conditions. The impact and significance on outcome in real life situations needs to be studied further. This study provides valuable input for optimizing the BLS-skills of lifeboat crewmembers.

PMID:34295867 | PMC:PMC8290161 | DOI:10.3389/fpubh.2021.666553

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How to get the most out of the ERS International Congress 2021 and an overview of the Early Career Member session

Breathe (Sheff). 2021 Jun;17(2):210057. doi: 10.1183/20734735.0057-2021.

ABSTRACT

This article provides a brief description of the Early Career Member session and guidance on how to get the most out of the European Respiratory Society (ERS) International Congress 2021, to help attendees plan their Congress in advance. https://bit.ly/3dBNrYC.

PMID:34295434 | PMC:PMC8291941 | DOI:10.1183/20734735.0057-2021

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Evolutionary dynamics of the elevational diversity gradient in passerine birds

Nat Ecol Evol. 2021 Jul 22. doi: 10.1038/s41559-021-01515-y. Online ahead of print.

ABSTRACT

Low-elevation regions harbour the majority of the world’s species diversity compared to high-elevation areas. This global gradient suggests that lowland species have had more time to diversify, or that net diversification rates have been higher in the lowlands. However, highlands seem to be cradles of diversity as they contain many young endemics, suggesting that their rates of speciation are exceptionally fast. Here we use a phylogenetic diversification model that accounts for the dispersal of species between different elevations to examine the evolutionary dynamics of the elevational diversity gradient in passerine birds, a group that has radiated globally to occupy almost all elevations and latitudes. We find strong support for a model in which passerines diversify at the same rate in the highlands and the lowlands but in which the per-capita rate of dispersal from high to low elevations is more than twice as fast as that in the reverse direction. This suggests that while there is no consistent trend in diversification across elevations, part of the diversity generated by highland regions migrates into the lowlands, thus setting up the observed gradient in passerine diversity. We find that this process drives tropical regions but for temperate areas, the analysis could be hampered by their lower richness. Despite their lower diversity, highland regions are disproportionally important for maintaining diversity in the adjacent lowlands.

PMID:34294897 | DOI:10.1038/s41559-021-01515-y

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The Transcriptome of Paired Major and Minor Salivary Gland Tissue in Patients With Primary Sjögren’s Syndrome

Front Immunol. 2021 Jul 6;12:681941. doi: 10.3389/fimmu.2021.681941. eCollection 2021.

ABSTRACT

BACKGROUND: While all salivary glands (SGs) can be involved in primary Sjögren’s syndrome (pSS), their respective role in pathogenesis remains unclear. Our objective was to assess immunopathway activation in paired parotid and labial gland tissue from biopsy-positive and biopsy-negative pSS and non-SS sicca patients.

METHODS: Paraffin-embedded, paired parotid and labial salivary gland tissue and peripheral blood mononuclear cells were obtained from 39 pSS and 20 non-SS sicca patients. RNA was extracted, complementary DNA libraries were prepared and sequenced. For analysis of differentially expressed genes (DEGs), patients were subdivided based on fulfillment of ACR-EULAR criteria and histopathology.

RESULTS: With principal component analysis, only biopsy-positive pSS could be separated from non-SS sicca patients based on SG gene expression. When comparing the transcriptome of biopsy-positive pSS and biopsy-negative non-SS sicca patients, 1235 and 624 DEGs (FDR<0.05, log2FC<-1 or >1) were identified for parotid and labial glands, respectively. The number of DEGs between biopsy-negative pSS and non-SS sicca patients was scarce. Overall, transcript expression levels correlated strongly between parotid and labial glands (R2 = 0.86, p-value<0.0001). Gene signatures present in both glands of biopsy-positive pSS patients included IFN-α signaling, IL-12/IL-18 signaling, CD3/CD28 T-cell activation, CD40 signaling in B-cells, DN2 B-cells, and FcRL4+ B-cells. Signature scores varied considerably amongst pSS patients.

CONCLUSION: Transcriptomes of paired major and minor SGs in pSS were overall comparable, although significant inter-individual heterogeneity in immunopathway activation existed. The SG transcriptome of biopsy-negative pSS was indistinguishable from non-SS sicca patients. Different patterns of SG immunopathway activation in pSS argue for personalized treatment approaches.

PMID:34295332 | PMC:PMC8291032 | DOI:10.3389/fimmu.2021.681941

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Functional network topology of the right insula affects emotion dysregulation in hyperactive-impulsive attention-deficit/hyperactivity disorder

Sci Rep. 2021 Jul 22;11(1):15045. doi: 10.1038/s41598-021-94426-8.

ABSTRACT

Emotion dysregulation is common in attention-deficit/hyperactivity disorder (ADHD). It is highly prevalent in young adult ADHD and related to reduced well-being and social impairments. Neuroimaging studies reported neural activity changes in ADHD in brain regions associated with emotion processing and regulation. It is however unknown whether deficits in emotion regulation relate to changes in functional brain network topology in these regions. We used a combination of graph analysis and structural equation modelling (SEM) to analyze resting-state functional connectivity in 147 well-characterized young adults with ADHD and age-matched healthy controls from the NeuroIMAGE database. Emotion dysregulation was gauged with four scales obtained from questionnaires and operationalized through a latent variable derived from SEM. Graph analysis was applied to resting-state data and network topology measures were entered into SEM models to identify brain regions whose local network integration and connectedness differed between subjects and was associated with emotion dysregulation. The latent variable of emotion dysregulation was characterized by scales gauging emotional distress, emotional symptoms, conduct symptoms, and emotional lability. In individuals with ADHD characterized by prominent hyperactivity-impulsivity, the latent emotion dysregulation variable was related to an increased clustering and local efficiency of the right insula. Thus, in the presence of hyperactivity-impulsivity, clustered network formation of the right insula may underpin emotion dysregulation in young adult ADHD.

PMID:34294803 | DOI:10.1038/s41598-021-94426-8

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Corrigendum to “Update of the EAU/ESPU guidelines on urinary tract infections in children” [J Pediatr Urol 17 (2021) 200-207]

J Pediatr Urol. 2021 Jul 19:S1477-5131(21)00324-7. doi: 10.1016/j.jpurol.2021.06.022. Online ahead of print.

NO ABSTRACT

PMID:34294583 | DOI:10.1016/j.jpurol.2021.06.022

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Physicochemical properties of heat-moisture treated, sodium stearate complexed starch: The effect of sodium stearate concentration

Carbohydr Polym. 2021 Oct 1;269:118263. doi: 10.1016/j.carbpol.2021.118263. Epub 2021 May 27.

ABSTRACT

Amylose‑sodium stearate (SS) complexes (2, 5 and 8%) in heat-moisture treated potato starch (HPS) were evaluated for their physicochemical properties. Based on the DSC thermograms, the amylose – SS complexes were successfully formed with high thermal stability, indicated by a melt temperature (Tpeak) of ≥ 112 °C for type I and ≥125 °C for type II complexes. Addition of 2% SS resulted in a single endothermal peak of the complexes, while 5 and 8% led to the formation of type I and II complexes with much higher enthalpy (ΔH) values. The XRD curve confirmed that the complexes were successfully formed. The pasting temperature increased from 66 °C for native to 91 °C for HPS145 complexed starch with 5% SS. Furthermore, the swelling power could be largely decreased, and the granular structure preserved. In addition, the inclusion complexation with SS on (HPS) succesfully improved the cook stabiliy.

PMID:34294296 | DOI:10.1016/j.carbpol.2021.118263

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Systematic study and uncertainty evaluation of P, T-odd molecular enhancement factors in BaF

J Chem Phys. 2021 Jul 21;155(3):034309. doi: 10.1063/5.0047344.

ABSTRACT

A measurement of the magnitude of the electric dipole moment of the electron (eEDM) larger than that predicted by the Standard Model (SM) of particle physics is expected to have a huge impact on the search for physics beyond the SM. Polar diatomic molecules containing heavy elements experience enhanced sensitivity to parity (P) and time-reversal (T)-violating phenomena, such as the eEDM and the scalar-pseudoscalar (S-PS) interaction between the nucleons and the electrons, and are thus promising candidates for measurements. The NL-eEDM collaboration is preparing an experiment to measure the eEDM and S-PS interaction in a slow beam of cold BaF molecules [P. Aggarwal et al., Eur. Phys. J. D 72, 197 (2018)]. Accurate knowledge of the electronic structure parameters, Wd and Ws, connecting the eEDM and the S-PS interaction to the measurable energy shifts is crucial for the interpretation of these measurements. In this work, we use the finite field relativistic coupled cluster approach to calculate the Wd and Ws parameters in the ground state of the BaF molecule. Special attention was paid to providing a reliable theoretical uncertainty estimate based on investigations of the basis set, electron correlation, relativistic effects, and geometry. Our recommended values of the two parameters, including conservative uncertainty estimates, are 3.13 ±0.12×1024Hzecm for Wd and 8.29 ± 0.12 kHz for Ws.

PMID:34293876 | DOI:10.1063/5.0047344

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Rethinking remdesivir for COVID-19: A Bayesian reanalysis of trial findings

PLoS One. 2021 Jul 23;16(7):e0255093. doi: 10.1371/journal.pone.0255093. eCollection 2021.

ABSTRACT

BACKGROUND: Following testing in clinical trials, the use of remdesivir for treatment of COVID-19 has been authorized for use in parts of the world, including the USA and Europe. Early authorizations were largely based on results from two clinical trials. A third study published by Wang et al. was underpowered and deemed inconclusive. Although regulators have shown an interest in interpreting the Wang et al. study, under a frequentist framework it is difficult to determine if the non-significant finding was caused by a lack of power or by the absence of an effect. Bayesian hypothesis testing does allow for quantification of evidence in favor of the absence of an effect.

FINDINGS: Results of our Bayesian reanalysis of the three trials show ambiguous evidence for the primary outcome of clinical improvement and moderate evidence against the secondary outcome of decreased mortality rate. Additional analyses of three studies published after initial marketing approval support these findings.

CONCLUSIONS: We recommend that regulatory bodies take all available evidence into account for endorsement decisions. A Bayesian approach can be beneficial, in particular in case of statistically non-significant results. This is especially pressing when limited clinical efficacy data is available.

PMID:34297766 | DOI:10.1371/journal.pone.0255093

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Post-ischemic normothermic machine perfusion and post-transplant cholangiopathy

Br J Surg. 2021 Jul 16:znab253. doi: 10.1093/bjs/znab253. Online ahead of print.

NO ABSTRACT

PMID:34297800 | DOI:10.1093/bjs/znab253

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Therapeutic anticoagulation after liver transplantation is not useful among patients with pre-transplant Yerdel-grade I/II portal vein thrombosis. A two-centre retrospective study

J Thromb Haemost. 2021 Jul 23. doi: 10.1111/jth.15472. Online ahead of print.

ABSTRACT

BACKGROUND: Portal vein thrombosis (PVT) is no longer a contraindication for liver transplantation (LT). While therapeutic anticoagulation (tAC) is recommended during the waiting period, there is no evidence for its usefulness in the prevention of PVT recurrence after LT.

OBJECTIVES: The aim of our study was to evaluate the role of tAC post-LT in the prevention of PVT recurrence.

PATIENTS/METHODS: All adult LTs performed in 2 high volume centres between 2003 and 2018, were retrospectively analysed. Only patients with PVT classified as Yerdel grade I or II and with standard portal reconstruction were included. PVT recurrence and tAC-associated morbidity within 1 year were compared between patients receiving tAC or not.

RESULTS: During the study period, out of 2612 LTs performed, 235 (9%) patients with PVT were included. 113 patients (48.1%) received post-LT tAC (tAC group) while 122 (51.9%) did not (non-tAC group). The incidence of bleeding events was significantly higher in the tAC group (26 (23%) vs. 5 (4.1%), p<0.01) and the initial hospitalization duration was longer (21 vs. 17.5 days, p<0.01). Within the first year, PVT recurrence was observed for 9 (3.8%) patients without any difference between the tAC and non-tAC groups (6 (5.1%) vs. 3 (2.5%), p=0.39). The only identified risk factor for PVT recurrence was the recipients’ age (OR=0.94, p=0.03). Graft (p=0.11) and patient (p=0.44) survival were similar between the 2 groups.

CONCLUSION: Therapeutic anticoagulation is not necessary in the prevention of grade I/II PVT recurrence and is associated with higher morbidity and longer hospital stay.

PMID:34297481 | DOI:10.1111/jth.15472

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Properties of a New Group of Cosmic Nuclei: Results from the Alpha Magnetic Spectrometer on Sodium, Aluminum, and Nitrogen

Phys Rev Lett. 2021 Jul 9;127(2):021101. doi: 10.1103/PhysRevLett.127.021101.

ABSTRACT

We report the properties of sodium (Na) and aluminum (Al) cosmic rays in the rigidity range 2.15 GV to 3.0 TV based on 0.46 million sodium and 0.51 million aluminum nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. We found that Na and Al, together with nitrogen (N), belong to a distinct cosmic ray group. In this group, we observe that, similar to the N flux, both the Na flux and Al flux are well described by the sums of a primary cosmic ray component (proportional to the silicon flux) and a secondary cosmic ray component (proportional to the fluorine flux). The fraction of the primary component increases with rigidity for the N, Na, and Al fluxes and becomes dominant at the highest rigidities. The Na/Si and Al/Si abundance ratios at the source, 0.036±0.003 for Na/Si and 0.103±0.004 for Al/Si, are determined independent of cosmic ray propagation.

PMID:34296911 | DOI:10.1103/PhysRevLett.127.021101

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Talking about chronic pain: Misalignment in discussions of the body, mind and social aspects in pain clinic consultations

Health (London). 2021 Jul 22:13634593211032875. doi: 10.1177/13634593211032875. Online ahead of print.

ABSTRACT

In Western societies, human existence and illness are mostly constructed from the perspective of mind-body dualism: body and mind are considered to function independently, and the body/the physical as primary and more real. Research shows, however, that mind-body dualism is no longer tenable, especially in healthcare contexts. This led to the rise the biopsychosocial model, in which bodily experiences, including illness, are seen an interplay of the physical and the psychological, and the social. This model is the current gold standard for treating chronic pain. As these perspectives on the body and illness are potentially conflicting, and discursively constructed, this paper examines whether they are a source of misalignment in interactions between chronic pain patients and their doctors in a pain clinic. The analysis shows these perspectives indeed lead to misalignment, for instance when discussing the relevance of psychotherapy, and lead to intricate uses of argumentative resources to account for the differing perspectives on (the treatment of) pain.

PMID:34291691 | DOI:10.1177/13634593211032875

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The wing scales of the Mother-of-pearl butterfly, Protogoniomorpha parhassus, are thin film reflectors causing strong iridescence and polarization

J Exp Biol. 2021 Jul 22:jeb.242983. doi: 10.1242/jeb.242983. Online ahead of print.

ABSTRACT

The dorsal wings of the Mother-of-pearl butterfly, Protogoniomorpha parhassus, display an angle-dependent pink, structural color. This effect is created by light interference in the lower lamina of the wing scales, which acts as an optical thin film. The scales feature extremely large windows that enhance the scale reflectance, because the upper lamina of ridges and crossribs is very sparse. Characteristic for thin film reflectors, the spectral shape of the reflected light strongly depends on the angle of light incidence, shifting from pink to yellow when changing the angles of illumination and observation from normal to skew, and also the degree of polarization strongly varies. The simultaneous spectral and polarization changes serve a possibly widespread, highly effective communication system among butterflies for intraspecific communication during flight.

PMID:34291802 | DOI:10.1242/jeb.242983

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Exposure radius of a local coal mine in an Arctic coastal system; correlation between PAHs and mercury as a marker for a local mercury source

Environ Monit Assess. 2021 Jul 21;193(8):499. doi: 10.1007/s10661-021-09287-5.

ABSTRACT

Mercury in the Arctic originates from emissions and releases at lower latitudes and, to a lesser extent, from local and regional sources. The relationship between mercury (Hg) and polycyclic aromatic hydrocarbons (PAHs) in sediment can be applied as an indicator of the mercury source. This research examines the Hg contamination gradient from a land-based coal mine to the surrounding coastal environment to quantify the impact of local sources. Total mercury and PAH (Σ14PAH) were measured in terrestrial and marine sediments as well as in marine biota. Samples were collected at the mine and two reference sites. Mercury and Σ14PAH concentrations in samples collected at the mine site were significantly higher than those at the reference sites. This was also found in the biota samples, although less pronounced. This work addresses the complexities of interpreting data concerning very low contaminant levels in a relatively pristine environment. A clear correlation between PAH and Hg concentration in sediment was found, although a large number of samples had levels below detection limits. PAH profiles, hierarchical clustering, and molecular diagnostic ratios provided further insight into the origin of PAHs and Hg, showing that signatures in sediments from the nearest reference site were more similar to the mine, which was not the case for the other reference site. The observed exposure radius from the mine was small and diluted from land to water to marine biota. Due to low contamination levels and variable PAH profiles, marine biota was less suitable for tracing the exposure radius for this local land-based Hg source. With an expected increase in mobility and availability of contaminants in the warming Arctic, changes in input of PAHs and Hg from land-based sources to the marine system need close monitoring.

PMID:34291327 | DOI:10.1007/s10661-021-09287-5

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Tranexamic Acid Is Not a Universal Hemostatic Agent

Hemasphere. 2021 Jul 19;5(8):e625. doi: 10.1097/HS9.0000000000000625. eCollection 2021 Aug.

NO ABSTRACT

PMID:34291198 | PMC:PMC8288894 | DOI:10.1097/HS9.0000000000000625

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Regeneration and activation of liver progenitor cells in liver cirrhosis

Genes Dis. 2020 Aug 8;8(5):623-628. doi: 10.1016/j.gendis.2020.07.016. eCollection 2021 Sep.

ABSTRACT

Cirrhosis is characterized as the progress of regenerative nodules surrounded by fibrous bands in response to chronic hepatic injury and causes portal hypertension and end-stage hepatic disease. Following liver injury, liver progenitor cells (LPCs) can be activated and differentiate into hepatocytes in order to awaken liver regeneration and reach homeostasis. Recent research has uncovered some new sources of LPCs. Here, we update the mechanisms of LPCs-mediated liver regeneration in cirrhosis by introducing the origin of LPCs and LPCs’ niche with a discussion of the influence of LPC-related cells. This article analyzes the mechanism of regeneration and activation of LPCs in cirrhosis in recent years aiming to provide help for clinical application.

PMID:34291133 | PMC:PMC8278536 | DOI:10.1016/j.gendis.2020.07.016

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