Editor's Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to authors, or important in this field. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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Article
Dysregulation of the Amniotic PPARγ Pathway by Phthalates: Modulation of the Anti-Inflammatory Activity of PPARγ in Human Fetal Membranes
Life 2022, 12(4), 544; https://doi.org/10.3390/life12040544 - 06 Apr 2022
Abstract
Phthalates are reprotoxic pollutants that are omnipresent in the environment. Detectable in amniotic fluid, these compounds (with the most concentrated being mono-2-ethylhexyl phthalate (MEHP)) are in direct contact with fetal membranes (FMs). They can lead to the premature rupture of FMs by deregulating [...] Read more.
Phthalates are reprotoxic pollutants that are omnipresent in the environment. Detectable in amniotic fluid, these compounds (with the most concentrated being mono-2-ethylhexyl phthalate (MEHP)) are in direct contact with fetal membranes (FMs). They can lead to the premature rupture of FMs by deregulating cellular and molecular pathways, such as, for example, the nuclear transcription factor peroxysome proliferator-activated receptor gamma (PPARγ) pathway. The objective was to study the impact of MEHP on the PPARγ pathway in FMs using amnion and choriodecidua across the three trimesters of pregnancy and the amniotic epithelial AV3 cell model by analyzing (i) PPARγ expression (mRNA and proteins) using RT-qPCR and Western blot assays; (ii) cytotoxicity and cell viability following MEHP treatment by lactate dehydrogenase (LDH) measurement and using Cell-counting Kit 8; and (iii) modulation by MEHP of PPARγ transcriptional activity (using a reporter gene assay) and PPARγ anti-inflammatory properties (by measuring IL6 and IL8 levels). PPARγ is expressed in the human amnion and choriodecidua during the three trimesters of pregnancy and in amniotic cells. In the AV3 cell line, MEHP is not cytotoxic and does not reduce cell viability, but it reduces PPARγ activity, here induced by a classical agonist without influencing its expression. MEHP also reduces PPARγ’s anti-inflammatory properties. In conclusion, PPARγ signaling is dysregulated by MEHP; this paves the way for future explorations to highlight the hypothesis of phthalates as an amniotic PPARγ disruptor that can explain the premature rupture of FMs. Full article
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Article
When Nothing Goes Right: Risk Factors and Biomarkers of Right Heart Failure after Left Ventricular Assist Device Implantation
Life 2022, 12(3), 459; https://doi.org/10.3390/life12030459 - 20 Mar 2022
Abstract
Right heart failure (RHF) is a severe complication after left ventricular assist device (LVAD) implantation. The aim of this study was to analyze the incidence, risk factors, and biomarkers for late RHF including the possible superiority of the device and implantation method. This [...] Read more.
Right heart failure (RHF) is a severe complication after left ventricular assist device (LVAD) implantation. The aim of this study was to analyze the incidence, risk factors, and biomarkers for late RHF including the possible superiority of the device and implantation method. This retrospective, single-center study included patients who underwent LVAD implantation between 2014 and 2018. Primary outcome was freedom from RHF over one-year after LVAD implantation; secondary outcomes included pre- and postoperative risk factors and biomarkers for RHF. Of the 145 consecutive patients (HeartMate 3/HVAD: n = 70/75; female: 13.8%), thirty-one patients (21.4%) suffered RHF after a mean LVAD support of median (IQR) 105 (118) days. LVAD implantation method (less invasive: 46.7% vs. 35.1%, p = 0.29) did not differ significantly in patients with or without RHF, whereas the incidence of RHF was lower in HeartMate 3 vs. HVAD patients (12.9% vs. 29.3%, p = 0.016). Multivariate Cox proportional hazard analysis identified HVAD (HR 4.61, 95% CI 1.12–18.98; p = 0.03), early post-op heart rate (HR 0.96, 95% CI 0.93–0.99; p = 0.02), and central venous pressure (CVP) (HR 1.21, 95% CI 1.05–1.39; p = 0.01) as independent risk factors for RHF, but no association of RHF with increased all-cause mortality (HR 1.00, 95% CI 0.99–1.01; p = 0.50) was found. To conclude, HVAD use, lower heart rate, and higher CVP early post-op were independent risk factors for RHF following LVAD implantation. Full article
(This article belongs to the Special Issue The Present and Future of Mechanical Circulatory Support (MCS))
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Article
The Possible Role of the Type I Chaperonins in Human Insulin Self-Association
Life 2022, 12(3), 448; https://doi.org/10.3390/life12030448 - 18 Mar 2022
Abstract
Insulin is a hormone that attends to energy metabolism by regulating glucose levels in the bloodstream. It is synthesised within pancreas beta-cells where, before being released into the serum, it is stored in granules as hexamers coordinated by Zn2+ and further packaged [...] Read more.
Insulin is a hormone that attends to energy metabolism by regulating glucose levels in the bloodstream. It is synthesised within pancreas beta-cells where, before being released into the serum, it is stored in granules as hexamers coordinated by Zn2+ and further packaged in microcrystalline structures. The group I chaperonin cpn60, known for its assembly-assisting function, is present, together with its cochaperonin cpn10, at each step of the insulin secretory pathway. However, the exact function of the heat shock protein in insulin biosynthesis and processing is still far from being understood. Here we explore the possibility that the molecular machine cpn60/cpn10 could have a role in insulin hexameric assembly and its further crystallization. Moreover, we also evaluate their potential protective effect in pathological insulin aggregation. The experiments performed with the cpn60 bacterial homologue, GroEL, in complex with its cochaperonin GroES, by using spectroscopic methods, microscopy and hydrodynamic techniques, reveal that the chaperonins in vitro favour insulin hexameric organisation and inhibit its aberrant aggregation. These results provide new details in the field of insulin assembly and its related disorders. Full article
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Article
Single-Cell Image-Based Analysis Reveals Chromatin Changes during the Acquisition of Tamoxifen Drug Resistance
Life 2022, 12(3), 438; https://doi.org/10.3390/life12030438 - 17 Mar 2022
Abstract
Cancer drug resistance is the leading cause of cancer related deaths. The development of drug resistance can be partially contributed to tumor heterogeneity and epigenetic plasticity. However, the detailed molecular mechanism underlying epigenetic modulated drug resistance remains elusive. In this work, we systematically [...] Read more.
Cancer drug resistance is the leading cause of cancer related deaths. The development of drug resistance can be partially contributed to tumor heterogeneity and epigenetic plasticity. However, the detailed molecular mechanism underlying epigenetic modulated drug resistance remains elusive. In this work, we systematically analyzed epigenetic changes in tamoxifen (Tam) responsive and resistant breast cancer cell line MCF7, and adopted a data-driven approach to identify key epigenetic features distinguishing between these two cell types. Significantly, we revealed that DNA methylation and H3K9me3 marks that constitute the heterochromatin are distinctively different between Tam-resistant and -responsive cells. We then performed time-lapse imaging of 5mC and H3K9me3 features using engineered probes. After Tam treatment, we observed a slow transition of MCF7 cells from a drug-responsive to -resistant population based on DNA methylation features. A similar trend was not observed using H3K9me3 probes. Collectively, our results suggest that DNA methylation changes partake in the establishment of Tam-resistant breast cancer cell lines. Instead of global changes in the DNA methylation level, the distribution of DNA methylation features inside the nucleus can be one of the drivers that facilitates the establishment of a drug resistant phenotype in MCF7. Full article
(This article belongs to the Special Issue Epigenetics and Nuclear Architecture)
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Article
Alkanes as Membrane Regulators of the Response of Early Membranes to Extreme Temperatures
Life 2022, 12(3), 445; https://doi.org/10.3390/life12030445 - 17 Mar 2022
Cited by 1
Abstract
One of the first steps in the origin of life was the formation of a membrane, a physical boundary that allowed the retention of molecules in concentrated solutions. The proto-membrane was likely formed by self-assembly of simple readily available amphiphiles, such as short-chain [...] Read more.
One of the first steps in the origin of life was the formation of a membrane, a physical boundary that allowed the retention of molecules in concentrated solutions. The proto-membrane was likely formed by self-assembly of simple readily available amphiphiles, such as short-chain fatty acids and alcohols. In the commonly accepted scenario that life originated near hydrothermal systems, how these very simple membrane bilayers could be stable enough in time remains a debated issue. We used various complementary techniques such as dynamic light scattering, small angle neutron scattering, neutron spin-echo spectroscopy, and Fourier-transform infrared spectroscopy to explore the stability of a novel protomembrane system in which the insertion of alkanes in the midplane is proposed to shift membrane stability to higher temperatures, pH, and hydrostatic pressures. We show that, in absence of alkanes, protomembranes transition into lipid droplets when temperature increases; while in presence of alkanes, membranes persist for longer times in a concentration-dependent manner. Proto-membranes containing alkanes are stable at higher temperatures and for longer times, have a higher bending rigidity, and can revert more easily to their initial state upon temperature variations. Hence, the presence of membrane intercalating alkanes could explain how the first membranes could resist the harsh and changing environment of the hydrothermal systems. Furthermore, modulating the quantity of alkanes in the first membranes appears as a possible strategy to adapt the proto-membrane behavior according to temperature fluctuations, and it offers a first glimpse into the evolution of the first membranes. Full article
(This article belongs to the Special Issue Biomolecular Dynamics Explored by Incoherent Neutron Spectroscopy)
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Communication
Why Is the UAG (Amber) Stop Codon Almost Absent in Highly Expressed Bacterial Genes?
Life 2022, 12(3), 431; https://doi.org/10.3390/life12030431 - 16 Mar 2022
Cited by 1
Abstract
The genome hypothesis postulates that genes in a genome tend to conform to their species’ usage of the codon catalog and the GC content of the DNA. Thus, codon frequencies differ across organisms, including the three termination codons in the standard genetic code. [...] Read more.
The genome hypothesis postulates that genes in a genome tend to conform to their species’ usage of the codon catalog and the GC content of the DNA. Thus, codon frequencies differ across organisms, including the three termination codons in the standard genetic code. Here, we analyze the frequencies of stop codons in a group of highly expressed genes from 196 prokaryotes under strong translational selection. The occurrence of the three translation termination codons is highly biased, with UAA (ochre) being the most prevalent in almost all bacteria. In contrast, UAG (amber) is the least frequent termination codon, e.g., only 321 occurrences (7.4%) in E. coli K-12 substr. W3110. Of the 253 highly expressed genes, only two end with an UAG codon. The strength of the selective bias against UAG in highly expressed genes varies among bacterial genomes, but it is not affected by the GC content of these genomes. In contrast, increased GC content results in a decrease in UAA abundance with a concomitant increase in UGA abundance. We propose that readthrough efficiency and context effects could explain the prevalence of UAA over UAG, particularly in highly expressed genes. Findings from this communication can be utilized for the optimization of gene expression. Full article
(This article belongs to the Section Genetics and Genomics)
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Article
2-Fluorofucose Attenuates Hydrogen Peroxide-Induced Oxidative Stress in HepG2 Cells via Nrf2/keap1 and NF-κB Signaling Pathways
Life 2022, 12(3), 406; https://doi.org/10.3390/life12030406 - 11 Mar 2022
Abstract
Fucosylation is one of the most important glycan terminal modifications that affects multiple biological activities of proteins. 2-Fluorofucose (2FF), its specific inhibitor, has recently been reported to reveal numerous biological effects by blocking fucosylation both in vitro and in vivo. The current study [...] Read more.
Fucosylation is one of the most important glycan terminal modifications that affects multiple biological activities of proteins. 2-Fluorofucose (2FF), its specific inhibitor, has recently been reported to reveal numerous biological effects by blocking fucosylation both in vitro and in vivo. The current study aimed to evaluate the effect of 2FF on hydrogen peroxide (H2O2)-induced oxidative damage in vitro. In our study, treatment with H2O2 increased the level of fucosylation, and 2FF improved the cell viability in H2O2-treated HepG2 cells. Our study also showed that 2FF significantly decreased the overproduction of reactive oxygen species (ROS) induced by H2O2 and the activities of catalase, glutathione and Mn-superoxide dismutase were remarkably increased by 2FF pretreatment. Furthermore, 2FF attenuated H2O2-induced early mitochondria dysfunction. The second part of the study revealed that 2FF enhanced antioxidant capacity by affecting Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Being pretreated with 2FF significantly increased the nuclear translocation of Nrf2 and simultaneously promoted the expression of downstream proteins, such as HO-1 and NQO1. Moreover, 2FF remarkably suppressed the expression of inflammation-associated proteins. Taken together, these data suggest that 2FF might have a potential therapeutic effect for oxidative stress. Full article
(This article belongs to the Section Pharmaceutical Science)
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Article
Genetic Workup for Charcot–Marie–Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years
Life 2022, 12(3), 402; https://doi.org/10.3390/life12030402 - 10 Mar 2022
Cited by 1
Abstract
Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution [...] Read more.
Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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Article
Dosimetric Comparison of Ultra-Hypofractionated and Conventionally Fractionated Radiation Therapy Boosts for Patients with High-Risk Prostate Cancer
Life 2022, 12(3), 394; https://doi.org/10.3390/life12030394 - 09 Mar 2022
Abstract
Recent comparison of an ultra-hypofractionated radiotherapy (UF-RT) boost to a conventionally fractionated (CF-RT) option showed similar toxicity and disease control outcomes. An analysis of the treatment plans for these patients is needed for evaluating calculated doses for different organs, treatment beam-on time, and [...] Read more.
Recent comparison of an ultra-hypofractionated radiotherapy (UF-RT) boost to a conventionally fractionated (CF-RT) option showed similar toxicity and disease control outcomes. An analysis of the treatment plans for these patients is needed for evaluating calculated doses for different organs, treatment beam-on time, and requirements for human and financial resources. Eighty-six plans for UF-RT and 93 plans for CF-RT schemes were evaluated. The biologically equivalent dose, EQD2, summed for the first phase and the boost, was calculated for dose-volume parameters for organs at risk (OARs), as well as for the PTV1. ArcCHECK measurements for the boost plans were used for a comparison of planned and delivered doses. Monitor units and beam-on times were recorded by the Eclipse treatment planning system. Statistical analysis was performed with a significance level of 0.05. Dosimetric parameter values for OARs were well within tolerance for both groups. EQD2 for the PTV1 was on average 84 Gy for UF-RT patients and 76 Gy for CF-RT patients. Gamma passing rate for planned/delivered doses comparison was above 98% for both groups with 3 mm/3% distance to agreement/dose difference criteria. Total monitor units per fraction were 647 ± 94 and 2034 ± 570 for CF-RT and UF-RT, respectively. The total delivery time for boost radiation for the patients in the UF-RT arm was, on average, four times less than the total time for a conventional regimen with statistically equal clinical outcomes for the two arms in this study. Full article
(This article belongs to the Special Issue Cancer Radiotherapy: Recent Advances and Challenges)
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Article
CRISPR-Cas Systems in Gut Microbiome of Children with Autism Spectrum Disorders
Life 2022, 12(3), 367; https://doi.org/10.3390/life12030367 - 03 Mar 2022
Abstract
The human gut microbiome is associated with various diseases, including autism spectrum disorders (ASD). Variations of the taxonomical composition in the gut microbiome of children with ASD have been observed repeatedly. However, features and parameters of the microbiome CRISPR-Cas systems in ASD have [...] Read more.
The human gut microbiome is associated with various diseases, including autism spectrum disorders (ASD). Variations of the taxonomical composition in the gut microbiome of children with ASD have been observed repeatedly. However, features and parameters of the microbiome CRISPR-Cas systems in ASD have not been investigated yet. Here, we demonstrate such an analysis in order to describe the overall changes in the microbiome CRISPR-Cas systems during ASD as well as to reveal their potential to be used in diagnostics and therapy. For the systems identification, we used a combination of the publicly available tools suited for completed genomes with subsequent filtrations. In the considered data, the microbiomes of children with ASD contained fewer arrays per Gb of assembly than the control group, but the arrays included more spacers on average. CRISPR arrays from the microbiomes of children with ASD differed from the control group neither in the fractions of spacers with protospacers from known genomes, nor in the sets of known bacteriophages providing protospacers. Almost all bacterial protospacers of the gut microbiome systems for both children with ASD and the healthy ones were located in prophage islands, leaving no room for the systems to participate in the interspecies competition. Full article
(This article belongs to the Special Issue Metagenomics: New Trends and Solutions)
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Article
Pulmonary Complications after COVID-19
Life 2022, 12(3), 357; https://doi.org/10.3390/life12030357 - 28 Feb 2022
Abstract
Coronavirus disease 2019 (COVID-19) is a threat to patients not only because of its acute course, but also because of various complications occurring in the following period, that is, more than 28 days after the onset of acute infection. The present study identified [...] Read more.
Coronavirus disease 2019 (COVID-19) is a threat to patients not only because of its acute course, but also because of various complications occurring in the following period, that is, more than 28 days after the onset of acute infection. The present study identified a total of 121 patients hospitalized 29 or more days after the first positive result of a PCR test for SARS-CoV-2, of whom 98 patients were included in the study. Patients were divided into two groups by the time interval between the positive COVID-19 test result and hospitalization date. The time intervals were week 5–11 in an ongoing-COVID group (57.1% of patients) and 12 or more weeks in a post-COVID-group (42.9%). The most frequent reason for hospitalization was respiratory tract infection (58.2%). Pneumonia accounted for 77.2% of these cases. Other reasons for hospitalization were interstitial lung disease (22.4%), pulmonary embolism (8.2%), and sarcoidosis (6.1%). The study group was further divided according to the causes of hospitalization into subgroups with infections and other causes. In the group with infectious diseases, there was a shorter time period between PCR positivity and hospitalization and there were significantly more frequent non-respiratory complications. In the entire sample, the in-hospital mortality was 5.1%. Full article
(This article belongs to the Special Issue Bacterial Infections, Treatment and Antibiotic Resistance)
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Article
Ethyl P-Methoxycinnamate: An Active Anti-Metastasis Agent and Chemosensitizer Targeting NFκB from Kaempferia galanga for Melanoma Cells
Life 2022, 12(3), 337; https://doi.org/10.3390/life12030337 - 24 Feb 2022
Abstract
The most common type of skin cancer is melanoma. While significant advances in chemotherapy have occurred in a few instances, only marginal progress has been made in treating metastatic melanoma. Natural medicine has traditionally been used to treat various illnesses, including cancer. The [...] Read more.
The most common type of skin cancer is melanoma. While significant advances in chemotherapy have occurred in a few instances, only marginal progress has been made in treating metastatic melanoma. Natural medicine has traditionally been used to treat various illnesses, including cancer. The purpose of this study was to identify the active compound in Kaempferia galanga, which could be used to treat melanoma as an anti-metastasis and chemosensitizer agent. The active compound in K. galanga was isolated and identified using chromatography and spectroscopy techniques, and given six compounds. Inhibitory activity on NFκB activation and cell viability was determined using reporter assay methods. Among the isolated compounds, ethyl p-methoxycinnamate (EPMC) demonstrated potent NFκB inhibitory activity against melanoma cell B16F10- NFκB Luc2 with an IC50 of 88.7 μM. Further investigation was conducted by evaluating the anti-metastasis effect of EPMC in vitro by using wound-healing assays, invasion tests, and molecular mechanism assays using Western blotting. NFκB has been implicated in tumorigenesis through the PI3K/Akt/NFκB pathway. The results of this study indicated that EPMCs act as inhibitors of p38 and thereby Akt phosphorylation inhibitors at serine 473, inhibiting NFκB-dependent transcription. Further analysis with paclitaxel demonstrated that the combinations could sensitize to apoptosis in response to well-known chemotherapy agents. Additional studies were conducted using the human melanoma cancer cell line SK-Mel 28. Along with the induction of apoptosis, we observed an increase in p-γH2AX expression (a molecular marker for double strand breaks in DNA damage) in response to treatment with paclitaxel and EPMC. The result showed EPMC to be a potential, viable adjuvant for improving the clinical efficacy of anti-metastatic and cancer chemotherapy. Full article
(This article belongs to the Special Issue Molecular Signaling of Natural Compounds in Oncology)
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Article
Comparison of Clinical Efficacy and Safety between 70–150 µm and 100–300 µm Doxorubicin Drug-Eluting Bead Transarterial Chemoembolization for Hepatocellular Carcinoma
Life 2022, 12(2), 297; https://doi.org/10.3390/life12020297 - 16 Feb 2022
Abstract
Background: This study aimed to compare the efficacy and safety of 70–150 μm doxorubicin drug-eluting bead (DEB) transarterial chemoembolization (TACE) with those of 100–300 μm DEB-TACE as first-line treatment in patients with hepatocellular carcinoma (HCC). Methods: We retrospectively investigated 72 patients who underwent [...] Read more.
Background: This study aimed to compare the efficacy and safety of 70–150 μm doxorubicin drug-eluting bead (DEB) transarterial chemoembolization (TACE) with those of 100–300 μm DEB-TACE as first-line treatment in patients with hepatocellular carcinoma (HCC). Methods: We retrospectively investigated 72 patients who underwent TACE with 70–150 μm DEBs (n = 40) or 100–300 μm DEBs (n = 32) for HCC in a tertiary center between March 2013 and May 2019. Initial treatment response and adverse events were assessed using the modified Response Evaluation Criteria in Solid Tumors and the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, respectively. Results: At the 2-month post-treatment assessment, the complete and objective response rates were 47.5% and 85.0%, respectively, for the 70–150 μm group and 34.4% and 81.3%, respectively, for the 100–300 μm group; however, the difference was not statistically significant (p > 0.05). In total, 65% patients in the 70–150 μm group and 59.4 % patients in the 100-300 μm group experienced at least one symptom of post-embolization syndrome after TACE; all symptoms were classified as grade 1 or 2. There was no significant difference between the two groups in terms of post-procedural laboratory changes such as changes in liver enzymes and bilirubin levels (p > 0.05). Laboratory toxicity of grade 3 occurred in three patients, all of which were transient elevation of liver enzyme levels. Hepatobiliary adverse events, such as bile duct injury, biloma, liver abscess, and hepatic infarction, were not observed in either treatment group. Conclusion: This study found no significant difference in tumor response between 70–150 μm and 100–300 μm DEB-TACE. Both groups showed favorable safety profiles, and the difference was not significant. Full article
(This article belongs to the Section Radiobiology and Nuclear Medicine)
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Article
Objective Perfusion Assessment in Gracilis Muscle Interposition—A Novel Software-Based Approach to Indocyanine Green Derived Near-Infrared Fluorescence in Reconstructive Surgery
Life 2022, 12(2), 278; https://doi.org/10.3390/life12020278 - 13 Feb 2022
Abstract
Background: Gracilis muscle interposition (GMI) is an established treatment option for complex perineal fistulas and reconstruction. The outcome is limited by complications such as necrosis, impaired wound healing and fistula persistence or recurrence. Quantifiable methods of assessing muscle flap perfusion intraoperatively are lacking. [...] Read more.
Background: Gracilis muscle interposition (GMI) is an established treatment option for complex perineal fistulas and reconstruction. The outcome is limited by complications such as necrosis, impaired wound healing and fistula persistence or recurrence. Quantifiable methods of assessing muscle flap perfusion intraoperatively are lacking. This study evaluates a novel and objective software-based assessment of indocyanine green near-infrared fluorescence (ICG-NIRF) in GMI. Methods: Intraoperative ICG-NIRF visualization data of five patients with inflammatory bowel disease (IBD) undergoing GMI for perineal fistula and reconstruction were analyzed retrospectively. A new software was utilized to generate perfusion curves for the specific regions of interest (ROIs) of each GMI by depicting the fluorescence intensity over time. Additionally, a pixel-to-pixel and perfusion zone analysis were performed. The findings were correlated with the clinical outcome. Results: Four patients underwent GMI without postoperative complications within 3 months. The novel perfusion indicators identified here (shape of the perfusion curve, maximum slope value, distribution and range) indicated adequate perfusion. In one patient, GMI failed. In this case, the perfusion indicators suggested impaired perfusion. Conclusions: We present a novel, software-based approach for ICG-NIRF perfusion assessment, identifying previously unknown objective indicators of muscle flap perfusion. Ready for intraoperative real-time use, this method has considerable potential to optimize GMI surgery in the future. Full article
(This article belongs to the Special Issue Recent Advances and Applications of Image-Guided Surgery)
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Article
Ex-Vivo Preservation with the Organ Care System in High Risk Heart Transplantation
Life 2022, 12(2), 247; https://doi.org/10.3390/life12020247 - 07 Feb 2022
Cited by 1
Abstract
Objective: Ex vivo organ perfusion is an advanced preservation technique that allows graft assessment and extended ex situ intervals. We hypothesized that its properties might be especially beneficial for high-risk recipients and/or donors with extended criteria. Methods: We reviewed the outcomes of 119 [...] Read more.
Objective: Ex vivo organ perfusion is an advanced preservation technique that allows graft assessment and extended ex situ intervals. We hypothesized that its properties might be especially beneficial for high-risk recipients and/or donors with extended criteria. Methods: We reviewed the outcomes of 119 consecutive heart transplant patients, which were divided into two groups: A (OCS) vs. B (conventional). Ex vivo organ perfusion was performed using the Organ Care System (OCS). Indications for OCS-usage were expected ischemic time of >4 h or >2 h plus given extended donor criteria. Results: Both groups included mostly redo cases (A: 89.7% vs. B: 78.4%; p = 0.121). Incidences of donors with previous cardiac arrest (%) (A: 32.4 vs. B: 22.2; p < 0.05) or LV-hypertrophy (%) (A: 19.1 vs. B: 8.3; p = 0.119) were also increased in Group A. Ex situ time (min) was significantly longer in Group A (A: 381 (74) vs. B: 228 (43); p < 0.05). Ventilation time (days) (A: 10.0 (19.9) vs. B: 24.3 (43.2); p = 0.057), postoperative need for ECLS (%) (A: 25.0 vs. B: 39.2; p = 0.112) and postoperative dialysis (chronic) (%) (A: 4.4 vs. B: 27.5; p < 0.001) were numerically better in the OCS group, without any difference in the occurrence of early graft rejection. The 30-d-survival (A: 92.4% vs. B: 90.2%; p = 0.745) and mid-term survival were statistically not different between both groups. Conclusions: OCS heart allowed safe transplantation of surgically complex recipients with excellent one-year outcomes, despite long preservation times and unfavourable donor characteristics. Furthermore, we observed trends towards decreased ventilation times and fewer ECLS treatments. In times of reduced organ availability and increasing recipient complexity, OCS heart is a valuable instrument that enables otherwise infeasible allocations and contributes to increase surgical safety. Full article
(This article belongs to the Special Issue Heart Failure and Heart Transplantation)
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Article
Whole Body MRI in the Detection of Lymph Node Metastases in Patients with Testicular Germ Cell Cancer
Life 2022, 12(2), 212; https://doi.org/10.3390/life12020212 - 29 Jan 2022
Abstract
Whole-Body Magnetic Resonance Imaging (WB-MRI) is increasingly used for metastatic screening in oncology. This prospective single center study assesses the diagnostic value of WB-MRI including diffusion weighted imaging (DWI) and identifies the sufficient protocol for metastatic lymph node detection in patients with testicular [...] Read more.
Whole-Body Magnetic Resonance Imaging (WB-MRI) is increasingly used for metastatic screening in oncology. This prospective single center study assesses the diagnostic value of WB-MRI including diffusion weighted imaging (DWI) and identifies the sufficient protocol for metastatic lymph node detection in patients with testicular germ cell cancer (TGCC). Forty-three patients underwent contrast enhanced thoraco-abdominopelvic CT (TAP-CT) and WB-MRI with DWI for metastatic lymph node screening. Two independent readers reviewed CTs and WB-MRIs. The diagnostic performance of different imaging protocols (CT, complete WB-MRI, T1W + DWI, T2W + DWI), the agreement between these protocols and the reference standard, the reproducibility of findings and the image quality (Signal and contrast to Noise Ratios, Likert scale) were studied. Reproducibility was very good regardless of both lesion locations (retroperitoneal vs distant lymph nodes, other lesions) and the reader. Diagnostic accuracy of MRI was ≥95% (regardless of the locations and imaging protocol); accuracy of CT was ≥93%. There was a strict overlap of 95% CIs associated with this accuracy between complete WB-MRI, T1W + DWI and T2W + DWI, regardless of the reader. Higher Likert score and SNR were observed for DWI, followed by T2W and T1W sequences. In conclusion, a fast WB-MRI protocol including T2W and DWI is a sufficient, accurate, non-irradiating alternative to TAP-CT for metastatic lymph node screening in TGCC. Full article
(This article belongs to the Special Issue MRI in Cancer: Ongoing Developments and Controversies)
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Article
Multi-Planar VMAT Plans for High-Grade Glioma and Glioblastoma Targeting the Hypothalamic-Pituitary Axis Sparing
Life 2022, 12(2), 195; https://doi.org/10.3390/life12020195 - 28 Jan 2022
Abstract
Background: This study aimed to identify the better arc configuration of volumetric modulated arc therapy (VMAT) for high-grade glioma and glioblastoma, focusing on a dose reduction to the hypothalamic–pituitary axis through an analysis of dose-volumetric parameters, as well as a correlation analysis between [...] Read more.
Background: This study aimed to identify the better arc configuration of volumetric modulated arc therapy (VMAT) for high-grade glioma and glioblastoma, focusing on a dose reduction to the hypothalamic–pituitary axis through an analysis of dose-volumetric parameters, as well as a correlation analysis between the planned target volume (PTV) to organs at risk (OAR) distance and the radiation dose. Method: Twenty-four patients with 9 high-grade glioma and 15 glioblastomas were included in this study. Identical CT, MRI and structure sets of each patient were used for coplanar VMAT (CO-VMAT), dual planar VMAT (DP-VMAT) and multi-planar VMAT (MP-VMAT) planning. The dose constraints adhered to the RTOG0825 and RTOG9006 protocols. The dose-volumetric parameters of each plan were collected for statistical analysis. Correlation analyses were performed between radiation dose and PTV-OARs distance. Results: The DP-VMAT and MP-VMAT achieved a significant dose reduction to most nearby OARs when compared to CO-VMAT, without compromising the dose to PTV, plan homogeneity and conformity. For centrally located OARs, including the hypothalamus, pituitary, brain stem and optic chiasm, the dose reductions ranged from 2.65 Gy to 3.91 Gy (p < 0.001) in DP-VMAT and from 2.57 Gy to 4 Gy (p < 0.001) in MP-VMAT. Similar dose reduction effects were achieved for contralaterally located OARs, including the hippocampus, optic nerve, lens and retina, ranging from 1.06 Gy to 4.37 Gy in DP-VMAT and from 0.54 Gy to 3.39 Gy in MP-VMAT. For ipsilaterally located OARs, DP-VMAT achieved a significant dose reduction of 1.75 Gy to Dmax for the optic nerve. In the correlation analysis, DP-VMAT and MP-VMAT showed significant dose reductions to centrally located OARs when the PTV-OAR distance was less than 4 cm. In particular, DP-VMAT offered better sparing to the optic chiasm when it was located less than 2 cm from the PTV than that of MP-VMAT and CO-VMAT. DP-VMAT and MP-VMAT also showed better sparing to the contralateral hippocampus and retina when they were located 3–8 cm from the PTV. Conclusion: The proposed DP-VMAT and MP-VMAT demonstrated significant dose reductions to centrally located and contralateral OARs and maintained the high plan qualities to PTV with good homogeneity and conformity when compared to CO-VMAT for high-grade glioma and glioblastoma. The benefit in choosing DP-VMAT and MP-VMAT over CO-VMAT was substantial when the PTV was located near the hypothalamus, pituitary, optic chiasm, contralateral hippocampus and contralateral retina. Full article
(This article belongs to the Special Issue Cancer Radiotherapy: Recent Advances and Challenges)
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Article
Fetal Membranes Contribute to Drug Transport across the Feto-Maternal Interface Utilizing the Breast Cancer Resistance Protein (BCRP)
Life 2022, 12(2), 166; https://doi.org/10.3390/life12020166 - 23 Jan 2022
Abstract
During pregnancy, the placenta is established as a primary organ for drug transport at the maternal-fetal interface. The fetal membranes (FM) also form an interface with maternal tissues; however, their role in drug transport has not been previously investigated. Knowledge of drug transport [...] Read more.
During pregnancy, the placenta is established as a primary organ for drug transport at the maternal-fetal interface. The fetal membranes (FM) also form an interface with maternal tissues; however, their role in drug transport has not been previously investigated. Knowledge of drug transport across this feto-maternal interface along with the placenta can improve new drug development and testing for use during pregnancy. We also hypothesize that extracellular vesicles (exosomes 30–160 nm) released from the FM and placental cells may also contain drug transport proteins and might impact drug trafficking across the feto-maternal interfaces. The objectives were to (1) localize the breast cancer resistance protein (BCRP) in human FM; (2) determine the drug transport function of BCRP in chorion trophoblast cells (CTCs) of the FM; and (3) investigate the presence of BCRP in FM cell-derived exosomes, as a paracrine modifier of the tissue environment for transport functions. The gene and protein expressions of ABCG2/BCRP in FMs were determined by quantitative real-time PCR (qRT-PCR) and western blotting (WB) and were localized by immunohistochemistry (IHC). The surface expression of BCRP in FM cells was determined by flow cytometry. The functional role of BCRP was assessed by an EFFLUX dye multidrug resistance assay. The presence of BCRP in exosomes derived from CTCs and BeWo cells was examined using ExoView®. Data derived from CTCs are compared with placental trophoblast cells (BeWo). BCRP is expressed and localized in the fetal membrane, primarily in the chorion trophoblast cell layer and scarcely in the amnion epithelial layer (AEC), and primarily localized on both AEC and CTC cell surfaces. Efflux assay data showed that FM cells have similar drug resistance activity as BeWo cells, suggesting that FM also have drug transportation capabilities. BeWo- and CTC-derived exosomes expressed limited BCRP protein on the surface, so it was predominantly contained in the exosomal lumen. As far as we are aware, this is the first study to report BCRP expression in fetal membrane cells and as cargo in fetal membrane-derived exosomes. We report that fetal membrane cells are capable of drug transportation. Based on these results, investigational drug trials should include the FM and its exosomes as possible drug transportation routes in pregnancy. Full article
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Article
Neutrophils in Extravascular Body Fluids: Cytological-Energy Analysis Enables Rapid, Reliable and Inexpensive Detection of Purulent Inflammation and Tissue Damage
Life 2022, 12(2), 160; https://doi.org/10.3390/life12020160 - 21 Jan 2022
Abstract
The simultaneous cytological and metabolic investigation of various extravascular body fluids (EBFs) provides clinically relevant information about the type and intensity of the immune response in particular organ systems. The oxidative burst of professional phagocytes with the concomitant production of reactive oxygen species [...] Read more.
The simultaneous cytological and metabolic investigation of various extravascular body fluids (EBFs) provides clinically relevant information about the type and intensity of the immune response in particular organ systems. The oxidative burst of professional phagocytes with the concomitant production of reactive oxygen species consumes a large amount of oxygen and is the cause of switch to the development of anaerobic metabolism. We assessed the relationships between percentages of neutrophils, aerobic and anaerobic metabolism, and tissue damage via the determination of aspartate aminotransferase catalytic activities (AST) in cerebrospinal fluid (CSF), pleural effusions (PE), abdominal effusions (AE), and synovial fluids (SF). EBFs with 0.0–20.0% neutrophils: 83.0% aerobic and 1.3% strongly anaerobic cases with median of AST = 13.8 IU/L in CSF; 68.0% aerobic and 9.0% strongly anaerobic cases with median of AST = 20.4 IU/L in PE; 77.5% aerobic and 10.5% strongly anaerobic cases with median of AST = 18.0 IU/L in AE; 64.1% aerobic and 7.7% strongly anaerobic cases with median of AST = 13.8 IU/L in SF. EBFs with 80.0–100.0% neutrophils: 4.2% aerobic and 73.7% strongly anaerobic cases with median of AST = 19.2 IU/L in CSF; 7.4% aerobic and 77.3% strongly anaerobic cases with median of AST = 145.2 IU/L in PE; 11.8% aerobic and 73.7% strongly anaerobic cases with median of AST = 61.8 IU/L in AE; 25.5% aerobic and 38.2% strongly anaerobic cases with median of AST = 37.2 IU/L in SF. The significant presence of neutrophils, concomitant strong anaerobic metabolism, and elevated AST in various EBFs are reliable signs of damaging purulent inflammation. Full article
(This article belongs to the Special Issue Current Research in Inflammatory Response to Injury and Diseases)
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Article
A Novel Anti-B7-H3 × Anti-CD3 Bispecific Antibody with Potent Antitumor Activity
Life 2022, 12(2), 157; https://doi.org/10.3390/life12020157 - 21 Jan 2022
Abstract
B7-H3 plays an important role in tumor apoptosis, proliferation, adhesion, angiogenesis, invasion, migration, and evasion of immune surveillance. It is overexpressed in various human solid tumor tissues. In patients, B7-H3 overexpression correlates with advanced stages, poor clinical outcomes, and resistance to therapy. The [...] Read more.
B7-H3 plays an important role in tumor apoptosis, proliferation, adhesion, angiogenesis, invasion, migration, and evasion of immune surveillance. It is overexpressed in various human solid tumor tissues. In patients, B7-H3 overexpression correlates with advanced stages, poor clinical outcomes, and resistance to therapy. The roles of B7-H3 in tumor progression make it a potential candidate for targeted therapy. Here, we generated a mouse anti-human B7-H3 antibody and demonstrated its binding activity via Tongji University Suzhou Instituteprotein-based and cell-based assays. We then developed a novel format anti-B7-H3 × anti-CD3 bispecific antibody based on the antibody-binding fragment of the anti-B7-H3 antibody and single-chain variable fragment structure of anti-CD3 antibody (OKT3) and demonstrated that this bispecific antibody mediated potent cytotoxic activities against various B7-H3-positive tumor cell lines in vitro by improving T cell activation and proliferation. This bispecific antibody also demonstrated potent antitumor activity in humanized mice xenograft models. These results revealed that the novel anti-B7-H3 × anti-CD3 bispecific antibody has the potential to be employed in treatment of B7-H3-positive solid tumors. Full article
(This article belongs to the Special Issue Bispecific Antibodies: Design, Isolation, Perspectives of Use)
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Article
Pediatric Headache in Primary Care and Emergency Departments: Consensus with RAND/UCLA Method
Life 2022, 12(2), 142; https://doi.org/10.3390/life12020142 - 19 Jan 2022
Cited by 3
Abstract
Headache is the most frequent neurological symptom in childhood and the main reason for admission to pediatric emergency departments. The aim of this consensus document is to define a shared clinical pathway between primary care pediatricians (PCP) and hospitals for the management of [...] Read more.
Headache is the most frequent neurological symptom in childhood and the main reason for admission to pediatric emergency departments. The aim of this consensus document is to define a shared clinical pathway between primary care pediatricians (PCP) and hospitals for the management of children presenting with headache. For the purposes of the study, a group of hospital pediatricians and a group of PCP from the Emilia Romagna’s health districts were selected to achieve consensus using the RAND/UCLA appropriateness method. Thirty-nine clinical scenarios were developed: for each scenario, participants were asked to rank the appropriateness of each option from 1 to 9. Agreement was reached if ≥75% of participants ranked within the same range of appropriateness. The answers, results, and discussion helped to define the appropriateness of procedures with a low level of evidence regarding different steps of the diagnostic-therapeutic process: primary care evaluation, emergency department evaluation, hospital admission, acute therapy, prophylaxis, and follow-up. The RAND proved to be a valid method to value appropriateness of procedures and define a diagnostic-therapeutic pathway suitable to the local reality in the management of pediatric headache. From our results, some useful recommendations were developed for optimizing the healthcare professionals’ network among primary care services and hospitals. Full article
(This article belongs to the Special Issue Migraine and Headache in Children and Adolescents)
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Article
Ritonavir and xk263 Binding-Unbinding with HIV-1 Protease: Pathways, Energy and Comparison
Life 2022, 12(1), 116; https://doi.org/10.3390/life12010116 - 13 Jan 2022
Abstract
Understanding non-covalent biomolecular recognition, which includes drug–protein bound states and their binding/unbinding processes, is of fundamental importance in chemistry, biology, and medicine. Fully revealing the factors that govern the binding/unbinding processes can further assist in designing drugs with desired binding kinetics. HIV protease [...] Read more.
Understanding non-covalent biomolecular recognition, which includes drug–protein bound states and their binding/unbinding processes, is of fundamental importance in chemistry, biology, and medicine. Fully revealing the factors that govern the binding/unbinding processes can further assist in designing drugs with desired binding kinetics. HIV protease (HIVp) plays an integral role in the HIV life cycle, so it is a prime target for drug therapy. HIVp has flexible flaps, and the binding pocket can be accessible by a ligand via various pathways. Comparing ligand association and dissociation pathways can help elucidate the ligand–protein interactions such as key residues directly involved in the interaction or specific protein conformations that determine the binding of a ligand under certain pathway(s). Here, we investigated the ligand unbinding process for a slow binder, ritonavir, and a fast binder, xk263, by using unbiased all-atom accelerated molecular dynamics (aMD) simulation with a re-seeding approach and an explicit solvent model. Using ritonavir-HIVp and xk263-HIVp ligand–protein systems as cases, we sampled multiple unbinding pathways for each ligand and observed that the two ligands preferred the same unbinding route. However, ritonavir required a greater HIVp motion to dissociate as compared with xk263, which can leave the binding pocket with little conformational change of HIVp. We also observed that ritonavir unbinding pathways involved residues which are associated with drug resistance and are distal from catalytic site. Analyzing HIVp conformations sampled during both ligand–protein binding and unbinding processes revealed significantly more overlapping HIVp conformations for ritonavir-HIVp rather than xk263-HIVp. However, many HIVp conformations are unique in xk263-HIVp unbinding processes. The findings are consistent with previous findings that xk263 prefers an induced-fit model for binding and unbinding, whereas ritonavir favors a conformation selection model. This study deepens our understanding of the dynamic process of ligand unbinding and provides insights into ligand–protein recognition mechanisms and drug discovery. Full article
(This article belongs to the Special Issue Computational Modeling of Kinetics in Biological Systems)
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Article
COVID-19—A Trigger Factor for Severe Immune-Mediated Thrombocytopenia in Active Rheumatoid Arthritis
Life 2022, 12(1), 77; https://doi.org/10.3390/life12010077 - 06 Jan 2022
Cited by 1
Abstract
Thrombocytopenia is defined as a platelet count below 150,000/mm3 for adults. There is still controversy about whether individuals with platelet counts of 100,000/mm3 to 150,000/mm3 should be classified as having genuine thrombocytopenia or borderline thrombocytopenia. Thrombocytopenia is considered mild when [...] Read more.
Thrombocytopenia is defined as a platelet count below 150,000/mm3 for adults. There is still controversy about whether individuals with platelet counts of 100,000/mm3 to 150,000/mm3 should be classified as having genuine thrombocytopenia or borderline thrombocytopenia. Thrombocytopenia is considered mild when the platelet count is between 70,000 and 150,000/mm3 and severe if the count is less than 20,000/mm3. Thrombocytopenia in rheumatoid arthritis is a rare complication, with an incidence estimated between 3 and 10%. The main etiological aspects include drug-induced thrombocytopenia and immune thrombocytopenic purpura. The most common hematological abnormalities in SARS-CoV-2 infection are lymphopenia and thrombocytopenia. It has been observed that the severity of thrombocytopenia correlates with the severity of the infection, being a poor prognosis indicator and a risk factor for mortality. COVID-19 can stimulate the immune system to destroy platelets by increasing the production of autoantibodies and immune complexes. Autoimmunity induced by viral infections can be related to molecular mimicry, cryptic antigen expression and also spreading of the epitope. During the COVID-19 pandemic, it is of great importance to include the SARS-CoV-2 infection in differential diagnoses, due to the increased variability in forms of presentation of this pathology. In this review, our aim is to present one of the most recently discovered causes of thrombocytopenia, which is the SARS-CoV-2 infection and the therapeutic challenges it poses in association with an autoimmune disease such as rheumatoid arthritis. Full article
(This article belongs to the Special Issue Frontiers in Vascular Biology)
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Article
Surveillance of Pathogenicity of Rhizoctonia solani Japanese Isolates with Varied Anastomosis Groups and Subgroups on Arabidopsis thaliana
Life 2022, 12(1), 76; https://doi.org/10.3390/life12010076 - 06 Jan 2022
Abstract
Rhizoctonia solani is a necrotrophic plant pathogen with a wide host range. R. solani is a species complex consisting of thirteen anastomosis groups (AGs) defined by compatibility of hyphal fusion reaction and subgroups based on cultural morphology. The relationship between such classifications and [...] Read more.
Rhizoctonia solani is a necrotrophic plant pathogen with a wide host range. R. solani is a species complex consisting of thirteen anastomosis groups (AGs) defined by compatibility of hyphal fusion reaction and subgroups based on cultural morphology. The relationship between such classifications and host specificity remains elusive. Here, we investigated the pathogenicity of seventeen R. solani isolates (AG-1 to 7) in Japan towards Arabidopsis thaliana using leaf and soil inoculations. The tested AGs, except AG-3 and AG-6, induced symptoms in both methods with variations in pathogenicity. The virulence levels differed even within the same AG and subgroup. Some isolates showed tissue-specific infection behavior. Thus, the AGs and their subgroups are suggested to be not enough to define the virulence (host and tissue specificity) of R. solani. We also evaluated the virulence of the isolates on Arabidopsis plants pretreated with salicylic acid, jasmonic acid, and ethylene. No obvious effects were detected on the symptom formation by the virulence isolates, but ethylene and salicylic acid slightly enhanced the susceptibility to the weak and nonvirulent isolates. R. solani seems to be able to overcome the induced defense by these phytohormones in the infection to Arabidopsis. Full article
(This article belongs to the Special Issue State of the Art in Plant Science)
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Article
Effects of Pre-Term Birth on the Cardio-Respiratory Responses to Hypoxic Exercise in Children
Life 2022, 12(1), 79; https://doi.org/10.3390/life12010079 - 06 Jan 2022
Cited by 1
Abstract
Pre-term birth is associated with numerous cardio-respiratory sequelae in children. Whether these impairments impact the responses to exercise in normoxia or hypoxia remains to be established. Fourteen prematurely-born (PREM) (Mean ± SD; gestational age 29 ± 2 weeks; age 9.5 ± 0.3 years), [...] Read more.
Pre-term birth is associated with numerous cardio-respiratory sequelae in children. Whether these impairments impact the responses to exercise in normoxia or hypoxia remains to be established. Fourteen prematurely-born (PREM) (Mean ± SD; gestational age 29 ± 2 weeks; age 9.5 ± 0.3 years), and 15 full-term children (CONT) (gestational age 39 ± 1 weeks; age 9.7 ± 0.9 years), underwent incremental exercise tests to exhaustion in normoxia (FiO2 = 20.9%) and normobaric hypoxia (FiO2 = 13.2%) on a cycle ergometer. Cardio-respiratory variables were measured throughout. Peak power output was higher in normoxia than hypoxia (103 ± 17 vs. 77 ± 18 W; p < 0.001), with no difference between CONT and PREM (94 ± 23 vs. 86 ± 19 W; p = 0.154). VO2peak was higher in normoxia than hypoxia in CONT (50.8 ± 7.2 vs. 43.8 ± 9.9 mL·kg−1·min−1; p < 0.001) but not in PREM (48.1 ± 7.5 vs. 45.0 ± 6.8 mL·kg−1·min−1; p = 0.137; interaction p = 0.044). Higher peak heart rate (187 ± 11 vs. 180 ± 10 bpm; p = 0.005) and lower stroke volume (72 ± 13 vs. 77 ± 14 mL; p = 0.004) were observed in normoxia versus hypoxia in CONT, with no such differences in PREM (p = 0.218 and >0.999, respectively). In conclusion, premature birth does not appear to exacerbate the negative effect of hypoxia on exercise capacity in children. Further research is warranted to identify whether prematurity elicits a protective effect, and to clarify the potential underlying mechanisms. Full article
(This article belongs to the Special Issue Cellular and Functional Response to Hypoxia)
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Article
Ginsenoside F1 Protects the Brain against Amyloid Beta-Induced Toxicity by Regulating IDE and NEP
Life 2022, 12(1), 58; https://doi.org/10.3390/life12010058 - 01 Jan 2022
Cited by 2
Abstract
Ginsenoside F1, the metabolite of Rg1, is one of the most important constituents of Panax ginseng. Although the effects of ginsenosides on amyloid beta (Aβ) aggregation in the brain are known, the role of ginsenoside F1 remains unclear. Here, we investigated the [...] Read more.
Ginsenoside F1, the metabolite of Rg1, is one of the most important constituents of Panax ginseng. Although the effects of ginsenosides on amyloid beta (Aβ) aggregation in the brain are known, the role of ginsenoside F1 remains unclear. Here, we investigated the protective effect of ginsenoside F1 against Aβ aggregation in vivo and in vitro. Treatment with 2.5 μM ginsenoside F1 reduced Aβ-induced cytotoxicity by decreasing Aβ aggregation in mouse neuroblastoma neuro-2a (N2a) and human neuroblastoma SH-SY5Y neuronal cell lines. Western blotting, real-time PCR, and siRNA analysis revealed an increased level of insulin-degrading enzyme (IDE) and neprilysin (NEP). Furthermore, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis confirmed that ginsenoside F1 could pass the blood–brain barrier within 2 h after administration. Immunostaining results indicate that ginsenoside F1 reduces Aβ plaques in the hippocampus of APPswe/PSEN1dE9 (APP/PS1) double-transgenic Alzheimer’s disease (AD) mice. Consistently, increased levels of IDE and NEP protein and mRNA were observed after the 8-week administration of 10 mg/kg/d ginsenoside F1. These data indicate that ginsenoside F1 is a promising therapeutic candidate for AD. Full article
(This article belongs to the Section Pharmaceutical Science)
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Article
An Interplay between Viruses and Bacteria Associated with the White Sea Sponges Revealed by Metagenomics
Life 2022, 12(1), 25; https://doi.org/10.3390/life12010025 - 24 Dec 2021
Abstract
Sponges are remarkable holobionts harboring extremely diverse microbial and viral communities. However, the interactions between the components within holobionts and between a holobiont and environment are largely unknown, especially for polar organisms. To investigate possible interactions within and between sponge-associated communities, we probed [...] Read more.
Sponges are remarkable holobionts harboring extremely diverse microbial and viral communities. However, the interactions between the components within holobionts and between a holobiont and environment are largely unknown, especially for polar organisms. To investigate possible interactions within and between sponge-associated communities, we probed the microbiomes and viromes of cold-water sympatric sponges Isodictya palmata (n = 2), Halichondria panicea (n = 3), and Halichondria sitiens (n = 3) by 16S and shotgun metagenomics. We showed that the bacterial and viral communities associated with these White Sea sponges are species-specific and different from the surrounding water. Extensive mining of bacterial antiphage defense systems in the metagenomes revealed a variety of defense mechanisms. The abundance of defense systems was comparable in the metagenomes of the sponges and the surrounding water, thus distinguishing the White Sea sponges from those inhabiting the tropical seas. We developed a network-based approach for the combined analysis of CRISPR-spacers and protospacers. Using this approach, we showed that the virus–host interactions within the sponge-associated community are typically more abundant (three out of four interactions studied) than the inter-community interactions. Additionally, we detected the occurrence of viral exchanges between the communities. Our work provides the first insight into the metagenomics of the three cold-water sponge species from the White Sea and paves the way for a comprehensive analysis of the interactions between microbial communities and associated viruses. Full article
(This article belongs to the Special Issue Metagenomics: New Trends and Solutions)
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Article
Major Surgical Trauma Impairs the Function of Natural Killer Cells but Does Not Affect Monocyte Cytokine Synthesis
Life 2022, 12(1), 13; https://doi.org/10.3390/life12010013 - 22 Dec 2021
Cited by 1
Abstract
Major traumatic and surgical injury increase the risk for infectious complications due to immune dysregulation. Upon stimulation with interleukin (IL) 12 by monocyte/macrophages, natural killer (NK) cells release interferon (IFN) γ that supports the elimination of the pathogen. In the present study, we [...] Read more.
Major traumatic and surgical injury increase the risk for infectious complications due to immune dysregulation. Upon stimulation with interleukin (IL) 12 by monocyte/macrophages, natural killer (NK) cells release interferon (IFN) γ that supports the elimination of the pathogen. In the present study, we investigated the impact of invasive spine surgery on the relationship between monocytes and NK cells upon exposure to Staphylococcus aureus. Mononuclear cells and serum were isolated from peripheral blood of patients before and up to 8 d after surgery and stimulated with inactivated S. aureus bacteria. NK cell and monocyte function were determined by flow cytometry. NK cells continuously lost their ability to produce IFN-γ during the first week after surgery independently from monocyte-derived IL-12 secretion. IFN-γ synthesis was minimal on day 8 and was associated with decreased expression of the IL-12 receptor and activation of transcription factors required for IFNG gene transcription. Addition of recombinant IL-12 could at least partially restore NK cell function. Pre-operative levels of growth/differentiation factor (GDF) 15 in the serum correlated with the extent of NK cell suppression and with hospitalization. Thus, NK cell suppression after major surgery might represent a therapeutic target to improve the immune defense against opportunistic infections. Full article
(This article belongs to the Special Issue Healing after Trauma)
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Article
Posterior Circulation Endovascular Thrombectomy for Large Vessels Occlusion in Patients Presenting with NIHSS Score ≤ 10
Life 2021, 11(12), 1423; https://doi.org/10.3390/life11121423 - 17 Dec 2021
Cited by 4
Abstract
Mechanical thrombectomy (MT) is currently the gold standard treatment for ischemic stroke due to large vessel occlusion (LVO). However, the evidence of clinical usefulness of MT in posterior circulation LVO (pc-LVO) is still doubtful compared to the anterior circulation, especially in patients with [...] Read more.
Mechanical thrombectomy (MT) is currently the gold standard treatment for ischemic stroke due to large vessel occlusion (LVO). However, the evidence of clinical usefulness of MT in posterior circulation LVO (pc-LVO) is still doubtful compared to the anterior circulation, especially in patients with mild neurological symptoms. The database of 10 high-volume stroke centers in Europe, including a period of three year and a half, was screened for patients with an acute basilar artery occlusion or a single dominant vertebral artery occlusion (“functional” BAO) presenting with a NIHSS ≤10, and with at least 3 months follow-up. A total of 63 patients were included. Multivariate analysis demonstrated that female gender (adjusted OR 0.04; 95% CI 0–0.84; p = 0.04) and combined technique (adj OR 0.001; 95% CI 0–0.81; p = 0.04) were predictors of worse outcome. Higher pc-ASPECTS (adj OR 4.75; 95% CI 1.33–16.94; p = 0.02) and higher Delta NIHSS (adj OR 2.06; 95% CI 1.16–3.65; p = 0.01) were predictors of better outcome. Delta NIHSS was the main predictor of good outcome at 90 days in patients with posterior circulation LVO presenting with NIHSS score ≤ 10. Full article
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Article
Diverse Effect of Two Cytokinins, Kinetin and Benzyladenine, on Plant Development, Biotic Stress Tolerance, and Gene Expression
Life 2021, 11(12), 1404; https://doi.org/10.3390/life11121404 - 15 Dec 2021
Abstract
The plant hormones cytokinins affect a various array of plant growth and development processes as well as responses to biotic and abiotic stresses. In this study, the opposite effect of two different cytokinins kinetin (N6-furfuryladenine) and benzyladenine (BA) on development and [...] Read more.
The plant hormones cytokinins affect a various array of plant growth and development processes as well as responses to biotic and abiotic stresses. In this study, the opposite effect of two different cytokinins kinetin (N6-furfuryladenine) and benzyladenine (BA) on development and on the tolerance of Arabidopsis and tobacco plants to virus, bacteria, and fungi infection was reported. Treatments of Arabidopsis and tobacco seedlings with saturated solutions of BA inhibited plant progress, while treatments with saturated water solution of kinetin promoted plant development. Furthermore, BA pre-treatments strongly reduced the number of TMV (Tobacco mosaic virus) lesions on tobacco and the tissue damage caused by the incompatible Pseudomonas bacteria on Arabidopsis and tobacco leaves. Similarly, BA pre-treatment significantly reduced the necrotic disease symptoms of Botrytis cinerea infection. Kinetin pre-treatments had a much weaker or no protective effect on the damage caused by the above pathogens. Accordingly, Arabidopsis gene expression profiles after treatments also showed that the two cytokinins have different effects on several plant processes. The gene expression results supported the more robust effect of BA, which up and downregulated more than 2000 genes, while only 436 genes were influenced by kinetin treatment. It is noteworthy that BA and kinetin treatment changed gene expressions in the same direction only in a relatively few cases (73 upregulated and 70 downregulated genes), and even 28 genes were regulated into the opposite directions by BA and kinetin. Both treatments had a strong effect on auxin and gibberellin-related genes, but only BA had a significant effect on cytokinin-induced processes. While kinetin exclusively activated the flavonoid synthesis genes, BA affected more significantly protein synthesis, photosynthesis, and plant defence-related genes. In conclusion, BA solution had sometimes the opposite and generally a much stronger effect than kinetin solution not only on the development and on biotic stress tolerance of tobacco and Arabidopsis plants but also on the gene expressions. The stronger protective effect of BA to necrotic stresses is probably due to its stronger senescence inhibitory effect on plant tissues, as supported by the stronger chlorophyll retardation of the BA-treated leaves. Full article
(This article belongs to the Section Plant Science)
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Article
Prevalence of Vancomycin-Resistant Enterococci and Antimicrobial Residues in Wastewater and Surface Water
Life 2021, 11(12), 1403; https://doi.org/10.3390/life11121403 - 15 Dec 2021
Cited by 1
Abstract
Due to the extensive use of antimicrobial agents in human and veterinary medicine, residues of various antimicrobials get into wastewater and, subsequently, surface water. On the one hand, a combination of processes in wastewater treatment plants aims to eliminate chemical and biological pollutants; [...] Read more.
Due to the extensive use of antimicrobial agents in human and veterinary medicine, residues of various antimicrobials get into wastewater and, subsequently, surface water. On the one hand, a combination of processes in wastewater treatment plants aims to eliminate chemical and biological pollutants; on the other hand, this environment may create conditions suitable for the horizontal transfer of resistance genes and potential selection of antibiotic-resistant bacteria. Wastewater and surface water samples (Morava River) were analyzed to determine the concentrations of 10 antibiotics and identify those exceeding so-called predicted no-effect environmental concentrations (PNECs). This study revealed that residues of five of the tested antimicrobials, namely ampicillin, clindamycin, tetracycline, tigecycline and vancomycin, in wastewater samples exceeded the PNEC. Vancomycin concentrations were analyzed with respect to the detected strains of vancomycin-resistant enterococci (VRE), in which the presence of resistance genes, virulence factors and potential relationship were analyzed. VRE were detected in 16 wastewater samples (11%) and two surface water samples (6%). The PNEC of vancomycin was exceed in 16% of the samples. Since the detected VRE did not correlate with the vancomycin concentrations, no direct relationship was confirmed between the residues of this antimicrobials and the presence of the resistant strains. Full article
(This article belongs to the Special Issue Bacterial Infections, Treatment and Antibiotic Resistance)
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Article
Risk Factors, Treatment and Prognosis of Patients with Lung Cancer after Heart Transplantation
Life 2021, 11(12), 1344; https://doi.org/10.3390/life11121344 - 04 Dec 2021
Cited by 1
Abstract
Long-term survival after heart transplantation (HTX) is impacted by adverse effects of immunosuppressive pharmacotherapy, and post-transplant lung cancer is a common occurrence. This study aimed to examine the risk factors, treatment, and prognosis of patients with post-transplant lung cancer. We included 625 adult [...] Read more.
Long-term survival after heart transplantation (HTX) is impacted by adverse effects of immunosuppressive pharmacotherapy, and post-transplant lung cancer is a common occurrence. This study aimed to examine the risk factors, treatment, and prognosis of patients with post-transplant lung cancer. We included 625 adult patients who received HTX at Heidelberg Heart Center between 1989 and 2018. Patients were stratified by diagnosis and staging of lung cancer after HTX. Analysis comprised donor and recipient characteristics, medications including immunosuppressive drugs, and survival after diagnosis of lung cancer. A total of 41 patients (6.6%) were diagnosed with lung cancer after HTX, 13 patients received curative care and 28 patients had palliative care. Mean time from HTX until diagnosis of lung cancer was 8.6 ± 4.0 years and 1.8 ± 2.7 years from diagnosis of lung cancer until last follow-up. Twenty-four patients (58.5%) were switched to an mTOR-inhibitor after diagnosis of lung cancer. Multivariate analysis showed recipient age (HR: 1.05; CI: 1.01–1.10; p = 0.02), COPD (HR: 3.72; CI: 1.88–7.37; p < 0.01), and history of smoking (HR: 20.39; CI: 2.73–152.13; p < 0.01) as risk factors for post-transplant lung cancer. Patients in stages I and II had a significantly better 1-year (100.0% versus 3.6%), 2-year (69.2% versus 0.0%), and 5-year survival (53.8% versus 0.0%) than patients in stages III and IV (p < 0.01). Given the poor prognosis of late-stage post-transplant lung cancer, routine reassessment of current smoking status, providing smoking cessation support, and intensified lung cancer screening in high-risk HTX recipients are advisable. Full article
(This article belongs to the Special Issue Heart Failure and Heart Transplantation)
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Article
Clinical Relevance of Secreted Small Noncoding RNAs in an Embryo Implantation Potential Prediction at Morula and Blastocyst Development Stages
Life 2021, 11(12), 1328; https://doi.org/10.3390/life11121328 - 01 Dec 2021
Cited by 1
Abstract
Despite the improvements in biotechnological approaches and the selection of controlled ovarian hyperstimulation protocols, the resulting pregnancy rate from in vitro fertilization (IVF) protocols still does not exceed 30–40%. In this connection, there is an acute question of the development of a non-invasive, [...] Read more.
Despite the improvements in biotechnological approaches and the selection of controlled ovarian hyperstimulation protocols, the resulting pregnancy rate from in vitro fertilization (IVF) protocols still does not exceed 30–40%. In this connection, there is an acute question of the development of a non-invasive, sensitive, and specific method for assessing the implantation potential of an embryo. A total of 110 subfertile couples were included in the study to undergo the IVF/ICSI program. Obtained embryos for transfer into the uterine cavity of patient cohort 1 (n = 60) and cohort 2 (n = 50) were excellent/good-quality blastocysts, and small noncoding RNA (sncRNA) content in the corresponding spent culture medium samples at the morula stage (n = 43) or at the blastocyst stage (n = 31) was analyzed by deep sequencing followed by qRT-PCR in real time. Two logistic regression models were developed to predict the implantation potential of the embryo with 100% sensitivity and 100% specificity: model 1 at the morula stage, using various combinations of hsa_piR_022258, hsa-let-7i-5p, hsa_piR_000765, hsa_piR_015249, hsa_piR_019122, and hsa_piR_008112, and model 2 at the blastocyst stage, using various combinations of hsa_piR_020497, hsa_piR_008113, hsa-miR-381-3p, hsa_piR_022258, and hsa-let-7a-5p. Protein products of sncRNA potential target genes participate in the selective turnover of proteins through the ubiquitination system and in the organization of the various cell cytoskeleton and nucleoskeleton structures, regulating the activity of the Hippo signaling pathway, which determines the fate specification of the blastomers. Full article
(This article belongs to the Special Issue Genomic and Transcriptomic Alterations in Cancer and Aging)
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Article
Properties of GABAergic Neurons Containing Calcium-Permeable Kainate and AMPA-Receptors
Life 2021, 11(12), 1309; https://doi.org/10.3390/life11121309 - 27 Nov 2021
Cited by 1
Abstract
Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs), as well as NMDARs, play a pivotal role in plasticity and in regulating neurotransmitter release. Here we visualized in the mature hippocampal neuroglial cultures the neurons expressing CP-AMPARs and CP-KARs. These neurons were visualized by [...] Read more.
Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs), as well as NMDARs, play a pivotal role in plasticity and in regulating neurotransmitter release. Here we visualized in the mature hippocampal neuroglial cultures the neurons expressing CP-AMPARs and CP-KARs. These neurons were visualized by a characteristic fast sustained [Ca2+]i increase in response to the agonist of these receptors, domoic acid (DoA), and a selective agonist of GluK1-containing KARs, ATPA. Neurons from both subpopulations are GABAergic. The subpopulation of neurons expressing CP-AMPARs includes a larger percentage of calbindin-positive neurons (39.4 ± 6.0%) than the subpopulation of neurons expressing CP-KARs (14.2 ± 7.5% of CB+ neurons). In addition, we have shown for the first time that NH4Cl-induced depolarization faster induces an [Ca2+]i elevation in GABAergic neurons expressing CP-KARs and CP-AMPARs than in most glutamatergic neurons. CP-AMPARs antagonist, NASPM, increased the amplitude of the DoA-induced Ca2+ response in GABAergic neurons expressing CP-KARs, indicating that neurons expressing CP-AMPARs innervate GABAergic neurons expressing CP-KARs. We assume that CP-KARs in inhibitory neurons are involved in the mechanism of outstripping GABA release upon hyperexcitation. Full article
(This article belongs to the Special Issue Glutamate Receptors)
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Article
Comparing Native Crystal Structures and AlphaFold2 Predicted Water-Soluble G Protein-Coupled Receptor QTY Variants
Life 2021, 11(12), 1285; https://doi.org/10.3390/life11121285 - 24 Nov 2021
Abstract
Accurate predictions of 3-dimensional protein structures by AlphaFold2 is a game-changer for biology, especially for structural biology. Here we present the studies of several native chemokine receptors including CCR5, CCR9, CXCR2 and CXCR4 determined by X-ray crystallography, and their water-soluble QTY counter parts [...] Read more.
Accurate predictions of 3-dimensional protein structures by AlphaFold2 is a game-changer for biology, especially for structural biology. Here we present the studies of several native chemokine receptors including CCR5, CCR9, CXCR2 and CXCR4 determined by X-ray crystallography, and their water-soluble QTY counter parts predicted by AlphaFold2. In the native structures, there are hydrophobic amino acids leucine (L), isoleucine (I), valine (V) and phenylalanine (F) in the transmembrane helices. These hydrophobic amino acids are systematically replaced by hydrophilic amino acids glutamine (Q), threonine (T), and tyrosine (Y). Thus, the QTY variants become water-soluble. We also present the superimposed structures of native CCR10, CXCR5, CXCR7 and an olfactory receptor OR1D2 and their water-soluble QTY variants. Since the CryoEM structural determinations for the QTY variants of CCR10QTY and OR1D2QTY are in progress, it will be of interest to compare them when the structures become available. The superimposed structures show remarkable similarity within RMSD 1Å–2Å despite significant sequence differences (~26%–~33%). We also show the differences of hydrophobicity patches between the native GPCR and their QTY variants. Our study provides insight into the subtle differences between the hydrophobic helices and hydrophilic helices, and may further stimulate designs of water-soluble membrane proteins and other aggregated proteins. Full article
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Article
COVID-19 and Artificial Intelligence: An Approach to Forecast the Severity of Diagnosis
Life 2021, 11(11), 1281; https://doi.org/10.3390/life11111281 - 22 Nov 2021
Cited by 3
Abstract
(1) Background: The new SARS-COV-2 pandemic overwhelmed intensive care units, clinicians, and radiologists, so the development of methods to forecast the diagnosis’ severity became a necessity and a helpful tool. (2) Methods: In this paper, we proposed an artificial intelligence-based multimodal approach to [...] Read more.
(1) Background: The new SARS-COV-2 pandemic overwhelmed intensive care units, clinicians, and radiologists, so the development of methods to forecast the diagnosis’ severity became a necessity and a helpful tool. (2) Methods: In this paper, we proposed an artificial intelligence-based multimodal approach to forecast the future diagnosis’ severity of patients with laboratory-confirmed cases of SARS-CoV-2 infection. At hospital admission, we collected 46 clinical and biological variables with chest X-ray scans from 475 COVID-19 positively tested patients. An ensemble of machine learning algorithms (AI-Score) was developed to predict the future severity score as mild, moderate, and severe for COVID-19-infected patients. Additionally, a deep learning module (CXR-Score) was developed to automatically classify the chest X-ray images and integrate them into AI-Score. (3) Results: The AI-Score predicted the COVID-19 diagnosis’ severity on the testing/control dataset (95 patients) with an average accuracy of 98.59%, average specificity of 98.97%, and average sensitivity of 97.93%. The CXR-Score module graded the severity of chest X-ray images with an average accuracy of 99.08% on the testing/control dataset (95 chest X-ray images). (4) Conclusions: Our study demonstrated that the deep learning methods based on the integration of clinical and biological data with chest X-ray images accurately predicted the COVID-19 severity score of positive-tested patients. Full article
(This article belongs to the Special Issue Old and New Pandemics: Challenges for Humans)
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Article
An Episomal CRISPR/Cas12a System for Mediating Efficient Gene Editing
Life 2021, 11(11), 1262; https://doi.org/10.3390/life11111262 - 18 Nov 2021
Abstract
(1) Background: Gene editing technology, as represented by CRISPR is a powerful tool used in biomedical science. However, the editing efficiency of such technologies, especially in induced pluripotent stem cells (iPSCs) and other types of stem cells, is low which hinders its application [...] Read more.
(1) Background: Gene editing technology, as represented by CRISPR is a powerful tool used in biomedical science. However, the editing efficiency of such technologies, especially in induced pluripotent stem cells (iPSCs) and other types of stem cells, is low which hinders its application in regenerative medicine; (2) Methods: A gene-editing system, COE, was designed and constructed based on CRISPR/Cas12a and Orip/EBNA1, and its editing efficiency was evaluated in human embryonic kidney 293T (HEK-293T) cells with flow cytometry and restriction fragment length polymorphism (RFLP) analysis. The COE was nucleofected into iPSCs, then, the editing efficiency was verified by a polymerase chain reaction and Sanger sequencing; (3) Results: With the extension of time, COE enables the generation of up to 90% insertion or deletion rates in HEK-293T cells. Furthermore, the deletion of a 2.5 kb fragment containing Exon 51 of the dystrophin gene (DMD) in iPSCs was achieved with high efficiency; out of 14 clones analyzed, 3 were positive. Additionally, the Exon 51-deleted iPSCs derived from cardiomyocytes had similar expression profiles to those of Duchenne muscular dystrophy (DMD) patient-specific iPSCs. Moreover, there was no residue of each component of the plasmid in the editing cells; (4) Conclusions: In this study, a novel, efficient, and safe gene-editing system, COE, was developed, providing a powerful tool for gene editing. Full article
(This article belongs to the Section Genetics and Genomics)
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Article
Promoter Demethylation Upregulates STEAP1 Gene Expression in Human Prostate Cancer: In Vitro and In Silico Analysis
Life 2021, 11(11), 1251; https://doi.org/10.3390/life11111251 - 17 Nov 2021
Cited by 1
Abstract
The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in several human tumors, particularly in prostate cancer (PCa). However, the mechanisms involved in its overexpression remain unknown. It is well known that epigenetic modifications may result in [...] Read more.
The Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is an oncogene overexpressed in several human tumors, particularly in prostate cancer (PCa). However, the mechanisms involved in its overexpression remain unknown. It is well known that epigenetic modifications may result in abnormal gene expression patterns, contributing to tumor initiation and progression. Therefore, this study aimed to analyze the methylation pattern of the STEAP1 gene in PCa versus non-neoplastic cells. Bisulfite amplicon sequencing of the CpG island at the STEAP1 gene promoter showed a higher methylation level in non-neoplastic PNT1A prostate cells than in human PCa samples. Bioinformatic analysis of the GEO datasets also showed the STEAP1 gene promoter as being demethylated in human PCa, and a negative association with STEAP1 mRNA expression was observed. These results are supported by the treatment of non-neoplastic PNT1A cells with DNMT and HDAC inhibitors, which induced a significant increase in STEAP1 mRNA expression. In addition, the involvement of HDAC in the regulation of STEAP1 mRNA expression was corroborated by a negative association between STEAP1 mRNA expression and HDAC4,5,7 and 9 in human PCa. In conclusion, our work indicates that STEAP1 overexpression in PCa can be driven by the hypomethylation of STEAP1 gene promoter. Full article
(This article belongs to the Special Issue Prostate Cancer)
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Article
A Label-Free Proteomic and Complementary Metabolomic Analysis of Leaves of the Resurrection Plant Xerophyta schlechteri during Dehydration
Life 2021, 11(11), 1242; https://doi.org/10.3390/life11111242 - 16 Nov 2021
Abstract
Vegetative desiccation tolerance, or the ability to survive the loss of ~95% relative water content (RWC), is rare in angiosperms, with these being commonly called resurrection plants. It is a complex multigenic and multi-factorial trait, with its understanding requiring a comprehensive systems biology [...] Read more.
Vegetative desiccation tolerance, or the ability to survive the loss of ~95% relative water content (RWC), is rare in angiosperms, with these being commonly called resurrection plants. It is a complex multigenic and multi-factorial trait, with its understanding requiring a comprehensive systems biology approach. The aim of the current study was to conduct a label-free proteomic analysis of leaves of the resurrection plant Xerophyta schlechteri in response to desiccation. A targeted metabolomics approach was validated and correlated to the proteomics, contributing the missing link in studies on this species. Three physiological stages were identified: an early response to drying, during which the leaf tissues declined from full turgor to a RWC of ~80–70%, a mid-response in which the RWC declined to 40% and a late response where the tissues declined to 10% RWC. We identified 517 distinct proteins that were differentially expressed, of which 253 proteins were upregulated and 264 were downregulated in response to the three drying stages. Metabolomics analyses, which included monitoring the levels of a selection of phytohormones, amino acids, sugars, sugar alcohols, fatty acids and organic acids in response to dehydration, correlated with some of the proteomic differences, giving insight into the biological processes apparently involved in desiccation tolerance in this species. Full article
(This article belongs to the Special Issue Plant Proteomics)
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Article
Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities
Life 2021, 11(11), 1217; https://doi.org/10.3390/life11111217 - 10 Nov 2021
Cited by 1
Abstract
Cross-talk between opioid and adrenergic receptors is well-characterized and involves second messenger systems, the formation of receptor heterodimers, and the presence of extracellular allosteric binding regions for the complementary ligand; however, the evolutionary origins of these interactions have not been investigated. We propose [...] Read more.
Cross-talk between opioid and adrenergic receptors is well-characterized and involves second messenger systems, the formation of receptor heterodimers, and the presence of extracellular allosteric binding regions for the complementary ligand; however, the evolutionary origins of these interactions have not been investigated. We propose that opioid and adrenergic ligands and receptors co-evolved from a common set of modular precursors so that they share binding functions. We demonstrate the plausibility of this hypothesis through a review of experimental evidence for molecularly complementary modules and report unexpected homologies between the two receptor types. Briefly, opioids form homodimers also bind adrenergic compounds; opioids bind to conserved extracellular regions of adrenergic receptors while adrenergic compounds bind to conserved extracellular regions of opioid receptors; opioid-like modules appear in both sets of receptors within key ligand-binding regions. Transmembrane regions associated with homodimerization of each class of receptors are also highly conserved across receptor types and implicated in heterodimerization. This conservation of multiple functional modules suggests opioid–adrenergic ligand and receptor co-evolution and provides mechanisms for explaining the evolution of their crosstalk. These modules also suggest the structure of a primordial receptor, providing clues for engineering receptor functions. Full article
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Article
Neuromuscular Activity during Cycling Performance in Hot/Dry and Hot/Humid Conditions
Life 2021, 11(11), 1149; https://doi.org/10.3390/life11111149 - 28 Oct 2021
Cited by 1
Abstract
To determine the relationships between limiting factors and neuromuscular activity during a self-paced 20-km cycling time trial and evaluate the effect of environmental conditions on fatigue indices. Methods: Ten endurance-trained and heat-acclimated athletes performed in three conditions (ambient temperature, relative humidity): HUMID (30 [...] Read more.
To determine the relationships between limiting factors and neuromuscular activity during a self-paced 20-km cycling time trial and evaluate the effect of environmental conditions on fatigue indices. Methods: Ten endurance-trained and heat-acclimated athletes performed in three conditions (ambient temperature, relative humidity): HUMID (30 °C, 90%), DRY (35 °C, 46%) and NEUTRAL (22 °C, 55%). Voluntary muscular contractions and electromagnetic stimulations were recorded before and after the time trials to assess fatigue. The data on performance, temperature, heat storage, electromyogram, heart rate and rating of perceived exertion data were analyzed. Results: Performance was impaired in DRY and HUMID compared with NEUTRAL environment (p < 0.05). The force developed by the vastus lateral muscle during stimulation of the femoral nerve remained unchanged across conditions. The percentage of integrated electromyogram activity, normalized by the value attained during the pre-trial maximal voluntary contraction, decreased significantly throughout the trial only in HUMID condition (p < 0.01). Neuromuscular activity in peripheral skeletal muscle started to fall from the 11th km in HUMID and the 15th km in DRY condition, although core temperature did not reach critical values. Conclusions: These alterations suggest that afferences from core/skin temperature regulate the central neural motor drive, reducing the active muscle recruited during prolonged exercise in the heat in order to prevent the system from hyperthermia. Full article
(This article belongs to the Special Issue Human Thermophysiology)
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Article
Clostridioides difficile and Vancomycin-Resistant Enterococci in COVID-19 Patients with Severe Pneumonia
Life 2021, 11(11), 1127; https://doi.org/10.3390/life11111127 - 22 Oct 2021
Cited by 3
Abstract
Broad-spectrum antibiotics administered to patients with severe COVID-19 pneumonia pose a risk of infection caused by Clostridioides difficile. This risk is reduced mainly by strict hygiene measures and early de-escalation of antibiotic therapy. Recently, oral vancomycin prophylaxis (OVP) has also been discussed. [...] Read more.
Broad-spectrum antibiotics administered to patients with severe COVID-19 pneumonia pose a risk of infection caused by Clostridioides difficile. This risk is reduced mainly by strict hygiene measures and early de-escalation of antibiotic therapy. Recently, oral vancomycin prophylaxis (OVP) has also been discussed. This retrospective study aimed to assess the prevalence of C. difficile in critical COVID-19 patients staying in an intensive care unit of a tertiary hospital department of anesthesiology, resuscitation, and intensive care from November 2020 to May 2021 and the rates of vancomycin-resistant enterococci (VRE) after the introduction of OVP and to compare the data with those from controls in the pre-pandemic period (November 2018 to May 2019). During the COVID-19 pandemic, there was a significant increase in toxigenic C. difficile rates to 12.4% of patients, as compared with 1.6% in controls. The peak rates were noted in February 2021 (25% of patients), immediately followed by initiation of OVP, changes to hygiene precautions, and more rapid de-escalation of antibiotic therapy. Subsequently, toxigenic C. difficile detection rates started to fall. There was a nonsignificant increase in VRE detected in non-gastrointestinal tract samples to 8.9% in the COVID-19 group, as compared to 5.3% in the control group. Molecular analysis confirmed mainly clonal spread of VRE. Full article
(This article belongs to the Special Issue Bacterial Infections, Treatment and Antibiotic Resistance)
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Article
Short-Term Sleep Fragmentation Dysregulates Autophagy in a Brain Region-Specific Manner
Life 2021, 11(10), 1098; https://doi.org/10.3390/life11101098 - 16 Oct 2021
Cited by 2
Abstract
In this study, we investigated autophagy, glial activation status, and corticotropin releasing factor (CRF) signaling in the brains of mice after 5 days of sleep fragmentation (SF). Three different brain regions including the striatum, hippocampus, and frontal cortex were selected for examination based [...] Read more.
In this study, we investigated autophagy, glial activation status, and corticotropin releasing factor (CRF) signaling in the brains of mice after 5 days of sleep fragmentation (SF). Three different brain regions including the striatum, hippocampus, and frontal cortex were selected for examination based on roles in sleep regulation and sensitivity to sleep disruption. For autophagy, we monitored the levels of various autophagic induction markers including beclin1, LC3II, and p62 as well as the levels of lysosomal associated membrane protein 1 and 2 (LAMP1/2) and the transcription factor EB (TFEB) which are critical for lysosome function and autophagy maturation stage. For the status of microglia and astrocytes, we determined the levels of Iba1 and GFAP in these brain regions. We also measured the levels of CRF and its cognate receptors 1 and 2 (CRFR1/2). Our results showed that 5 days of SF dysregulated autophagy in the striatum and hippocampus but not in the frontal cortex. Additionally, 5 days of SF activated microglia in the striatum but not in the hippocampus or frontal cortex. In the striatum, CRFR2 but not CRFR1 was significantly increased in SF-experienced mice. CRF did not alter its mRNA levels in any of the three brain regions assessed. Our findings revealed that autophagy processes are sensitive to short-term SF in a region-specific manner and suggest that autophagy dysregulation may be a primary initiator for brain changes and functional impairments in the context of sleep disturbances and disorders. Full article
(This article belongs to the Section Physiology and Pathology)
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Article
Foliar Fungal Endophytes in a Tree Diversity Experiment Are Driven by the Identity but Not the Diversity of Tree Species
Life 2021, 11(10), 1081; https://doi.org/10.3390/life11101081 - 13 Oct 2021
Abstract
Symbiotic foliar fungal endophytes can have beneficial effects on host trees and might alleviate climate-induced stressors. Whether and how the community of foliar endophytes is dependent on the tree neighborhood is still under debate with contradicting results from different tree diversity experiments. Here, [...] Read more.
Symbiotic foliar fungal endophytes can have beneficial effects on host trees and might alleviate climate-induced stressors. Whether and how the community of foliar endophytes is dependent on the tree neighborhood is still under debate with contradicting results from different tree diversity experiments. Here, we present our finding regarding the effect of the tree neighborhood from the temperate, densely planted and 12-years-old Kreinitz tree diversity experiment. We used linear models, redundancy analysis, Procrustes analysis and Holm-corrected multiple t-tests to quantify the effects of the plot-level tree neighborhood on the diversity and composition of foliar fungal endophytes in Fagus sylvatica, Quercus petraea and Picea abies. Against our expectations, we did not find an effect of tree diversity on endophyte diversity. Endophyte composition, however, was driven by the identity of the host species. Thirteen endophytes where overabundant in tree species mixtures, which might indicate frequent spillover or positive interactions between foliar endophytes. The independence of the diversity of endophytes from the diversity of tree species might be attributed to the small plot size and the high density of tree individuals. However, the mechanistic causes for these cryptic relationships still remain to be uncovered. Full article
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Communication
Robust Neutralizing Antibody Responses 6 Months Post Vaccination with BNT162b2: A Prospective Study in 308 Healthy Individuals
Life 2021, 11(10), 1077; https://doi.org/10.3390/life11101077 - 12 Oct 2021
Cited by 15
Abstract
Elucidating long-term immunity following COVID-19 vaccination is essential for decision-making regarding booster shots. The aim of this study was to investigate the kinetics of neutralizing antibodies (Nabs) against SARS-CoV-2 up to six months after the second vaccination dose with the BNT162b2 mRNA vaccine. [...] Read more.
Elucidating long-term immunity following COVID-19 vaccination is essential for decision-making regarding booster shots. The aim of this study was to investigate the kinetics of neutralizing antibodies (Nabs) against SARS-CoV-2 up to six months after the second vaccination dose with the BNT162b2 mRNA vaccine. Nabs levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and 3 and 6 months after the second vaccination (NCT04743388). Three hundred and eight healthy individuals without malignant disease were included in this study. At six months, 2.59% of the participants had a Nabs value less than 30%, while 11.9% had Nabs values of less than 50%. Importantly, 58% of the subjects had Nabs values of more than 75%. Nabs were initially eliminated at a relatively slow rate, but after three months their elimination was 5.7 times higher. Older age was inversely associated with Nabs levels at all examined timepoints. Interestingly, a population modeling analysis estimated that half of the subjects will have Nabs values less than 73.8% and 64.6% at 9 and 12 months, respectively, post vaccination completion. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at six months following full vaccination with BNT162b2 in healthy individuals, which was more pronounced among older persons. These data may inform the public health policies regarding the prioritization of booster vaccine shots. Full article
(This article belongs to the Special Issue Virology Applications to COVID-19 Pandemic)
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Article
Sorafenib Combined with Chemoembolization for Locally Advanced Hepatocellular Carcinoma with Macroscopic Vascular Invasion: A Propensity Score Analysis
Life 2021, 11(10), 1066; https://doi.org/10.3390/life11101066 - 10 Oct 2021
Cited by 1
Abstract
The purpose of this study was to compare the efficacy and safety of transarterial chemoembolization (TACE) plus sorafenib with those of TACE alone in patients with locally advanced hepatocellular carcinoma (HCC). Treatment-naïve patients with preserved hepatic reserve (Child–Pugh score ≤ 7) who received [...] Read more.
The purpose of this study was to compare the efficacy and safety of transarterial chemoembolization (TACE) plus sorafenib with those of TACE alone in patients with locally advanced hepatocellular carcinoma (HCC). Treatment-naïve patients with preserved hepatic reserve (Child–Pugh score ≤ 7) who received TACE plus sorafenib (n = 91) or TACE alone (n = 109) for locally advanced HCC with macrovascular invasion were retrospectively evaluated. Propensity score matching (PSM) was used to correct selection bias, and 63 pairs were created. In the entire study population, the median progression-free survival (PFS) and overall survival (OS) with TACE plus sorafenib were better than those with TACE alone. After PSM, the median PFS (7.0 vs. 4.3 months; p = 0.017) and OS (17.5 vs. 12.8 months; p = 0.049) were again significantly longer with TACE plus sorafenib than with TACE alone. Stratified Cox regression analysis and doubly robust estimation revealed that treatment type was significantly associated with both PFS and OS. In the subgroup analysis, TACE plus sorafenib did not show a significant survival benefit for patients with main portal vein or inferior vena cava invasion. Major complications were similar in both groups (p = 0.330). In conclusion, TACE plus sorafenib showed better survival outcomes than TACE alone in patients with locally advanced HCC. Full article
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Article
CXCR4-CCR7 Heterodimerization Is a Driver of Breast Cancer Progression
Life 2021, 11(10), 1049; https://doi.org/10.3390/life11101049 - 07 Oct 2021
Cited by 1
Abstract
Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to [...] Read more.
Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to the acquisition of the pro-metastatic properties remain poorly understood. We demonstrate here that the CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signalling responses in invasive breast cancer cell lines as well as primary mammary human tumour cells. Furthermore, for the first time, we have documented the presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumours where number of CXCR4-CCR7 complexes directly correlate with the severity of the disease. The functional significance of the CXCR4-CCR7 association was also demonstrated when their forced heterodimerization led to the acquisition of invasive phenotype in non-metastatic breast cancer cells. Taken together, our data establish the CXCR4-CCR7 receptor complex as a new functional unit, which is responsible for the acquisition of breast cancer cell metastatic phenotype and which may serve as a novel biomarker for invasive mammary tumours. Full article
(This article belongs to the Special Issue Chemokines and Their Receptors)
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Article
Comparison of the Effect of Unfractionated Heparin and Enoxaparin Sodium at Different Doses on the Course of COVID-19-Associated Coagulopathy
Life 2021, 11(10), 1032; https://doi.org/10.3390/life11101032 - 30 Sep 2021
Cited by 3
Abstract
Background: COVID-19-associated coagulopathy (CAC) exacerbates the course of coronavirus infection and contributes to increased mortality. Current recommendations for CAC treatment include the use of low-molecular weight heparins (LMWH) at prophylactic or therapeutic doses, as well as the use of unfractionated heparin (UFH). Methods: [...] Read more.
Background: COVID-19-associated coagulopathy (CAC) exacerbates the course of coronavirus infection and contributes to increased mortality. Current recommendations for CAC treatment include the use of low-molecular weight heparins (LMWH) at prophylactic or therapeutic doses, as well as the use of unfractionated heparin (UFH). Methods: A randomised, controlled trial enrolled 126 patients hospitalised in the intensive care unit with severe COVID-19 complicated by CAC. The effects of LMWH at preventive and therapeutic doses and UFH at therapeutic doses on mortality and intubation rates were compared. Results: The number of intubations and deaths showed no significant difference depending on the anticoagulant therapy used. However, multivariate logistic regression models revealed an increased risk of intubation (p = 0.026, odds ratio (OR) = 3.33, 95% confidence interval (CI) 1.15–9.59), and an increased risk of death (p = 0.046, OR = 3.01, 95% CI 1.02–8.90), for patients treated with LMWH at a prophylactic dose but not at a therapeutic dose as compared to patients treated with UFH when controlling for other risk factors. Conclusions: The use of unfractionated heparin in the treatment of COVID-19-associated coagulopathy seems to be more effective at reducing the risk of intubation and death than enoxaparin at prophylactic doses. Full article
(This article belongs to the Section Epidemiology)
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Article
NMR Reveals the Conformational Changes of Cytochrome C upon Interaction with Cardiolipin
Life 2021, 11(10), 1031; https://doi.org/10.3390/life11101031 - 30 Sep 2021
Abstract
Conformational change of cytochrome c (cyt c) caused by interaction with cardiolipin (CL) is an important step during apoptosis, but the underlying mechanism is controversial. To comprehensively clarify the structural transformations of cyt c upon interaction with CL and avoid the unpredictable alias [...] Read more.
Conformational change of cytochrome c (cyt c) caused by interaction with cardiolipin (CL) is an important step during apoptosis, but the underlying mechanism is controversial. To comprehensively clarify the structural transformations of cyt c upon interaction with CL and avoid the unpredictable alias that might come from protein labeling or mutations, the conformation of purified yeast iso–1 cyt c with natural isotopic abundance in different contents of CL was measured by using NMR spectroscopy, in which the trimethylated group of the protein was used as a natural probe. The data demonstrate that cyt c has two partially unfolded conformations when interacted with CL: one with Fe–His33 coordination and the other with a penta–coordination heme. The Fe–His33 coordination conformation can be converted into a penta–coordination heme conformation in high content of CL. The structure of cyt c becomes partially unfolded with more exposed heme upon interaction with CL, suggesting that cyt c prefers a high peroxidase activity state in the mitochondria, which, in turn, makes CL easy to be oxidized, and causes the release of cyt c into the cytoplasm as a trigger in apoptosis. Full article
(This article belongs to the Special Issue Application of Nuclear Magnetic Resonance Method in Protein Research)
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Article
Reduced Plasma Ascorbate and Increased Proportion of Dehydroascorbic Acid Levels in Patients Undergoing Hemodialysis
Life 2021, 11(10), 1023; https://doi.org/10.3390/life11101023 - 28 Sep 2021
Cited by 1
Abstract
Ascorbate functions as an electron donor and scavenges free radicals. Dehydroascorbic acid (DHA), the oxidized form of ascorbate, is generated as a result of these reactions. While low plasma ascorbate levels have been reported in hemodialysis patients worldwide, no studies have measured DHA [...] Read more.
Ascorbate functions as an electron donor and scavenges free radicals. Dehydroascorbic acid (DHA), the oxidized form of ascorbate, is generated as a result of these reactions. While low plasma ascorbate levels have been reported in hemodialysis patients worldwide, no studies have measured DHA because it is not generalized. In this study, we aimed to clarify whether plasma ascorbate levels are low in dialysis patients and whether plasma ascorbate levels fluctuate before and after dialysis. Moreover, we applied our previously established method to measure the plasma ascorbate and DHA levels in chronic kidney disease (CKD) stage G3–G5 non-hemodialysis-dependent patients, and pre- and post-dialysis plasma ascorbate and DHA levels in CKD stage G5D hemodialysis patients. The sample size was calculated using G-power software. The pre-dialysis plasma total ascorbate levels, including DHA, were significantly (56%) lower in hemodialysis patients than in non-hemodialysis-dependent CKD patients. After dialysis, there was a 40% reduction in the plasma total ascorbate levels. Hemodialysis increased the post-dialysis plasma proportions of DHA from 37% to 55%. The study results demonstrated lower plasma total ascorbate levels in hemodialysis patients compared with in non-hemodialysis-dependent CKD patients; these low levels in hemodialysis patients were further reduced by hemodialysis and increased DHA proportion. Full article
(This article belongs to the Special Issue Antimicrobial Mechanisms of Vitamin C)
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