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Life, Volume 11, Issue 9 (September 2021) – 127 articles

Cover Story (view full-size image): The article by Nordeen et al. reviews the background and context of basic studies that have contributed to the ground-breaking clinical trials employing high testosterone therapy to treat castrate-resistant prostate cancer. Studies from the bench will continue to contribute to the optimization of high testosterone therapy and the identification of exploitable vulnerabilities that accompany the adaptation made by cancer cells to manipulate their androgen environment. View this paper
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Article
Hematopoietic Prostaglandin D Synthase Inhibitor PK007 Decreases Muscle Necrosis in DMD mdx Model Mice
Life 2021, 11(9), 994; https://doi.org/10.3390/life11090994 - 21 Sep 2021
Cited by 1
Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein. The acute phase of DMD is characterized by muscle necrosis and increased levels of the pro-inflammatory mediator, prostaglandin D2 (PGD2). Inhibiting the production of [...] Read more.
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein. The acute phase of DMD is characterized by muscle necrosis and increased levels of the pro-inflammatory mediator, prostaglandin D2 (PGD2). Inhibiting the production of PGD2 by inhibiting hematopoietic prostaglandin D synthase (HPGDS) may alleviate inflammation and decrease muscle necrosis. We tested our novel HPGDS inhibitor, PK007, in the mdx mouse model of DMD. Our results show that hindlimb grip strength was two-fold greater in the PK007-treated mdx group, compared to untreated mdx mice, and displayed similar muscle strength to strain control mice (C57BL/10ScSn). Histological analyses showed a decreased percentage of regenerating muscle fibers (~20% less) in tibialis anterior (TA) and gastrocnemius muscles and reduced fibrosis in the TA muscle in PK007-treated mice. Lastly, we confirmed that the DMD blood biomarker, muscle creatine kinase activity, was also reduced by ~50% in PK007-treated mdx mice. We conclude that our HPGDS inhibitor, PK007, has effectively reduced muscle inflammation and fibrosis in a DMD mdx mouse model. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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Article
Computational Insights into the Interaction between Cytoadherence Receptor gC1qR and the DBLβ12 Domain of a Plasmodium falciparum PfEMP1 Ligand
Life 2021, 11(9), 993; https://doi.org/10.3390/life11090993 - 21 Sep 2021
Cited by 1
Abstract
Human receptor gC1qR is a 32 kD protein that mediates the cytoadherence of Plasmodium falciparum-infected erythrocytes (IEs) to human brain microvascular endothelial cells (HBMEC) and platelets. The cytoadherence of IEs to gC1qR has been associated with severe malaria symptoms. The cytoadherence to [...] Read more.
Human receptor gC1qR is a 32 kD protein that mediates the cytoadherence of Plasmodium falciparum-infected erythrocytes (IEs) to human brain microvascular endothelial cells (HBMEC) and platelets. The cytoadherence of IEs to gC1qR has been associated with severe malaria symptoms. The cytoadherence to gC1qR is mediated by the Duffy binding-like β12 (DBLβ12) domain of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), PFD0020c. Here, we report the structural insights into the binding of the DBLβ12 domain of PfEMP1 with the human receptor gC1qR using computational methods. A molecular model of the DBLβ12 domain was generated and used for protein–protein docking with the host receptor gC1qR. The protein–protein docking revealed that the DBLβ12 asymmetrically interacts with two subunits of the gC1qR trimer at the solution face of gC1qR. A total of 21 amino acid residues of DBLβ12 interact with 26 amino acid residues in the gC1qR trimer through 99 nonbonding interactions and 4 hydrogen bonds. Comparative analysis of binding sites on the DBL domain fold for the two receptors gC1qR and ICAM1 showed that the two sites are distinct. This is the first study that provides structural insights into DBLβ12 binding with its receptor gC1qR and may help in designing novel antisevere malaria interventions. Full article
(This article belongs to the Special Issue Cellular Interactions between Protozoan Pathogens and Hosts)
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Article
The Procoagulant Activity of Emoxilane®: A New Appealing Therapeutic Use in Epistaxis of the Combination of Sodium Hyaluronate, Silver Salt, α-tocopherol and D-panthenol
Life 2021, 11(9), 992; https://doi.org/10.3390/life11090992 - 21 Sep 2021
Cited by 1
Abstract
Epistaxis is one of the most frequent hemorrhages resulting from local or systemic factors. Its management without hospitalization has prompted an interest in locally applied hemostatic agents. Generally, the therapy approaches involve sprays or creams acting as a physical barrier, even used as [...] Read more.
Epistaxis is one of the most frequent hemorrhages resulting from local or systemic factors. Its management without hospitalization has prompted an interest in locally applied hemostatic agents. Generally, the therapy approaches involve sprays or creams acting as a physical barrier, even used as tampons or gauze. In this study, we have investigated the activity of Emoxilane®, a combination of sodium hyaluronate, silver salt, α-tocopherol acetate and D-panthenol, which is known to be able to separately act in a different biological manner. Our in vitro results, obtained on endothelial and nasal epithelial cells, have shown that the association of these molecules presented a notable antioxidant activity mainly due to the α-tocopherol and D-panthenol and a significant antimicrobial role thanks to the silver compound. Moreover, remarkable hemostatic activity was found by evaluating plasmin inhibition attributable to the sodium hyaluronate. Interestingly, on human plasma, we have confirmed that Emoxilane® strongly induced the increase of thrombin levels. These data suggest that the use of this association could represent an appealing pharmacological approach to actively induce hemostasis during epistaxis. Our future perspective will aim to the creation of a formulation for an easy topical application in the nose which is able to contrast the bleeding. Full article
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Editorial
Mitochondria: From Physiology to Pathology
Life 2021, 11(9), 991; https://doi.org/10.3390/life11090991 - 21 Sep 2021
Cited by 3
Abstract
Over the past decade, the role of mitochondria has extended beyond those tasks for which these organelles are historically known [...] Full article
(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)
Article
Metabolomic Response of the Creeping Wood Sorrel Oxalis corniculata to Low-Dose Radiation Exposure from Fukushima’s Contaminated Soil
Life 2021, 11(9), 990; https://doi.org/10.3390/life11090990 - 20 Sep 2021
Cited by 3
Abstract
The biological consequences of the Fukushima nuclear accident have been intensively studied using the pale grass blue butterfly Zizeeria maha and its host plant, the creeping wood sorrel Oxalis corniculata. Here, we performed metabolomic analyses of Oxalis leaves from Okinawa to examine [...] Read more.
The biological consequences of the Fukushima nuclear accident have been intensively studied using the pale grass blue butterfly Zizeeria maha and its host plant, the creeping wood sorrel Oxalis corniculata. Here, we performed metabolomic analyses of Oxalis leaves from Okinawa to examine the plant metabolites that were upregulated or downregulated in response to low-dose radiation exposure from Fukushima’s contaminated soil. The cumulative dose of radiation to the plants was 5.7 mGy (34 μGy/h for 7 days). The GC-MS analysis revealed a systematic tendency of downregulation among the metabolites, some of which were annotated as caproic acid, nonanoic acid, azelaic acid, and oleic acid. Others were annotated as fructose, glucose, and citric acid, involved in the carbohydrate metabolic pathways. Notably, the peak annotated as lauric acid was upregulated. In contrast, the LC-MS analysis detected many upregulated metabolites, some of which were annotated as either antioxidants or stress-related chemicals involved in defense pathways. Among them, only three metabolite peaks had a single annotation, one of which was alfuzosin, an antagonist of the α1-adrenergic receptor. We conclude that this Oxalis plant responded metabolically to low-dose radiation exposure from Fukushima’s contaminated soil, which may mediate the ecological “field effects” of the developmental deterioration of butterflies in Fukushima. Full article
(This article belongs to the Special Issue Radioactive Pollution and Biological Effects of Radioactivity)
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Article
Seminal Plasma Protein N-Glycan Peaks Are Potential Predictors of Semen Pathology and Sperm Chromatin Maturity in Men
Life 2021, 11(9), 989; https://doi.org/10.3390/life11090989 - 20 Sep 2021
Cited by 3
Abstract
Background: Male infertility is increasingly becoming a health and demographic problem. While it may originate from congenital or acquired diseases, it can also result from environmental exposure. Hence, the complexity of involved molecular mechanisms often requires a multiparametric approach. This study aimed to [...] Read more.
Background: Male infertility is increasingly becoming a health and demographic problem. While it may originate from congenital or acquired diseases, it can also result from environmental exposure. Hence, the complexity of involved molecular mechanisms often requires a multiparametric approach. This study aimed to associate semen parameters with sperm DNA fragmentation, chromatin maturity and seminal plasma protein N-glycosylation. Methods: The study was conducted with 166 participants, 20–55 y old, 82 normozoospermic and 84 with pathological diagnosis. Sperm was analyzed by Halosperm assay and aniline blue staining, while seminal plasma total protein N-glycans were analyzed by ultra-high-performance liquid chromatography. Results: Sperm DNA fragmentation was significantly increased in the pathological group and was inversely correlated with sperm motility and viability. Seminal plasma total protein N-glycans were chromatographically separated in 37 individual peaks. The pattern of seminal plasma N-glycan peaks (SPGP) showed that SPGP14 significantly differs between men with normal and pathological semen parameters (p < 0.001). The multivariate analysis showed that when sperm chromatin maturity increases by 10%, SPGP17 decreases by 14% while SPGP25 increases by 25%. Conclusion: DNA integrity and seminal plasma N-glycans are associated with pathological sperm parameters. Specific N-glycans are also associated with sperm chromatin maturity and have a potential in future fertility research and clinical diagnostics. Full article
(This article belongs to the Section Reproductive and Developmental Biology)
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Review
Secreted Effectors Modulating Immune Responses to Toxoplasma gondii
Life 2021, 11(9), 988; https://doi.org/10.3390/life11090988 - 20 Sep 2021
Cited by 7
Abstract
Toxoplasma gondii is an obligate intracellular parasite that chronically infects a third of humans. It can cause life-threatening encephalitis in immune-compromised individuals. Congenital infection also results in blindness and intellectual disabilities. In the intracellular milieu, parasites encounter various immunological effectors that have been [...] Read more.
Toxoplasma gondii is an obligate intracellular parasite that chronically infects a third of humans. It can cause life-threatening encephalitis in immune-compromised individuals. Congenital infection also results in blindness and intellectual disabilities. In the intracellular milieu, parasites encounter various immunological effectors that have been shaped to limit parasite infection. Parasites not only have to suppress these anti-parasitic inflammatory responses but also ensure the host organism’s survival until their subsequent transmission. Recent advancements in T. gondii research have revealed a plethora of parasite-secreted proteins that suppress as well as activate immune responses. This mini-review will comprehensively examine each secreted immunomodulatory effector based on the location of their actions. The first section is focused on secreted effectors that localize to the parasitophorous vacuole membrane, the interface between the parasites and the host cytoplasm. Murine hosts are equipped with potent IFNγ-induced immune-related GTPases, and various parasite effectors subvert these to prevent parasite elimination. The second section examines several cytoplasmic and ER effectors, including a recently described function for matrix antigen 1 (MAG1) as a secreted effector. The third section covers the repertoire of nuclear effectors that hijack transcription factors and epigenetic repressors that alter gene expression. The last section focuses on the translocation of dense-granule effectors and effectors in the setting of T. gondii tissue cysts (the bradyzoite parasitophorous vacuole). Full article
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Review
Anemia in Sports: A Narrative Review
Life 2021, 11(9), 987; https://doi.org/10.3390/life11090987 - 20 Sep 2021
Cited by 7
Abstract
Recent years have brought about new understandings regarding the pathogenesis of anemia in sports. From hemodilution and redistribution considered to contribute to the so-called “sports anemia” to iron deficiency caused by increased demands, dietary restrictions, decreased absorption, increased losses, hemolysis, and sequestration, to [...] Read more.
Recent years have brought about new understandings regarding the pathogenesis of anemia in sports. From hemodilution and redistribution considered to contribute to the so-called “sports anemia” to iron deficiency caused by increased demands, dietary restrictions, decreased absorption, increased losses, hemolysis, and sequestration, to genetic determinants of different types of anemia (some related to sport), the anemia in athletes deserves a careful and multifactorial approach. Dietary factors that reduce iron absorption (e.g., phytate, polyphenols) and that augment iron’s bioavailability (e.g., ascorbic acid) should be considered. Celiac disease, more prevalent in female athletes, may underlie an unexplained iron deficiency anemia. Iron loss during exercise occurs in several ways: sweating, hematuria, gastrointestinal bleeding, inflammation, and intravascular and extravascular hemolysis. From a practical point of view, assessing iron status, especially in the athletes at risk for iron deficiency (females, adolescents, in sports with dietary restrictions, etc.), may improve the iron balance and possibly the performance. Hemoglobin and serum ferritin are measures that are easily employable for the evaluation of patients’ iron status. Cutoff values should probably be further assessed with respect to the sex, age, and type of sport. A healthy gut microbiome influences the iron status. Athletes at risk of iron deficiency should perform non-weight-bearing, low-intensity sports to avoid inducing hemolysis. Full article
(This article belongs to the Special Issue Exercise and Health Related Quality of Life)
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Review
The Causal Relationship between Endothelin-1 and Hypertension: Focusing on Endothelial Dysfunction, Arterial Stiffness, Vascular Remodeling, and Blood Pressure Regulation
Life 2021, 11(9), 986; https://doi.org/10.3390/life11090986 - 20 Sep 2021
Cited by 13
Abstract
Hypertension (HTN) is one of the most prevalent diseases worldwide and is among the most important risk factors for cardiovascular and cerebrovascular complications. It is currently thought to be the result of disturbances in a number of neural, renal, hormonal, and vascular mechanisms [...] Read more.
Hypertension (HTN) is one of the most prevalent diseases worldwide and is among the most important risk factors for cardiovascular and cerebrovascular complications. It is currently thought to be the result of disturbances in a number of neural, renal, hormonal, and vascular mechanisms regulating blood pressure (BP), so crucial importance is given to the imbalance of a number of vasoactive factors produced by the endothelium. Decreased nitric oxide production and increased production of endothelin-1 (ET-1) in the vascular wall may promote oxidative stress and low-grade inflammation, with the development of endothelial dysfunction (ED) and increased vasoconstrictor activity. Increased ET-1 production can contribute to arterial aging and the development of atherosclerotic changes, which are associated with increased arterial stiffness and manifestation of isolated systolic HTN. In addition, ET-1 is involved in the complex regulation of BP through synergistic interactions with angiotensin II, regulates the production of catecholamines and sympathetic activity, affects renal hemodynamics and water–salt balance, and regulates baroreceptor activity and myocardial contractility. This review focuses on the relationship between ET-1 and HTN and in particular on the key role of ET-1 in the pathogenesis of ED, arterial structural changes, and impaired vascular regulation of BP. The information presented includes basic concepts on the role of ET-1 in the pathogenesis of HTN without going into detailed analyses, which allows it to be used by a wide range of specialists. Also, the main pathological processes and mechanisms are richly illustrated for better understanding. Full article
(This article belongs to the Special Issue Frontiers in Vascular Biology)
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Communication
Exploitation of Thermal Sensitivity and Hyperalgesia in a Mouse Model of Dystonia
Life 2021, 11(9), 985; https://doi.org/10.3390/life11090985 - 19 Sep 2021
Cited by 1
Abstract
Neuropathic pain is characterized by mechanical allodynia and thermal hyperalgesia to heat, and it affects some 20% of European population. Patients suffering from several neurologic diseases experience neuropathic pain, often finding no relief in therapy. Transgenic mice expressing the gene encoding the human [...] Read more.
Neuropathic pain is characterized by mechanical allodynia and thermal hyperalgesia to heat, and it affects some 20% of European population. Patients suffering from several neurologic diseases experience neuropathic pain, often finding no relief in therapy. Transgenic mice expressing the gene encoding the human mutant (hMT) or the human wild-type (hWT) torsin A represent a preclinical model of DYT1 dystonia which is the most common form of early-onset inherited dystonia. Baseline thermal sensitivity and hyperalgesia to heat have never been studied in models of dystonia. Therefore, the aim of this research has been to characterize thermal sensitivity in baseline conditions and hyperalgesia to heat after the induction of neuropathic pain through the spinal nerve ligation (SNL) model in mice overexpressing human wild-type and mutated torsin A in comparison to non-transgenic C57BL/6 mice. According to our results, the paw withdrawal latency time to heat in the Hargreaves’ test is significantly lower in the hMT mice (Kruskal–Wallis test = 6.933; p = 0.0312*; hMT vs. hWT p = 0.0317*). On the other hand, no significant differences in SNL-induced thermal hyperalgesia was found among the three strains (Friedman test = 4.933; p = 0.1019). Future studies are needed to better understand the role of torsin A in sensory processing of heat stimuli. Full article
(This article belongs to the Special Issue Rare Neurological Diseases)
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Review
Potential Biomarkers of miR-371–373 Gene Cluster in Tumorigenesis
Life 2021, 11(9), 984; https://doi.org/10.3390/life11090984 - 19 Sep 2021
Cited by 4
Abstract
microRNAs (miRNAs) are small non-coding RNA transcripts (20–24 nucleotides) that bind to their complementary sequences in the 3′-untranslated regions (3′-UTR) of targeted genes to negatively or positively regulate their expression. miRNAs affect the expression of genes in cells, thereby contributing to several important [...] Read more.
microRNAs (miRNAs) are small non-coding RNA transcripts (20–24 nucleotides) that bind to their complementary sequences in the 3′-untranslated regions (3′-UTR) of targeted genes to negatively or positively regulate their expression. miRNAs affect the expression of genes in cells, thereby contributing to several important biological processes, including tumorigenesis. Identifying the miRNA cluster as a human embryonic stem cell (hESC)-specific miRNAs initially led to the identification of miR-371, miR-372, miR-373, and miR-373*, which can ultimately be translated into mature miRNAs. Recent evidence suggests that miR-371–373 genes are abnormally expressed in various cancers and act either as oncogenes or tumor suppressors, indicating they may be suitable as molecular biomarkers for cancer diagnosis and prevention. In this article, we summarize recent studies linking miR-371–373 functions to tumorigenesis and speculate on the potential applications of miR-371–373 as biomarkers for cancer diagnosis and treatment. Full article
(This article belongs to the Special Issue Molecular Mechanism and Therapeutic Effect of Drugs in Cancer)
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Article
The Complementarity Principle—One More Step towards Analytical Docking on the Example of Dihydrofolate Reductase Complexes
Life 2021, 11(9), 983; https://doi.org/10.3390/life11090983 - 19 Sep 2021
Cited by 2
Abstract
New approaches to assessing the “enzyme–ligand” complementarity, taking into account hydrogens, have been proposed. The approaches are based on the calculation of three-dimensional maps of the electron density of the receptor–ligand complexes. The action of complementarity factors, first proposed in this article, has [...] Read more.
New approaches to assessing the “enzyme–ligand” complementarity, taking into account hydrogens, have been proposed. The approaches are based on the calculation of three-dimensional maps of the electron density of the receptor–ligand complexes. The action of complementarity factors, first proposed in this article, has been demonstrated on complexes of human dihydrofolate reductase (DHFR) with ligands. We found that high complementarity is ensured by the formation of the most effective intermolecular contacts, which are provided due to predominantly paired atomic–atomic interactions, while interactions of the bifurcate and more disoriented type are minimized. An analytical docking algorithm based on the proposed receptor–ligand complementarity factors is proposed. Full article
(This article belongs to the Topic Stochastic Models and Experiments in Ecology and Biology)
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Article
Narrow Precursor Mass Range for DIA–MS Enhances Protein Identification and Quantification in Arabidopsis
Life 2021, 11(9), 982; https://doi.org/10.3390/life11090982 - 18 Sep 2021
Cited by 1
Abstract
Data independent acquisition–mass spectrometry (DIA–MS) is becoming widely utilised for robust and accurate quantification of samples in quantitative proteomics. Here, we describe the systematic evaluation of the effects of DIA precursor mass range on total protein identification and quantification. We show that a [...] Read more.
Data independent acquisition–mass spectrometry (DIA–MS) is becoming widely utilised for robust and accurate quantification of samples in quantitative proteomics. Here, we describe the systematic evaluation of the effects of DIA precursor mass range on total protein identification and quantification. We show that a narrow mass range of precursors (~250 m/z) for DIA–MS enables a higher number of protein identifications. Subsequent application of DIA with narrow precursor range (from 400 to 650 m/z) on an Arabidopsis sample with spike-in known proteins identified 34.7% more proteins than in conventional DIA (cDIA) with a wide precursor range of 400–1200 m/z. When combining several DIA–MS analyses with narrow precursor ranges (i.e., 400–650, 650–900 and 900–1200 m/z), we were able to quantify 10,099 protein groups with a median coefficient of variation of <6%. These findings represent a 54.7% increase in the number of proteins quantified than with cDIA analysis. This is particularly important for low abundance proteins, as exemplified by the six-protein mix spike-in. In cDIA only five out of the six-protein mix were quantified while our approach allowed accurate quantitation of all six proteins. Full article
(This article belongs to the Special Issue Plant Proteomics)
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Review
A Narrative Overview of Current Anesthetic Drugs in Electroconvulsive Therapy
Life 2021, 11(9), 981; https://doi.org/10.3390/life11090981 - 18 Sep 2021
Cited by 2
Abstract
Electroconvulsive therapy (ECT) is a definitive treatment for patients with psychiatric disorders that are severe, acute, or refractory to pharmacologic therapy. Providing anesthesia for ECT is challenging, as the effect of drugs on hemodynamics, seizure duration, comfort, and recovery must be considered. We [...] Read more.
Electroconvulsive therapy (ECT) is a definitive treatment for patients with psychiatric disorders that are severe, acute, or refractory to pharmacologic therapy. Providing anesthesia for ECT is challenging, as the effect of drugs on hemodynamics, seizure duration, comfort, and recovery must be considered. We highlight and aim to review the common anesthetics used in ECT and related evidence. While drugs such as methohexital, succinylcholine, and etomidate have been used in the past, other drugs such as dexmedetomidine, ketamine, and remifentanil may provide a more balanced anesthetic with a greater safety profile in select populations. Overall, it is essential to consider the patient’s co-morbidities and associated risks when deciding on an anesthetic drug. Full article
(This article belongs to the Section Pharmaceutical Science)
Article
The Abiotic Formation of Pyrrole under Volcanic, Hydrothermal Conditions—An Initial Step towards Life’s First Breath?
Life 2021, 11(9), 980; https://doi.org/10.3390/life11090980 - 17 Sep 2021
Cited by 1
Abstract
Porphyrins, corrins, and tetrapyrroles constitute macrocycles in essential biomolecules such as heme, chlorophyll, cobalamin, and cofactor F430. The chemical synthesis as well as the enzymatic synthesis of these macrocycles starts from pyrrole derivatives. We here show that pyrrole and dimethyl pyrrole can be [...] Read more.
Porphyrins, corrins, and tetrapyrroles constitute macrocycles in essential biomolecules such as heme, chlorophyll, cobalamin, and cofactor F430. The chemical synthesis as well as the enzymatic synthesis of these macrocycles starts from pyrrole derivatives. We here show that pyrrole and dimethyl pyrrole can be formed under the simulated volcanic, hydrothermal conditions of Early Earth, starting from acetylene, propyne, and ammonium salts in the presence of NiS or CoS as catalysts. Full article
(This article belongs to the Special Issue Organic Chemical Evolution regarding the Origin(s) of Life)
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Article
Declining Mortality Rate of Hospitalised Patients in the Second Wave of the COVID-19 Epidemics in Italy: Risk Factors and the Age-Specific Patterns
Life 2021, 11(9), 979; https://doi.org/10.3390/life11090979 - 17 Sep 2021
Cited by 5
Abstract
Background: Mortality rate from COVID-19 in Italy is among the world’s highest. We aimed to ascertain whether there was any reduction of in-hospital mortality in patients hospitalised for COVID-19 in the second-wave period (October 2020–January 2021) compared to the first one (February–May 2020); [...] Read more.
Background: Mortality rate from COVID-19 in Italy is among the world’s highest. We aimed to ascertain whether there was any reduction of in-hospital mortality in patients hospitalised for COVID-19 in the second-wave period (October 2020–January 2021) compared to the first one (February–May 2020); further, we verified whether there were clusters of hospitalised patients who particularly benefitted from reduced mortality rate. Methods: Data collected related to in-patients’ demographics, clinical, laboratory, therapies and outcome. Primary end-point was time to in-hospital death. Factors associated were evaluated by uni- and multivariable analyses. A flow diagram was created to determine the rate of in-hospital death according to individual and disease characteristics. Results: A total of 1561 patients were included. The 14-day cumulative incidence of in-hospital death by competing risk regression was of 24.8% (95% CI: 21.3–28.5) and 15.9% (95% CI: 13.7–18.2) in the first and second wave. We observed that the highest relative reduction of death from first to second wave (more than 47%) occurred mainly in the clusters of patients younger than 70 years. Conclusions: Progress in care and supporting therapies did affect population over 70 years to a lesser extent. Preventive and vaccination campaigns should focus on individuals whose risk of death from COVID-19 remains high. Full article
(This article belongs to the Section Epidemiology)
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Article
Dystrophin Dp71 Subisoforms Localize to the Mitochondria of Human Cells
Life 2021, 11(9), 978; https://doi.org/10.3390/life11090978 - 16 Sep 2021
Abstract
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by deficiency in dystrophin, a protein product encoded by the DMD gene. Mitochondrial dysfunction is now attracting much attention as a central player in DMD pathology. However, dystrophin has never been explored [...] Read more.
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by deficiency in dystrophin, a protein product encoded by the DMD gene. Mitochondrial dysfunction is now attracting much attention as a central player in DMD pathology. However, dystrophin has never been explored in human mitochondria. Here, we analyzed dystrophin in cDNAs and mitochondrial fractions of human cells. Mitochondrial fraction was obtained using a magnetic-associated cell sorting (MACS) technology. Dystrophin was analyzed by reverse transcription (RT)-PCR and western blotting using an antibody against the dystrophin C-terminal. In isolated mitochondrial fraction from HEK293 cells, dystrophin was revealed as a band corresponding to Dp71b and Dp71ab subisoforms. Additionally, in mitochondria from HeLa, SH-SY5Y, CCL-136 and HepG2 cells, signals for Dp71b and Dp71ab were revealed as well. Concomitantly, dystrophin mRNAs encoding Dp71b and Dp71ab were disclosed by RT-PCR in these cells. Primary cultured myocytes from three dystrophinopathy patients showed various levels of mitochondrial Dp71 expression. Coherently, levels of mRNA were different in all cells reflecting the protein content, which indicated predominant accumulation of Dp71. Dystrophin was demonstrated to be localized to human mitochondrial fraction, specifically as Dp71 subisoforms. Myocytes derived from dystrophinopathy patients manifested different levels of mitochondrial Dp71, with higher expression revealed in myocytes from Becker muscular dystrophy (BMD) patient-derived myocytes. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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Article
Effect of Eicosapentaenoic Acid Supplementation on Murine Preadipocytes 3T3-L1 Cells Activated with Lipopolysaccharide and/or Tumor Necrosis Factor-α
Life 2021, 11(9), 977; https://doi.org/10.3390/life11090977 - 16 Sep 2021
Abstract
The beneficial effect of n-3 fatty acids can be related to anti-inflammatory properties. The aim of the study was to analyzed the effect of eicosapentaenoic acid (EPA) on 3T3-L1 cells (murine embryonic fibroblasts‒preadipocytes) activated with inflammatory factors (IF). Cells were incubated with 50 [...] Read more.
The beneficial effect of n-3 fatty acids can be related to anti-inflammatory properties. The aim of the study was to analyzed the effect of eicosapentaenoic acid (EPA) on 3T3-L1 cells (murine embryonic fibroblasts‒preadipocytes) activated with inflammatory factors (IF). Cells were incubated with 50 µmol of EPA for 48 h, and then activated with lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α). The level of cycloxygenase-2 (Prostaglandin-Endoperoxide Synthase 2, PTGS2, COX-2), cytosolic prostaglandin synthase E2 (cPGES), fatty acid binding protein 4 (FABP4), toll-like receptor 4 (TLR4), glucose receptor type 4 (GLUT-4), and cannabinoid receptor 2 (CB2) was determined using Western blot analysis. The phospholipase A2 (Pla2g4a), and prostaglandin-Endoperoxide Synthase 2 (Ptgs2) gene expression was analyzed by real-time qPCR. After EPA and IF activation, a significant decrease in the COX-2, cPGES, and TRL4 protein levels was observed. Incubation of cells with EPA and IF resulted in a decrease in Ptgs2 and an increase in the Pla2g4a gene. A significant increase in the CB2 protein was observed in adipocytes co-treated with EPA and IF. The results indicated an anti-inflammatory properties of EPA. Interestingly, the activation of the GLUT4 receptor by EPA suggests an unique role of this FA in the regulation of the adipocyte metabolism and prevention of insulin resistance. Full article
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Article
Scum of the Earth: A Hypothesis for Prebiotic Multi-Compartmentalised Environments
Life 2021, 11(9), 976; https://doi.org/10.3390/life11090976 - 16 Sep 2021
Cited by 3
Abstract
Compartmentalisation by bioenergetic membranes is a universal feature of life. The eventual compartmentalisation of prebiotic systems is therefore often argued to comprise a key step during the origin of life. Compartments may have been active participants in prebiotic chemistry, concentrating and spatially organising [...] Read more.
Compartmentalisation by bioenergetic membranes is a universal feature of life. The eventual compartmentalisation of prebiotic systems is therefore often argued to comprise a key step during the origin of life. Compartments may have been active participants in prebiotic chemistry, concentrating and spatially organising key reactants. However, most prebiotically plausible compartments are leaky or unstable, limiting their utility. Here, we develop a new hypothesis for an origin of life environment that capitalises upon, and mitigates the limitations of, prebiotic compartments: multi-compartmentalised layers in the near surface environment—a ’scum’. Scum-type environments benefit from many of the same ensemble-based advantages as microbial biofilms. In particular, scum layers mediate diffusion with the wider environments, favouring preservation and sharing of early informational molecules, along with the selective concentration of compatible prebiotic compounds. Biofilms are among the earliest traces imprinted by life in the rock record: we contend that prebiotic equivalents of these environments deserve future experimental investigation. Full article
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Article
The Combinatorial Fusion Cascade to Generate the Standard Genetic Code
Life 2021, 11(9), 975; https://doi.org/10.3390/life11090975 - 16 Sep 2021
Abstract
Combinatorial fusion cascade was proposed as a transition stage between prebiotic chemistry and early forms of life. The combinatorial fusion cascade consists of three stages: eight initial complimentary pairs of amino acids, four protocodes, and the standard genetic code. The initial complimentary pairs [...] Read more.
Combinatorial fusion cascade was proposed as a transition stage between prebiotic chemistry and early forms of life. The combinatorial fusion cascade consists of three stages: eight initial complimentary pairs of amino acids, four protocodes, and the standard genetic code. The initial complimentary pairs and the protocodes are divided into dominant and recessive entities. The transitions between these stages obey the same combinatorial fusion rules for all amino acids. The combinatorial fusion cascade mathematically describes the codon assignments in the standard genetic code. It explains the availability of amino acids with the even and odd numbers of codons, the appearance of stop codons, inclusion of novel canonical amino acids, exceptional high numbers of codons for amino acids arginine, leucine, and serine, and the temporal order of amino acid inclusion into the genetic code. The temporal order of amino acids within the cascade is congruent with the consensus temporal order previously derived from the similarities between the available hypotheses. The control over the combinatorial fusion cascades would open the road for a novel technology to develop artificial microorganisms. Full article
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Article
Improving the Biological Value of Olive and Soybean Oil Blends with Olive Leaf Extract Obtained by Ultrasound-Assisted Extraction towards the Preparation of a Sauce Product
Life 2021, 11(9), 974; https://doi.org/10.3390/life11090974 - 15 Sep 2021
Cited by 2
Abstract
French sauce from different blends of soybean and olive oils was prepared and the oxidative stability of the optimum sauce sample, enriched with various amounts of olive leaf polyphenolic extract (OLE) (obtained via ultrasound-assisted extraction), was investigated over 90 days of storage. The [...] Read more.
French sauce from different blends of soybean and olive oils was prepared and the oxidative stability of the optimum sauce sample, enriched with various amounts of olive leaf polyphenolic extract (OLE) (obtained via ultrasound-assisted extraction), was investigated over 90 days of storage. The microbiological and sensory properties of the samples containing the optimum amounts of OLE, as a substitution for synthetic preservatives, were studied. According to the results, the addition of olive oil at higher levels (75% and 100%) could affect the physicochemical properties of the sauce as compared to the control sample. It was also found that the addition of olive oil (up to 50%) would not significantly impact the sauce properties. Regarding the OLE enrichment in the samples, it was found that high levels of OLE could improve the oxidative stability of the samples. It was also found that OLE could be used as a preservative instead of commercial ones. Overall, this study suggests the potential use of olive oil and olive leaf extract in the preparation of French sauce to boost its nutritional value and its stability. Full article
(This article belongs to the Special Issue Advances in Edible Oil Processing)
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Article
Sleep Apnea in Idiopathic Pulmonary Fibrosis: A Molecular Investigation in an Experimental Model of Fibrosis and Intermittent Hypoxia
Life 2021, 11(9), 973; https://doi.org/10.3390/life11090973 - 15 Sep 2021
Cited by 1
Abstract
Background: High prevalence of obstructive sleep apnea (OSA) is reported in incident and prevalent forms of idiopathic pulmonary fibrosis (IPF). We previously reported that Intermittent Hypoxia (IH), the major pathogenic element of OSA, worsens experimental lung fibrosis. Our objective was to investigate the [...] Read more.
Background: High prevalence of obstructive sleep apnea (OSA) is reported in incident and prevalent forms of idiopathic pulmonary fibrosis (IPF). We previously reported that Intermittent Hypoxia (IH), the major pathogenic element of OSA, worsens experimental lung fibrosis. Our objective was to investigate the molecular mechanisms involved. Methods: Impact of IH was evaluated on C57BL/6J mice developing lung fibrosis after intratracheal instillation of Bleomycin (BLM). Mice were Pre-exposed 14 days to IH before induction of lung fibrosis or Co-challenged with IH and BLM for 14 days. Weight loss and survival were daily monitored. After experimentations, lungs were sampled for histology, and protein and RNA were extracted. Results: Co-challenge or Pre-exposure of IH and BLM induced weight loss, increased tissue injury and collagen deposition, and pro-fibrotic markers. Major worsening effects of IH exposure on lung fibrosis were observed when mice were Pre-exposed to IH before developing lung fibrosis with a strong increase in sXBP1 and ATF6N ER stress markers. Conclusion: Our results showed that IH exacerbates BLM-induced lung fibrosis more markedly when IH precedes lung fibrosis induction, and that this is associated with an enhancement of ER stress markers. Full article
(This article belongs to the Special Issue Cellular and Functional Response to Hypoxia)
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Article
Autism Spectrum Disorder in Pediatric Idiopathic Intracranial Hypertension
Life 2021, 11(9), 972; https://doi.org/10.3390/life11090972 - 15 Sep 2021
Cited by 1
Abstract
In recent years, the substantial burden of medical comorbidities in autism spectrum disorder (ASD) populations has been described. We report a retrospective observational case series of pediatric patients with suspected idiopathic intracranial hypertension (IIH) and concurrent ASD. Pediatric subjects with suspected IIH aged [...] Read more.
In recent years, the substantial burden of medical comorbidities in autism spectrum disorder (ASD) populations has been described. We report a retrospective observational case series of pediatric patients with suspected idiopathic intracranial hypertension (IIH) and concurrent ASD. Pediatric subjects with suspected IIH aged 2–18 years were identified by review of a pediatric neuro-ophthalmologist’s database spanning from July 1993 to April 2013. ASD diagnoses were identified within this cohort by an ICD-9 diagnosis code search and database review. Three subjects had concurrent ASD diagnoses; all were non-obese males. Since the retrospective observational case series was performed in April 2013, we identified three additional IIH cases in boys with ASD. Our experience suggests that IIH may be a comorbidity of ASD, particularly in non-obese boys. Full article
(This article belongs to the Special Issue Idiopathic Intracranial Hypertension)
Article
Mitotic Arrest-Deficient 2 Like 2 (MAD2L2) Interacts with Escherichia coli Effector Protein EspF
Life 2021, 11(9), 971; https://doi.org/10.3390/life11090971 - 15 Sep 2021
Cited by 1
Abstract
Enteropathogenic (EPEC) and Enterohemorrhagic (EHEC) Escherichia coli are considered emerging zoonotic pathogens of worldwide distribution. The pathogenicity of the bacteria is conferred by multiple virulence determinants, including the locus of enterocyte effacement (LEE) pathogenicity island, which encodes a type III secretion system (T3SS) [...] Read more.
Enteropathogenic (EPEC) and Enterohemorrhagic (EHEC) Escherichia coli are considered emerging zoonotic pathogens of worldwide distribution. The pathogenicity of the bacteria is conferred by multiple virulence determinants, including the locus of enterocyte effacement (LEE) pathogenicity island, which encodes a type III secretion system (T3SS) and effector proteins, including the multifunctional secreted effector protein (EspF). EspF sequences differ between EPEC and EHEC serotypes in terms of the number and residues of SH3-binding polyproline-rich repeats and N-terminal localization sequence. The aim of this study was to discover additional cellular interactions of EspF that may play important roles in E. coli colonization using the Yeast two-hybrid screening system (Y2H). Y2H screening identified the anaphase-promoting complex inhibitor Mitotic Arrest-Deficient 2 Like 2 (MAD2L2) as a host protein that interacts with EspF. Using LUMIER assays, MAD2L2 was shown to interact with EspF variants from EHEC O157:H7 and O26:H11 as well as EPEC O127:H6. MAD2L2 is targeted by the non-homologous Shigella effector protein invasion plasmid antigen B (IpaB) to halt the cell cycle and limit epithelial cell turnover. Therefore, we postulate that interactions between EspF and MAD2L2 serve a similar function in promoting EPEC and EHEC colonization, since cellular turnover is a key method for bacteria removal from the epithelium. Future work should investigate the biological importance of this interaction that could promote the colonization of EPEC and EHEC E. coli in the host. Full article
(This article belongs to the Special Issue Advances in Bacterial Metabolism, Gene Regulation, and Pathogenesis)
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Perspective
Bee Products: A Representation of Biodiversity, Sustainability, and Health
Life 2021, 11(9), 970; https://doi.org/10.3390/life11090970 - 15 Sep 2021
Cited by 5
Abstract
Biodiversity strengthens the productivity of any ecosystem (agricultural land, forest, lake, etc.). The loss of biodiversity contributes to food and energy insecurity; increases vulnerability to natural disasters, such as floods or tropical storms; and decreases the quality of both life and health. Wild [...] Read more.
Biodiversity strengthens the productivity of any ecosystem (agricultural land, forest, lake, etc.). The loss of biodiversity contributes to food and energy insecurity; increases vulnerability to natural disasters, such as floods or tropical storms; and decreases the quality of both life and health. Wild and managed bees play a key role in maintaining the biodiversity and in the recovery and restoration of degraded habitats. The novelty character of this perspective is to give an updated representation of bee products’ biodiversity, sustainability, and health relationship. The role of bees as bioindicators, their importance in the conservation of biodiversity, their ecosystem services, and the variety of the bee products are described herein. An overview of the main components of bee products, their biological potentials, and health is highlighted and detailed as follows: (i) nutritional value of bee products, (ii) bioactive profile of bee products and the related beneficial properties; (iii) focus on honey and health through a literature quantitative analysis, and (iv) bee products explored through databases. Moreover, as an example of the interconnection between health, biodiversity, and sustainability, a case study, namely the “Cellulose Park”, realized in Rome (Italy), is presented here. This case study highlights how bee activities can be used to assess and track changes in the quality of agricultural ecosystems—hive products could be valid indicators of the quality and health of the surrounding environment, as well as the changes induced by the biotic and abiotic factors that impact the sustainability of agricultural production and biodiversity conservation in peri-urban areas. Full article
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Article
Complementary Feeding Indicators in Relation to Micronutrient Status of Ghanaian Children Aged 6–23 Months: Results from a National Survey
Life 2021, 11(9), 969; https://doi.org/10.3390/life11090969 - 15 Sep 2021
Cited by 2
Abstract
Background: Optimal complementary feeding is critical for adequate growth and development in infants and young children. The associations between complementary feeding and growth have been studied well, but less is known about the relationship between complementary feeding and micronutrient status. Methods: Using data [...] Read more.
Background: Optimal complementary feeding is critical for adequate growth and development in infants and young children. The associations between complementary feeding and growth have been studied well, but less is known about the relationship between complementary feeding and micronutrient status. Methods: Using data from a national cross-sectional survey conducted in Ghana in 2017, we examined how multiple WHO-recommended complementary feeding indicators relate to anemia and the micronutrient status of children aged 6–23 months. Results: In total, 42%, 38%, and 14% of the children met the criteria for minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum acceptable diet (MAD), respectively. In addition, 71% and 52% of the children consumed iron-rich foods and vitamin A-rich foods, respectively. The prevalence of anemia, iron deficiency (ID), iron deficiency anemia (IDA) and vitamin A deficiency (VAD) was 46%, 45%, 27%, and 10%, respectively. Inverse associations between MMF and socio-economic status were found, and MMF was associated with an increased risk of ID (55%; p < 0.013) and IDA (38%; p < 0.002). Conclusion: The pathways connecting complementary feeding and micronutrient status are complex. Findings related to MMF should be further investigated to ensure that complementary feeding programs account for the potential practice of frequent feeding with nutrient-poor foods. Full article
(This article belongs to the Special Issue Pediatric Nutrition for a Healthy Life)
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Article
Can Fetuin A Be Utilized in the Evaluation of Elderly Patients with Acute Myocardial Infarction?
Life 2021, 11(9), 968; https://doi.org/10.3390/life11090968 - 15 Sep 2021
Abstract
Background: Lower baseline Fetuin-A (FA) is associated with left ventricular remodeling and cardiovascular death (CVD) at 4 months after acute myocardial infarction (AMI). However, the association between FA levels, incomplete ST segment resolution (STR) following primary percutaneous coronary intervention (PCI) and early mortality [...] Read more.
Background: Lower baseline Fetuin-A (FA) is associated with left ventricular remodeling and cardiovascular death (CVD) at 4 months after acute myocardial infarction (AMI). However, the association between FA levels, incomplete ST segment resolution (STR) following primary percutaneous coronary intervention (PCI) and early mortality in AMI has not been previously studied. Methods: We enrolled 100 patients with AMI, which we divided in two groups: 21 patients who suffered sudden cardiac death (SCD) in the first 7 days after PCI and 79 controls. We measured FA, NT-proBNP and troponin levels and correlated them with the occurrence of death in the first week after revascularization. We also tested the cut-off value of FA to determine STR at 90 min after PCI. Results: SCD was most frequently caused by pump failure (n = 10, 47.6%) and ventricular arrhythmias (n = 9, 42.5%). Plasma FA levels correlated with NT-proBNP values (r = −0.47, p = 0.04) and were significantly lower in patients presenting SCD (115 (95–175) vs. 180 (105–250) ng/mL, p = 0.03). Among all three biomarkers, FA was the only one associated with incomplete STR after PCI on the multivariate logistic regression (cut-off value of 175 ng/mL, Se = 74%, Sp = 61.1%). Death rate was highest (n = 16/55, 30%) in patients with FA levels below the cut-off value of 175 ng/mL. Conclusion: Lower FA is associated with higher early mortality and incomplete STR after primary percutaneous revascularization in patients with AMI. Measurement of FA levels in addition to NT-proBNP, troponin and STR might enable more accurate identification of high-risk patients. Full article
(This article belongs to the Special Issue Myocardial Infarction 2021)
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Article
Subcellular Localization of Fad1p in Saccharomyces cerevisiae: A Choice at Post-Transcriptional Level?
Life 2021, 11(9), 967; https://doi.org/10.3390/life11090967 - 14 Sep 2021
Cited by 2
Abstract
FAD synthase is the last enzyme in the pathway that converts riboflavin into FAD. In Saccharomyces cerevisiae, the gene encoding for FAD synthase is FAD1, from which a sole protein product (Fad1p) is expected to be generated. In this work, we [...] Read more.
FAD synthase is the last enzyme in the pathway that converts riboflavin into FAD. In Saccharomyces cerevisiae, the gene encoding for FAD synthase is FAD1, from which a sole protein product (Fad1p) is expected to be generated. In this work, we showed that a natural Fad1p exists in yeast mitochondria and that, in its recombinant form, the protein is able, per se, to both enter mitochondria and to be destined to cytosol. Thus, we propose that FAD1 generates two echoforms—that is, two identical proteins addressed to different subcellular compartments. To shed light on the mechanism underlying the subcellular destination of Fad1p, the 3′ region of FAD1 mRNA was analyzed by 3′RACE experiments, which revealed the existence of (at least) two FAD1 transcripts with different 3′UTRs, the short one being 128 bp and the long one being 759 bp. Bioinformatic analysis on these 3′UTRs allowed us to predict the existence of a cis-acting mitochondrial localization motif, present in both the transcripts and, presumably, involved in protein targeting based on the 3′UTR context. Here, we propose that the long FAD1 transcript might be responsible for the generation of mitochondrial Fad1p echoform. Full article
(This article belongs to the Special Issue Mitochondria: From Physiology to Pathology)
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Article
When Is a Reaction Network a Metabolism? Criteria for Simple Metabolisms That Support Growth and Division of Protocells
Life 2021, 11(9), 966; https://doi.org/10.3390/life11090966 - 14 Sep 2021
Cited by 4
Abstract
With the aim of better understanding the nature of metabolism in the first cells and the relationship between the origin of life and the origin of metabolism, we propose three criteria that a chemical reaction system must satisfy in order to constitute a [...] Read more.
With the aim of better understanding the nature of metabolism in the first cells and the relationship between the origin of life and the origin of metabolism, we propose three criteria that a chemical reaction system must satisfy in order to constitute a metabolism that would be capable of sustaining growth and division of a protocell. (1) Biomolecules produced by the reaction system must be maintained at high concentration inside the cell while they remain at low or zero concentration outside. (2) The total solute concentration inside the cell must be higher than outside, so there is a positive osmotic pressure that drives cell growth. (3) The metabolic rate (i.e., the rate of mass throughput) must be higher inside the cell than outside. We give examples of small-molecule reaction systems that satisfy these criteria, and others which do not, firstly considering fixed-volume compartments, and secondly, lipid vesicles that can grow and divide. If the criteria are satisfied, and if a supply of lipid is available outside the cell, then continued growth of membrane surface area occurs alongside the increase in volume of the cell. If the metabolism synthesizes more lipid inside the cell, then the membrane surface area can increase proportionately faster than the cell volume, in which case cell division is possible. The three criteria can be satisfied if the reaction system is bistable, because different concentrations can exist inside and out while the rate constants of all the reactions are the same. If the reaction system is monostable, the criteria can only be satisfied if there is a reason why the rate constants are different inside and out (for example, the decay rates of biomolecules are faster outside, or the formation rates of biomolecules are slower outside). If this difference between inside and outside does not exist, a monostable reaction system cannot sustain cell growth and division. We show that a reaction system for template-directed RNA polymerization can satisfy the requirements for a metabolism, even if the small-molecule reactions that make the single nucleotides do not. Full article
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Review
Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery
Life 2021, 11(9), 965; https://doi.org/10.3390/life11090965 - 14 Sep 2021
Cited by 2
Abstract
Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug [...] Read more.
Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug targets. DUBs have shown significant roles in regulating breast cancer growth, metastasis, resistance to current therapies, and several canonical oncogenic signaling pathways. In addition, specific DUB inhibitors have been identified and are expected to benefit breast cancer patients in the future. Here, we review current knowledge about the effects and molecular mechanisms of DUBs in breast cancer, providing novel insight into treatments of breast cancer-targeting DUBs. Full article
(This article belongs to the Collection Tumor Progression, Microenvironments, and Therapeutics)
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