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Volume 11
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Life, Volume 11, Issue 12 (December 2021) – 158 articles

Cover Story (view full-size image): Due to a reduced immune function in elderly patients, young patients with a robust immune system are theoretically expected to benefit more from the anti-PD1 immunotherapy approach. In contrast to this hypothesis, recent studies in patients with metastatic melanoma have demonstrated that immunotherapy, especially with anti-PD1 treatment, is less effective in patients below 65 years, on average, with significantly lower responses and reduced overall survival compared to patients above 65 years of age. Besides, data on young patients are even more sparse. Hence, in this review, we focus on age-dependent differences in the previously described resistance mechanisms to the treatment, and discuss the development of potential combination treatment strategies for enhancing the anti-tumor efficacy of anti-PD1 treatment in young melanoma patients. View this paper.
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22 pages, 1874 KiB  
Review
MicroRNAs as Potential Biomarkers for Exercise-Based Cancer Rehabilitation in Cancer Survivors
by Yanping Jiang, Kulsoom Ghias, Sanjeev Gupta and Ananya Gupta
Life 2021, 11(12), 1439; https://doi.org/10.3390/life11121439 - 20 Dec 2021
Cited by 2 | Viewed by 3079
Abstract
Expression and functions of microRNAs (miRNAs) have been widely investigated in cancer treatment-induced complications and as a response to physical activity, respectively, but few studies focus on the application of miRNAs as biomarkers in exercise-based cancer rehabilitation. Research has shown that certain miRNA [...] Read more.
Expression and functions of microRNAs (miRNAs) have been widely investigated in cancer treatment-induced complications and as a response to physical activity, respectively, but few studies focus on the application of miRNAs as biomarkers in exercise-based cancer rehabilitation. Research has shown that certain miRNA expression is altered substantially due to tissue damage caused by cancer treatment and chronic inflammation. MiRNAs are released from the damaged tissue and can be easily detected in blood plasma. Levels of the miRNA present in peripheral circulation can therefore be used to measure the extent of tissue damage. Moreover, damage to tissues such as cardiac and skeletal muscle significantly affects the individual’s health-related fitness, which can be determined using physiologic functional assessments. These physiologic parameters are a measure of tissue health and function and can therefore be correlated with the levels of circulating miRNAs. In this paper, we reviewed miRNAs whose expression is altered during cancer treatment and may correlate to physiological, physical, and psychological changes that significantly impact the quality of life of cancer survivors and their role in response to physical activity. We aim to identify potential miRNAs that can not only be used for monitoring changes that occur in health-related fitness during cancer treatment but can also be used to evaluate response to exercise-based rehabilitation and monitor individual progress through the rehabilitation programme. Full article
(This article belongs to the Special Issue Non-coding RNAs in Cellular Differentiation, Development, and Diseases)
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14 pages, 962 KiB  
Article
Psychosocial Risk and Health Behaviors as Predictors of Clinical Events in Patients Wait-Listed for a New Heart: Results from 7 Years of Follow-Up
by Kathleen Gali, Gerdi Weidner, Jacqueline M. A. Smits, Jan Beyersmann and Heike Spaderna
Life 2021, 11(12), 1438; https://doi.org/10.3390/life11121438 - 20 Dec 2021
Cited by 1 | Viewed by 2528
Abstract
We examined the long-term relationship of psychosocial risk and health behaviors on clinical events in patients awaiting heart transplantation (HTx). Psychosocial characteristics (e.g., depression), health behaviors (e.g., dietary habits, smoking), medical factors (e.g., creatinine), and demographics (e.g., age, sex) were collected at the [...] Read more.
We examined the long-term relationship of psychosocial risk and health behaviors on clinical events in patients awaiting heart transplantation (HTx). Psychosocial characteristics (e.g., depression), health behaviors (e.g., dietary habits, smoking), medical factors (e.g., creatinine), and demographics (e.g., age, sex) were collected at the time of listing in 318 patients (82% male, mean age = 53 years) enrolled in the Waiting for a New Heart Study. Clinical events were death/delisting due to deterioration, high-urgency status transplantation (HU-HTx), elective transplantation, and delisting due to clinical improvement. Within 7 years of follow-up, 92 patients died or were delisted due to deterioration, 121 received HU-HTx, 43 received elective transplantation, and 39 were delisted due to improvement. Adjusting for demographic and medical characteristics, the results indicated that frequent consumption of healthy foods (i.e., foods high in unsaturated fats) and being physically active increased the likelihood of delisting due improvement, while smoking and depressive symptoms were related to death/delisting due to clinical deterioration while awaiting HTx. In conclusion, psychosocial and behavioral characteristics are clearly associated with clinical outcomes in this population. Interventions that target psychosocial risk, smoking, dietary habits, and physical activity may be beneficial for patients with advanced heart failure waiting for a cardiac transplant. Full article
(This article belongs to the Collection Heart Failure and Heart Transplantation)
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16 pages, 1049 KiB  
Review
The Role of the CREB Protein Family Members and the Related Transcription Factors in Radioresistance Mechanisms
by Gianmarco Stati, Francesca Passaretta, Florelle Gindraux, Lucia Centurione and Roberta Di Pietro
Life 2021, 11(12), 1437; https://doi.org/10.3390/life11121437 - 20 Dec 2021
Cited by 4 | Viewed by 3417
Abstract
In the framework of space flight, the risk of radiation carcinogenesis is considered a “red” risk due to the high likelihood of occurrence as well as the high potential impact on the quality of life in terms of disease-free survival after space missions. [...] Read more.
In the framework of space flight, the risk of radiation carcinogenesis is considered a “red” risk due to the high likelihood of occurrence as well as the high potential impact on the quality of life in terms of disease-free survival after space missions. The cyclic AMP response element-binding protein (CREB) is overexpressed both in haematological malignancies and solid tumours and its expression and function are modulated following irradiation. The CREB protein is a transcription factor and member of the CREB/activating transcription factor (ATF) family. As such, it has an essential role in a wide range of cell processes, including cell survival, proliferation, and differentiation. Among the CREB-related nuclear transcription factors, NF-κB and p53 have a relevant role in cell response to ionising radiation. Their expression and function can decide the fate of the cell by choosing between death or survival. The aim of this review was to define the role of the CREB/ATF family members and the related transcription factors in the response to ionising radiation of human haematological malignancies and solid tumours. Full article
(This article belongs to the Special Issue Space Flight Factors and Cytoskeleton Organization)
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20 pages, 4006 KiB  
Article
Dynamics of Spring Regrowth and Comparative Production Performance of 50 Autumn-Sown Alfalfa Cultivars in the Coastal Saline Soil of North China
by Shichao Wang, Dong Fang, Asif Ameen, Xiaolin Li, Kai Guo, Xiaojing Liu and Lipu Han
Life 2021, 11(12), 1436; https://doi.org/10.3390/life11121436 - 20 Dec 2021
Cited by 5 | Viewed by 2181
Abstract
Alfalfa (Medicago sativa L.) production is affected by many factors, including management practices, soil conditions, and the environmental elements of the target area. Varietal differences, in terms of agronomic performance and forage yield, among 50 alfalfa cultivars under six harvest systems following [...] Read more.
Alfalfa (Medicago sativa L.) production is affected by many factors, including management practices, soil conditions, and the environmental elements of the target area. Varietal differences, in terms of agronomic performance and forage yield, among 50 alfalfa cultivars under six harvest systems following regrowth were evaluated during the growing season of 2019–2020 under non-irrigated rainfed conditions in a coastal saline-alkali soil region of North China. Days to harvesting, plant height, canopy area, growth rate, and forage yield were assessed to rank the cultivars. Furthermore, the key factor influencing the regrowth of the second year after over-wintering was identified based on the growth status before over-wintering by using the Boston Matrix method. Results showed significant (p < 0.05) differences among cultivars and harvests regarding plant height, canopy area, and forage yield. Alfalfa forage yield ranged between 24.2 t ha−1 yr−1 and 32.7 t ha−1 yr−1. The highest forage yield was obtained in cultivar Guochan No.1, and was lowest in cultivar Magnum 601. Forage yield reached the greatest values for the first harvest, and then decreased gradually and changed stably. The forage yield of the third, fourth, fifth, and sixth harvest ranged from 3.4 t ha−1 to 4.3 t ha−1 (averaged across 50 cultivars), which represented 10.8% to 15.2% of the annual total forage production. We also observed that forage yield correlated strongly, but negatively, with the growth rate. According to subordinate function value analysis, Womu No.1, WL440HQ, Weston, Surprise, and WL354HQ proved optimum cultivars for general cultivation in this coastal area. In future, development of alfalfa cultivars with improved regrowth and tolerance to heavy saline-alkali soil and early spring drought would be necessary to increase forage yield under rainfed conditions in coastal saline-alkali areas of North China. Full article
(This article belongs to the Section Plant Science)
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12 pages, 828 KiB  
Article
It More than Adds Up: Interaction of Antibiotic Mixing and Temperature
by Marie-Claire Danner, Sharon Omonor Azams, Anne Robertson, Daniel Perkins, Volker Behrends and Julia Reiss
Life 2021, 11(12), 1435; https://doi.org/10.3390/life11121435 - 20 Dec 2021
Cited by 3 | Viewed by 2354 | Correction
Abstract
Use of antibiotics for the treatment and prevention of bacterial infections in humans, agri- and aquaculture as well as livestock rearing leads to antibiotic pollution of fresh water and these antibiotics have an impact on free-living bacteria. While we know which antibiotics are [...] Read more.
Use of antibiotics for the treatment and prevention of bacterial infections in humans, agri- and aquaculture as well as livestock rearing leads to antibiotic pollution of fresh water and these antibiotics have an impact on free-living bacteria. While we know which antibiotics are most common in natural environments such as rivers and streams, there is considerable uncertainty regarding antibiotics’ interactions with one another and the effect of abiotic factors such as temperature. Here, we used an experimental approach to explore the effects of antibiotic identity, concentration, mixing and water temperature on the growth of Pseudomonas fluorescens, a common, ubiquitous bacterium. We exposed P. fluorescens to the four antibiotics most commonly found in surface waters (ciprofloxacin, ofloxacin, sulfamethoxazole and sulfapyridine) and investigated antibiotic interactions for single and mixed treatments at different, field-realistic temperatures. We observed an overall dependence of antibiotic potency on temperature, as temperature increased efficacy of ciprofloxacin and ofloxacin with their EC50 lowered by >75% with a 10 °C temperature increase. Further, we show that mixtures of ciprofloxacin and ofloxacin, despite both belonging to the fluoroquinolone class, exhibit low-temperature-dependent synergistic effects in inhibiting bacterial growth. These findings highlight the context dependency of antibiotic efficacy. They further suggest antibiotic-specific off-target effects that only affect the bacteria once they enter a certain temperature range. This has important implications as freshwater systems already contain multi-drug antibiotic cocktails and are changing temperature due to environmental warming. These factors will interact and affect aquatic food webs, and hence this creates an urgent need to adapt and improve laboratory testing conditions to closer reflect natural environments. Full article
(This article belongs to the Section Microbiology)
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13 pages, 1335 KiB  
Article
Atopic Dermatitis Severity, Patient Perception of the Disease, and Personality Characteristics: How Are They Related to Quality of Life?
by Liborija Lugović-Mihić, Jelena Meštrović-Štefekov, Iva Ferček, Nives Pondeljak, Elvira Lazić-Mosler and Ana Gašić
Life 2021, 11(12), 1434; https://doi.org/10.3390/life11121434 - 20 Dec 2021
Cited by 5 | Viewed by 2705
Abstract
Introduction: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin condition that greatly affects patients’ quality of life, psychological condition, and social relationships. Materials And Methods: To analyze different aspects of AD patients’ quality of life, we used the SCORing Atopic Dermatitis (SCORAD) [...] Read more.
Introduction: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin condition that greatly affects patients’ quality of life, psychological condition, and social relationships. Materials And Methods: To analyze different aspects of AD patients’ quality of life, we used the SCORing Atopic Dermatitis (SCORAD) index (for AD severity), the Dermatology Life Quality Index (DLQI), the World Health Organization Quality of Life Brief Version (WHOQOL-BREF), the Brief Illness Perception Questionnaire (Brief IPQ), and the Crown–Crisp Experiential Index (CCEI) to analyze personality traits. The study included 84 AD patients, 42 with clinical manifestations and 42 in remission. Results: SCORAD values correlated positively and linearly with DLQI (r = 0.551; p < 0.001) and with disease impact on life, disease control, and disease symptoms (r = 0.350–0.398; p ≤ 0.023). DLQI was also related to certain personality characteristics (free-floating anxiety disorder, obsession, somatization, and depression (p ≤ 0.032)). Symptomatic AD patients had a significantly more impaired DLQI than asymptomatic patients (p < 0.001) and the two groups differed in some IPQ dimensions, but they did not differ significantly concerning the WHOQOL-BREF dimensions and personality traits (CCEI). Conclusion: Since AD patient quality of life was dependent not only on disease severity but was also influenced by patient personality characteristics (anxiety disorder, obsession, somatization, depression), many factors need to be taken into account to create effective, patient-specific therapy regimens. Full article
(This article belongs to the Special Issue Mechanisms Underlying Skin Pathologies)
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17 pages, 11707 KiB  
Case Report
Bilateral Optic Disc Swelling as a Plausible Common Ocular Sign of Autoinflammatory Diseases: Report of Three Patients with Blau Syndrome or Cryopyrin-Associated Periodic Syndrome
by Toshihiko Matsuo, Masato Yashiro, Osamu Yamasaki, Takehiro Tanaka and Akira Manki
Life 2021, 11(12), 1433; https://doi.org/10.3390/life11121433 - 19 Dec 2021
Cited by 4 | Viewed by 2532
Abstract
The aim of this study is to describe bilateral optic disc swelling in three consecutive patients with Blau syndrome or cryopyrin-associated periodic syndrome at a single institution. Case 1 was a 30-year-old woman receiving 25 mg etanercept twice weekly who had been diagnosed [...] Read more.
The aim of this study is to describe bilateral optic disc swelling in three consecutive patients with Blau syndrome or cryopyrin-associated periodic syndrome at a single institution. Case 1 was a 30-year-old woman receiving 25 mg etanercept twice weekly who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 5 months old and genetically diagnosed with Blau syndrome with CARD15/NOD2 mutation (N670K) at 13 years old. At 10 years old, she began to have uveitis with optic disc swelling in both eyes, resulting in macular degeneration and optic disc atrophy at 17 years old only when etanercept was introduced. Case 2 was a 21-year-old man receiving adalimumab every 2 weeks who had been diagnosed as early-onset sarcoidosis by biopsy of skin rashes at 1.5 years old and genetically diagnosed as Blau syndrome with CARD15/NOD2 mutation (C495Y) at 5 years old. At 8 years old, around the time of adalimumab introduction, he began to show bilateral optic disc swelling which continued until the age of 16 years when the dose of adalimumab was increased. Case 3 was a 20-year-old woman receiving canakinumab every 8 weeks for systemic symptoms such as fever, headache, vomiting, and abdominal pain and later for sensorineural hearing disturbance on both sides. She had been diagnosed genetically with cryopyrin-associated periodic syndrome with NLRP3 mutation (Y859C) at 7 years old. At 5 years old, she was found to have bilateral optic disc swelling, which continued until the age of 10 years when she began receiving canakinumab (IL-1β inhibitor). Bilateral optic disc swelling might be tentatively designated as a plausible common ocular feature, if it occurred, in autoinflammatory diseases to pay more attention to ophthalmic complications in rare diseases. Full article
(This article belongs to the Collection Retinal Disease and Metabolism)
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9 pages, 687 KiB  
Article
Considering Predictive Factors in the Diagnosis of Clinically Significant Prostate Cancer in Patients with PI-RADS 3 Lesions
by Caleb Natale, Christopher R. Koller, Jacob W. Greenberg, Joshua Pincus and Louis S. Krane
Life 2021, 11(12), 1432; https://doi.org/10.3390/life11121432 - 19 Dec 2021
Cited by 4 | Viewed by 2764
Abstract
The use of multi-parametric magnetic resonance imaging (mpMRI) in conjunction with the Prostate Imaging Reporting and Data System (PI-RADS) is standard practice in the diagnosis, surveillance, and staging of prostate cancer. The risk associated with lesions graded at a PI-RADS score of 3 [...] Read more.
The use of multi-parametric magnetic resonance imaging (mpMRI) in conjunction with the Prostate Imaging Reporting and Data System (PI-RADS) is standard practice in the diagnosis, surveillance, and staging of prostate cancer. The risk associated with lesions graded at a PI-RADS score of 3 is ambiguous. Further characterization of the risk associated with PI-RADS 3 lesions would be useful in guiding further work-up and intervention. This study aims to better characterize the utility of PI-RADS 3 and associated risk factors in detecting clinically significant prostate cancer. From a prospectively maintained IRB-approved dataset of all veterans undergoing mpMRI fusion biopsy at the Southeastern Louisiana Veterans Healthcare System, we identified a cohort of 230 PI-RADS 3 lesions from a dataset of 283 consecutive UroNav-guided biopsies in 263 patients from October 2017 to July 2020. Clinically significant prostate cancer (Gleason Grade ≥ 2) was detected in 18 of the biopsied PI-RADS 3 lesions, representing 7.8% of the overall sample. Based on binomial analysis, PSA densities of 0.15 or greater were predictive of clinically significant disease, as was PSA. The location of the lesion within the prostate was not shown to be a statistically significant predictor of prostate cancer overall (p = 0.87), or of clinically significant disease (p = 0.16). The majority of PI-RADS 3 lesions do not represent clinically significant disease; therefore, it is possible to reduce morbidity through biopsy. PSA density is a potential adjunctive factor in deciding which patients with PI-RADS 3 lesions require biopsy. Furthermore, while the risk of prostate cancer for African-American men has been debated in the literature, our findings indicate that race is not predictive of identifying prostate cancer, with comparable Gleason grade distributions on histology between races. Full article
(This article belongs to the Special Issue MRI in Cancer: Ongoing Developments and Controversies)
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18 pages, 3663 KiB  
Article
Combined Transcriptome and Lipidomic Analyses of Lipid Biosynthesis in Macadamia ternifolia Nuts
by Rui Shi, Haidong Bai, Biao Li, Can Liu, Zhiping Ying, Zhi Xiong and Wenlin Wang
Life 2021, 11(12), 1431; https://doi.org/10.3390/life11121431 - 18 Dec 2021
Cited by 1 | Viewed by 2324
Abstract
Macadamia nuts are considered a high-quality oil crop worldwide. To date, the lipid diversity and the genetic factors that mediate storage lipid biosynthesis in Macadamia ternifolia are poorly known. Here, we performed a comprehensive transcriptomic and lipidomic data analysis to understand the mechanism [...] Read more.
Macadamia nuts are considered a high-quality oil crop worldwide. To date, the lipid diversity and the genetic factors that mediate storage lipid biosynthesis in Macadamia ternifolia are poorly known. Here, we performed a comprehensive transcriptomic and lipidomic data analysis to understand the mechanism of lipid biosynthesis by using young, medium-aged, and mature fruit kernels. Our lipidomic analysis showed that the M. ternifolia kernel was a rich source of unsaturated fatty acids. Moreover, different species of triacylglycerols, diacylglycerol, ceramides, phosphatidylethanolamine, and phosphatidic acid had altered accumulations during the developmental stages. The transcriptome analysis revealed a large percentage of differently expressed genes during the different stages of macadamia growth. Most of the genes with significant differential expression performed functional activity of oxidoreductase and were enriched in the secondary metabolite pathway. The integration of lipidomic and transcriptomic data allowed for the identification of glycerol-3-phosphate acyltransferase, diacylglycerol kinase, phosphatidylinositols, nonspecific phospholipase C, pyruvate kinase 2, 3-ketoacyl-acyl carrier protein reductase, and linoleate 9S-lipoxygenase as putative candidate genes involved in lipid biosynthesis, storage, and oil quality. Our study found comprehensive datasets of lipidomic and transcriptomic changes in the developing kernel of M. ternifolia. In addition, the identification of candidate genes provides essential prerequisites to understand the molecular mechanism of lipid biosynthesis in the kernel of M. ternifolia. Full article
(This article belongs to the Section Plant Science)
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14 pages, 2256 KiB  
Article
Differential Regulation of Myocardial E3 Ligases and Deubiquitinases in Ischemic Heart Failure
by Kristin Klaeske, Maria Dix, Volker Adams, Khalil Jawad, Sandra Eifert, Christian Etz, Diyar Saeed, Michael A. Borger and Maja-Theresa Dieterlen
Life 2021, 11(12), 1430; https://doi.org/10.3390/life11121430 - 18 Dec 2021
Cited by 4 | Viewed by 2003
Abstract
The pathological changes of ubiquitination and deubiquitination following myocardial infarction (MI) and chronic heart failure (CHF) have been sparsely examined. We investigated the expression of muscle-specific E3 ubiquitin ligases and deubiquitinases in MI and CHF. Therefore, mice were assigned to coronary artery ligation [...] Read more.
The pathological changes of ubiquitination and deubiquitination following myocardial infarction (MI) and chronic heart failure (CHF) have been sparsely examined. We investigated the expression of muscle-specific E3 ubiquitin ligases and deubiquitinases in MI and CHF. Therefore, mice were assigned to coronary artery ligation for 3 days or 10 weeks as well as for sham operation (each n = 10). Expression of E3 ligases (MAFBX, MURF1, CHIP, ITCH, MDM2) and deubiquitinases (A20, CYLD, UCH-L1, USP14, USP19) was determined. After MI and in CHF, the mRNA expression of MURF1, CHIP and MDM2 (all p < 0.05) was decreased. Protein expression analyses revealed that ITCH expression decreased in CHF (p = 0.01), whereas MDM2 expression increased in MI (p = 0.02) and decreased in CHF (p = 0.02). Except for USP19 mRNA expression that decreased at 3 days and 10 weeks (both p < 0.01), the expression of other deubiquitinases remained unaffected after MI and CHF. The expression of myocardial E3 ligases is differentially regulated following MI, raising the question of whether an upstream regulation exists that is activated by MI for tissue protection or whether the downregulation of E3 ligases enables myocardial hypertrophy following MI. Full article
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14 pages, 1056 KiB  
Article
Low-Level Elevations of Procalcitonin Are Associated with Increased Mortality in Acute Heart Failure Patients, Independent of Concomitant Infection
by Fabrice F. Darche, Moritz Biener, Matthias Müller-Hennessen, Rasmus Rivinius, Kiril M. Stoyanov, Barbara R. Milles, Hugo A. Katus, Norbert Frey and Evangelos Giannitsis
Life 2021, 11(12), 1429; https://doi.org/10.3390/life11121429 - 18 Dec 2021
Cited by 1 | Viewed by 1879
Abstract
We aimed to evaluate the prognostic value of procalcitonin (PCT) in acute heart failure (AHF) patients, especially in those without underlying infection. We enrolled patients presenting with acute dyspnea to the emergency department (ED) of Heidelberg University Hospital and studied the prognostic role [...] Read more.
We aimed to evaluate the prognostic value of procalcitonin (PCT) in acute heart failure (AHF) patients, especially in those without underlying infection. We enrolled patients presenting with acute dyspnea to the emergency department (ED) of Heidelberg University Hospital and studied the prognostic role of PCT on all-cause death. Of 312 patients, AHF was diagnosed in 139 patients. Of these, 125 patients had AHF without signs of infection, and 14 had AHF complicated by respiratory or other infection. The optimal prognostic PCT cutoff value for mortality prediction was calculated by a receiver operating characteristics curve. In patients with AHF, the prognostic PCT cutoff value was 0.08 ng/mL. The Kaplan–Meier survival analysis showed that AHF patients with PCT values > 0.08 ng/mL had a higher all-cause mortality at 120 days than those with PCT values ≤ 0.08 ng/mL (log-rank p = 0.0123). Similar results could be obtained after subdivision into AHF patients with and without signs of overt infection. In both cases, mortality was higher in patients with PCT levels above the prognostic PCT cutoff than in those with values ranging below this threshold. Moreover, we show that the prognostic PCT cutoff values for mortality prediction ranged below the established PCT cutoff for the guidance of antibiotic therapy. In conclusion, the data of our study revealed that low-level elevations of PCT were associated with an increased mortality in patients with AHF, irrespective of concomitant respiratory or other infection. PCT should thus be further used as a marker in the risk stratification of AHF. Full article
(This article belongs to the Collection Heart Failure and Heart Transplantation)
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13 pages, 3756 KiB  
Article
Enhanced Conformational Sampling of Nanobody CDR H3 Loop by Generalized Replica-Exchange with Solute Tempering
by Ren Higashida and Yasuhiro Matsunaga
Life 2021, 11(12), 1428; https://doi.org/10.3390/life11121428 - 18 Dec 2021
Cited by 2 | Viewed by 2463
Abstract
The variable domains of heavy-chain antibodies, known as nanobodies, are potential substitutes for IgG antibodies. They have similar affinities to antigens as antibodies, but are more heat resistant. Their small size allows us to exploit computational approaches for structural modeling or design. Here, [...] Read more.
The variable domains of heavy-chain antibodies, known as nanobodies, are potential substitutes for IgG antibodies. They have similar affinities to antigens as antibodies, but are more heat resistant. Their small size allows us to exploit computational approaches for structural modeling or design. Here, we investigate the applicability of an enhanced sampling method, a generalized replica-exchange with solute tempering (gREST) for sampling CDR-H3 loop structures of nanobodies. In the conventional replica-exchange methods, temperatures of only a whole system or scaling parameters of a solute molecule are selected for temperature or parameter exchange. In gREST, we can flexibly select a part of a solute molecule and a part of the potential energy terms as a parameter exchange region. We selected the CDR-H3 loop and investigated which potential energy term should be selected for the efficient sampling of the loop structures. We found that the gREST with dihedral terms can explore a global conformational space, but the relaxation to the global equilibrium is slow. On the other hand, gREST with all the potential energy terms can sample the equilibrium distribution, but the structural exploration is slower than with dihedral terms. The lessons learned from this study can be applied to future studies of loop modeling. Full article
(This article belongs to the Special Issue Multiscale Simulation Methods for Living Systems: Applications to Biomolecules and Cells)
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13 pages, 3565 KiB  
Article
Modulation of Epithelial Mesenchymal Transition after AGTR-1 Gene Edition by Crispr/Cas9 and Losartan Treatment in Mammary Tumor Cell Line: A Comparative Study between Human and Canine Species
by Marina Gobbe Moschetta-Pinheiro, Jucimara Colombo, Bianca Lara Venâncio de Godoy, Julia Ferreira Balan, Bianca Carlos Nascimento and Debora Aparecida Pires de Campos Zuccari
Life 2021, 11(12), 1427; https://doi.org/10.3390/life11121427 - 18 Dec 2021
Cited by 3 | Viewed by 2178
Abstract
Breast cancer is the most prevalent tumor type among women and female dogs. Tumor malignancy is characterized by the epithelial-to-mesenchymal transition (EMT) which leads to the metastasis formation. The inhibition of angiotensin II type I receptor (AGTR1) by an antagonist such as losartan [...] Read more.
Breast cancer is the most prevalent tumor type among women and female dogs. Tumor malignancy is characterized by the epithelial-to-mesenchymal transition (EMT) which leads to the metastasis formation. The inhibition of angiotensin II type I receptor (AGTR1) by an antagonist such as losartan can suppress angiogenesis, consequently contributing to the metastasis control. The aim of this study was to analyze the capacity of losartan and AGTR-1 gene edition to modulate the EMT process in triple negative/metastatic mammary tumor cells, compared to existing treatment protocols such as carboplatin. The cell lines CF41.Mg and MDA-MB-468, were cultured and treated with carboplatin, losartan, or submitted to AGTR-1 gene edition by CRISPR/Cas9. EMT markers and PARP-1 protein and gene expression were evaluated by immunofluorescence or immunocytochemistry and qRT-PCR, respectively. Cell migration capacity was also evaluated. For CF41.Mg and MDA-MB-468 cell lines, there was an increase in E-cadherin and a decrease in N-cadherin and PARP-1 protein and gene expression after treatment with carboplatin, losartan, both in combination and after AGTR-1 gene edition. There was a decrease in VEGF and PARP-1 protein and gene expression after AGTR-1 gene edition. Moreover, in both lines, reduction in invasion rate was observed after all treatments. Our data suggest that losartan and the gene edition of AGTR-1 by CRISPR/Cas9 were able to block the DNA repair and control the EMT process, such as carboplatin. The results in the canine species are unprecedented, as there are no data in the literature that demonstrate the action of losartan in this tumor type. Full article
(This article belongs to the Special Issue Cell Culture and Genome Modification Technologies: from Biology to Biomedical Applications)
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22 pages, 2577 KiB  
Article
Biodiversity and Community Analysis of Plant-Parasitic and Free-Living Nematodes Associated with Maize and Other Rotational Crops from Punjab, Pakistan
by Aatika Sikandar, Tabassum Ara Khanum and Yuanyuan Wang
Life 2021, 11(12), 1426; https://doi.org/10.3390/life11121426 - 17 Dec 2021
Cited by 7 | Viewed by 2613
Abstract
Maize (Zea mays L.) is one of Pakistan’s essential staple food crops. Plant-parasitic nematodes (PPNs) are a significant restraint in maize production. However, free-living nematodes (FLNs) provide crucial ecological functions such as suppressing pests and nutrient mineralization. This study aimed to assess [...] Read more.
Maize (Zea mays L.) is one of Pakistan’s essential staple food crops. Plant-parasitic nematodes (PPNs) are a significant restraint in maize production. However, free-living nematodes (FLNs) provide crucial ecological functions such as suppressing pests and nutrient mineralization. This study aimed to assess the community analysis of plant-parasitic and free-living nematodes associated with maize and other rotational crops (those cultivated in sequence with the maize in the same field) from Punjab, Pakistan. The occurrence percentage was observed per 500 g soil for each nematode genus. The present study revealed that 24 species of plant-parasitic and free-living nematodes were identified from maize crops and other rotational crops from 16 localities through Punjab, Pakistan. Nematode communities were analyzed by absolute frequency, relative frequency, relative density, and prominence value, while cluster analysis was based on the presence or absence of nematode in different localities. The overall proportion of plant-parasitic nematodes was 35%, while free-living soil nematodes recovered 65%, out of 210 samples of maize and other rotational crops. Several major genera of plant-parasitic nematodes were reported during the present study viz., Ditylenchus, Filenchus, Helicotylenchus, Hemicriconemoides, Heterodera, Hoplolaimus, Malenchus, Pratylenchus, Psilenchus, Rotylenchulus, Seinura, Telotylenchus, Tylenchorhynchus, and Xiphinema Community relationship revealed the overall dominance of Heterodera zeae, with the highest incidence (55.71%) followed by Tylenchorhynchus elegans (33.33%) and Helicotylenchus certus (24.76%). The results provide valuable information on the community structure of nematodes in maize and other rotational crops of maize in Punjab, Pakistan. Moreover, this data can be used as a preventive measure before PPN incidence results in greater losses on maize. Full article
(This article belongs to the Special Issue Plant–Nematode Interaction)
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13 pages, 5459 KiB  
Article
Inhibition of HDACs Suppresses Cell Proliferation and Cell Migration of Gastric Cancer by Regulating E2F5 Targeting BCL2
by Arshad Ali, Ayaz Ali, Shaker Khan, Muhammad Ibrahim, Mohammed Ali Alshehri and Anand Thirupathi
Life 2021, 11(12), 1425; https://doi.org/10.3390/life11121425 - 17 Dec 2021
Cited by 4 | Viewed by 2187
Abstract
(1) Background: Gastric cancer (GC) is the most common high death-rate cancer type worldwide, with an enhanced prevalence and increased rate of mortality. Although significant evidence on surgery strategy has been generated for the treatment of GC, conclusions are still uncertain regarding profound [...] Read more.
(1) Background: Gastric cancer (GC) is the most common high death-rate cancer type worldwide, with an enhanced prevalence and increased rate of mortality. Although significant evidence on surgery strategy has been generated for the treatment of GC, conclusions are still uncertain regarding profound metastatic or persevering gastric cancer. Therefore, it is essential to develop novel and effective biomarkers or therapeutic targets for the diagnosis of GC. Histone deacetylations (HDACs) are important epigenetic regulators that control the aberrant transcription of critical genes that are mainly involved in cell proliferation, cell migration, regulation of the cell cycle, and different signal pathways. (2) Methods: Expression analysis of HDACs family members and E2F5 in gastric cancer cell lines was determined by RT-PCR and Western blotting. The cell proliferation was determined through an MTT assay. Cell migration was determined using a wound-healing assay. Flow cytometry experiments were used to determine cell-cycle analysis. The statistical software OriginPro 2015 (OriginLab, Northampton, MA, USA) was used to analyze data. A p value of < 0.05 was regarded as significant. (3) Results: The present study shows that E2F5 expression is upregulated in GC cancer cell lines compared to normal cell lines, and is positively associated with the level of HDACs and BCL2. HDACi and knocking down of E2F5 as tumor suppressors inhibited cell proliferation, migration invasion, and blocked the cell cycle in gastric cancer cells by suppressing BCL2. The results conclude that the anticancer mechanism of HDACi was determined by regulating E2F5 via targeting BCL2. (4) Conclusions: Our results suggest that the HDAC–E2F5–BCL2 signaling axis might be a novel potential biomarker in gastric cancer. Full article
(This article belongs to the Special Issue Cancer Cell Metastasis: The In Vitro Approach)
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18 pages, 1123 KiB  
Review
Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer
by Luisa Salvatori, Francesco Spallotta, Carlo Gaetano and Barbara Illi
Life 2021, 11(12), 1424; https://doi.org/10.3390/life11121424 - 17 Dec 2021
Cited by 3 | Viewed by 2395
Abstract
Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO [...] Read more.
Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO levels generally have protective effects, higher NO concentrations induce cytotoxic/cytostatic actions. In recent years, evidences have been accumulated unveiling S-nitrosylation as a major NO-dependent post-translational mechanism ruling gene expression. S-nitrosylation is a reversible, highly regulated phenomenon in which NO reacts with one or few specific cysteine residues of target proteins generating S-nitrosothiols. By inducing this chemical modification, NO might exert epigenetic regulation through direct effects on both DNA and histones as well as through indirect actions affecting the functions of transcription factors and transcriptional co-regulators. In this light, S-nitrosylation may also impact on cancer cell gene expression programs. Indeed, it affects different cell pathways and functions ranging from the impairment of DNA damage repair to the modulation of the activity of signal transduction molecules, oncogenes, tumor suppressors, and chromatin remodelers. Nitrosylation is therefore a versatile tool by which NO might control gene expression programs in health and disease. Full article
(This article belongs to the Section Genetics and Genomics)
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9 pages, 538 KiB  
Article
Posterior Circulation Endovascular Thrombectomy for Large Vessels Occlusion in Patients Presenting with NIHSS Score ≤ 10
by Andrea M. Alexandre, Iacopo Valente, Arturo Consoli, Pietro Trombatore, Luca Scarcia, Mariangela Piano, Nicola Limbucci, Joseph Domenico Gabrieli, Riccardo Russo, Antonio Armando Caragliano, Maria Ruggiero, Andrea Saletti, Guido Andrea Lazzarotti, Marco Pileggi, Mirco Cosottini, Fabio Pilato, Artur Slomka, Francesca Colò, Francesca Giubbolini, Giovanni Frisullo, Giacomo Della Marca, Aldobrando Broccolini and Alessandro Pedicelliadd Show full author list remove Hide full author list
Life 2021, 11(12), 1423; https://doi.org/10.3390/life11121423 - 17 Dec 2021
Cited by 11 | Viewed by 2734
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
(This article belongs to the Section Physiology and Pathology)
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16 pages, 2638 KiB  
Article
Activation of the Hippo Pathway in Rana sylvatica: Yapping Stops in Response to Anoxia
by Aakriti Gupta and Kenneth B. Storey
Life 2021, 11(12), 1422; https://doi.org/10.3390/life11121422 - 17 Dec 2021
Cited by 3 | Viewed by 2399
Abstract
Wood frogs (Rana sylvatica) display well-developed anoxia tolerance as one component of their capacity to endure prolonged whole-body freezing during the winter months. Under anoxic conditions, multiple cellular responses are triggered to efficiently cope with stress by suppressing gene transcription and [...] Read more.
Wood frogs (Rana sylvatica) display well-developed anoxia tolerance as one component of their capacity to endure prolonged whole-body freezing during the winter months. Under anoxic conditions, multiple cellular responses are triggered to efficiently cope with stress by suppressing gene transcription and promoting activation of mechanisms that support cell survival. Activation of the Hippo signaling pathway initiates a cascade of protein kinase reactions that end with phosphorylation of YAP protein. Multiple pathway components of the Hippo pathway were analyzed via immunoblotting, qPCR or DNA-binding ELISAs to assess the effects of 24 h anoxia and 4 h aerobic recovery, compared with controls, on liver and heart metabolism of wood frogs. Immunoblot results showed significant increases in the relative levels of multiple proteins of the Hippo pathway representing an overall activation of the pathway in both organs under anoxia stress. Upregulation of transcript levels further confirmed this. A decrease in YAP and TEAD protein levels in the nuclear fraction also indicated reduced translocation of these proteins. Decreased DNA-binding activity of TEAD at the promoter region also suggested repression of gene transcription of its downstream targets such as SOX2 and OCT4. Furthermore, changes in the protein levels of two downstream targets of TEAD, OCT4 and SOX2, established regulated transcriptional activity and could possibly be associated with the activation of the Hippo pathway. Increased levels of TAZ in anoxic hearts also suggested its involvement in the repair mechanism for damage caused to cardiac muscles during anoxia. In summary, this study provides the first insights into the role of the Hippo pathway in maintaining cellular homeostasis in response to anoxia in amphibians. Full article
(This article belongs to the Section Animal Science)
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12 pages, 1389 KiB  
Article
Decorin Concentrations in Aqueous Humor of Patients with Diabetic Retinopathy
by Shermaine W. Y. Low, Tanuja Vaidya, Santosh G. K. Gadde, Thirumalesh B. Mochi, Devesh Kumar, Iris S. Kassem, Deborah M. Costakos, Baseer Ahmad, Swaminathan Sethu, Arkasubhra Ghosh and Shyam S. Chaurasia
Life 2021, 11(12), 1421; https://doi.org/10.3390/life11121421 - 17 Dec 2021
Cited by 5 | Viewed by 2163
Abstract
Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the extracellular matrix (ECM), causing fluid leakage and ischemic retinal neovascularization. Current treatment strategies include intravitreal anti-vascular endothelial growth factor (VEGF) or steroidal injections, [...] Read more.
Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the extracellular matrix (ECM), causing fluid leakage and ischemic retinal neovascularization. Current treatment strategies include intravitreal anti-vascular endothelial growth factor (VEGF) or steroidal injections, laser photocoagulation, or vitrectomy in severe cases. However, treatment may require multiple modalities or repeat treatments due to variable response. Though DR management has achieved great success, improved, long-lasting, and predictable treatments are needed, including new biomarkers and therapeutic approaches. Small-leucine rich proteoglycans, such as decorin, constitute an integral component of retinal endothelial ECM. Therefore, any damage to microvasculature can trigger its antifibrotic and antiangiogenic response against retinal vascular pathologies, including DR. We conducted a cross-sectional study to examine the association between aqueous humor (AH) decorin levels, if any, and severity of DR. A total of 82 subjects (26 control, 56 DR) were recruited. AH was collected and decorin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Decorin was significantly increased in the AH of DR subjects compared to controls (p = 0.0034). AH decorin levels were increased in severe DR groups in ETDRS and Gloucestershire classifications. Decorin concentrations also displayed a significant association with visual acuity (LogMAR) measurements. In conclusion, aqueous humor decorin concentrations were found elevated in DR subjects, possibly due to a compensatory response to the retinal microvascular changes during hyperglycemia. Full article
(This article belongs to the Collection Retinal Disease and Metabolism)
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8 pages, 601 KiB  
Case Report
Photobiomodulation Therapy Applied after 6 Months for the Management of a Severe Inferior Alveolar Nerve Injury
by Marwan El Mobadder, Samir Nammour, Marlin Ortega and Kinga Grzech-Leśniak
Life 2021, 11(12), 1420; https://doi.org/10.3390/life11121420 - 17 Dec 2021
Cited by 3 | Viewed by 2691
Abstract
Despite its significant negative impact on the quality of life, the methods for the management of the inferior alveolar nerve (IAN) injury are still limited. In this case report, the patient did not show any improvement from the day of the iatrogenic accident [...] Read more.
Despite its significant negative impact on the quality of life, the methods for the management of the inferior alveolar nerve (IAN) injury are still limited. In this case report, the patient did not show any improvement from the day of the iatrogenic accident until 6 months. A significant improvement of the symptoms started to appear only at 6 months when PBMT was applied. A total of 42 sessions of PBMT took place. The application zone included intraoral and extraoral areas. The parameters were: Delivery power of 0.1 W, for 40 s, continuous wave (CW), contact mode, and delivered energy of 4 J. The delivered energy density related to the fiber diameter was 1415 J/cm2. Each treated point was considered to be 1 cm2 of diameter. At the end of the treatment, all of the symptoms disappeared except for an abnormal sensation on touching the mucosa and gingiva of the concerned area. No side effects were noted. This case report shows that PBMT can be a very promising approach for the management of severe cases that are not improving with conventional methods. Full article
(This article belongs to the Special Issue Clinical Applications & Fundamental Researches in Dentistry)
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40 pages, 8513 KiB  
Article
Hitting Times of Some Critical Events in RNA Origins of Life
by Caleb Deen Bastian and Hershel Rabitz
Life 2021, 11(12), 1419; https://doi.org/10.3390/life11121419 - 17 Dec 2021
Viewed by 2328
Abstract
Can a replicase be found in the vast sequence space by random drift? We partially answer this question through a proof-of-concept study of the times of occurrence (hitting times) of some critical events in the origins of life for low-dimensional RNA sequences using [...] Read more.
Can a replicase be found in the vast sequence space by random drift? We partially answer this question through a proof-of-concept study of the times of occurrence (hitting times) of some critical events in the origins of life for low-dimensional RNA sequences using a mathematical model and stochastic simulation studies from Python software. We parameterize fitness and similarity landscapes for polymerases and study a replicating population of sequences (randomly) participating in template-directed polymerization. Under the ansatz of localization where sequence proximity correlates with spatial proximity of sequences, we find that, for a replicating population of sequences, the hitting and establishment of a high-fidelity replicator depends critically on the polymerase fitness and sequence (spatial) similarity landscapes and on sequence dimension. Probability of hitting is dominated by landscape curvature, whereas hitting time is dominated by sequence dimension. Surface chemistries, compartmentalization, and decay increase hitting times. Compartmentalization by vesicles reveals a trade-off between vesicle formation rate and replicative mass, suggesting that compartmentalization is necessary to ensure sufficient concentration of precursors. Metabolism is thought to be necessary to replication by supplying precursors of nucleobase synthesis. We suggest that the dynamics of the search for a high-fidelity replicase evolved mostly during the final period and, upon hitting, would have been followed by genomic adaptation of genes and to compartmentalization and metabolism, effecting degree-of-freedom gains of replication channel control over domain and state to ensure the fidelity and safe operations of the primordial genetic communication system of life. Full article
(This article belongs to the Collection Experimentally Testing Origin of Life Hypotheses in the Laboratory, at Field Analogs and Computationally)
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10 pages, 960 KiB  
Article
House Dust Mite Precision Allergy Molecular Diagnosis (PAMD@) in the Th2-prone Atopic Dermatitis Endotype
by Ruperto González-Pérez, Paloma Poza-Guedes, Fernando Pineda, Miriam Castillo and Inmaculada Sánchez-Machín
Life 2021, 11(12), 1418; https://doi.org/10.3390/life11121418 - 17 Dec 2021
Cited by 11 | Viewed by 3223
Abstract
Atopic dermatitis (AD) endotyping might be important for developing personalized diagnostic and therapeutic strategies to the different phenotypes. The current study investigated the IgE molecular profile to Dermatophagoides pteronyssinus (D. pteronyssinus) in a subset of patients afflicted with varying severity stages [...] Read more.
Atopic dermatitis (AD) endotyping might be important for developing personalized diagnostic and therapeutic strategies to the different phenotypes. The current study investigated the IgE molecular profile to Dermatophagoides pteronyssinus (D. pteronyssinus) in a subset of patients afflicted with varying severity stages of atopic dermatitis in a subtropical region subjected to a high perennial house dust mite (HDM) exposure. We selected patients showing a clinically relevant sensitization to HDM with mild-to-moderate and severe AD according to their basal Severity Scoring Atopic Dermatitis (SCORAD) index. Skin prick test (SPT) with standardized mite extracts, as well as a Precision Allergy Molecular Diagnosis (PAMD@) panel including nine different D. pteronyssinus allergens and the related protein allergenic characterization, were assessed in all serum samples. A total of 80 European American AD patients with the marked T2 endotype confirmed their eligibility for the study. Major allergens (Der p 23, Der p 2, and Der p 1) were present in more than 86% of all subjects, with mid-tier allergens (Der p 5, Der p 7, and Der p 21) reaching up to 65%. A serodominant role for Der p 11 could not be quantitatively confirmed in the present cohort. The proposed component resolved diagnosis (CRD) panel appeared to be sufficient to obtain a precise D. pteronyssinus molecular diagnosis in AD patients subjected to a climate-dependent high-mite allergen exposure. The raised seroprevalence of IgE response to Der p 23 confirmed this constituent as a major D. pteronyssinus allergen in severe stages of atopic dermatitis. A clinically driven molecular approach appears to be essential to frame a more precise diagnosis and therapy of this heterogeneous allergic condition. Full article
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15 pages, 3086 KiB  
Article
Efficient Generation of P53 Biallelic Mutations in Diannan Miniature Pigs Using RNA-Guided Base Editing
by Honghui Li, Wenmin Cheng, Bowei Chen, Shaoxia Pu, Ninglin Fan, Xiaolin Zhang, Deling Jiao, Dejia Shi, Jianxiong Guo, Zhuo Li, Yubo Qing, Baoyu Jia, Hong-Ye Zhao and Hong-Jiang Wei
Life 2021, 11(12), 1417; https://doi.org/10.3390/life11121417 - 17 Dec 2021
Cited by 3 | Viewed by 2774
Abstract
The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than [...] Read more.
The base editing 3 (BE3) system, a single-base gene editing technology developed using CRISPR/Cas9n, has a broad range of applications for human disease model construction and gene therapy, as it is highly efficient, accurate, and non-destructive. P53 mutations are present in more than 50% of human malignancies. Due to the similarities between humans and pigs at the molecular level, pig models carrying P53 mutations can be used to research the mechanism of tumorigenesis and improve tumor diagnosis and treatment. According to pathogenic mutations of the human P53 gene at W146* and Q100*, sgRNAs were designed to target exon 4 and exon 5 of the porcine P53 gene. The target editing efficiencies of the two sgRNAs were 61.9% and 50.0%, respectively. The editing efficiency of the BE3 system was highest (about 60%) when C (or G) was at the 5th base. Puromycin screening revealed that 75.0% (21/28) and 68.7% (22/32) of cell colonies contained a P53 mutation at sgRNA-Exon5 and sgRNA-Exon4, respectively. The reconstructed embryos from sgRNA-Exon5-5# were transferred into six recipient gilts, all of which aborted. The reconstructed embryos from sgRNA-Exon4-7# were transferred into 6 recipient gilts, 3 of which became pregnant, resulting in 14 live and 3 dead piglets. Sequencing analyses of the target site confirmed 1 P53 monoallelic mutation and 16 biallelic mutations. The qPCR analysis showed that the P53 mRNA expression level was significantly decreased in different tissues of the P53 mutant piglets (p < 0.05). Additionally, confocal microscopy and western blot analysis revealed an absence of P53 expression in the P53 mutant fibroblasts, livers, and lung tissues. In conclusion, a porcine cancer model with a P53 point mutation can be obtained via the BE3 system and somatic cell nuclear transfer (SCNT). Full article
(This article belongs to the Special Issue Gene Editing of Large Mammals)
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2 pages, 556 KiB  
Reply
Reply to Nayak, P.K. Comment on “Samulewski et al. Magnetite Synthesis in the Presence of Cyanide or Thiocyanate under Prebiotic Chemistry Conditions. Life 2020, 10, 34”
by Rafael Block Samulewski, Flávio F. Ivashita, Andrea Paesano, Jr. and Dimas Augusto Morozin Zaia
Life 2021, 11(12), 1416; https://doi.org/10.3390/life11121416 - 17 Dec 2021
Viewed by 1316
Abstract
We have considered the criticisms raised by Pranaba K. Nayak [...] Full article
(This article belongs to the Collection What's on Board in the Journal Life)
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9 pages, 1758 KiB  
Case Report
An Unusual Presentation of Crohn’s Disease Diagnosed Following Accidental Ingestion of Fruit Pits: Report of Two Cases and Review of the Literature
by Emanuele Sinagra, Dario Raimondo, Salvatore Marco Iacopinelli, Francesca Rossi, Giuseppe Conoscenti, Maria Angela Di Maggio, Sergio Testai, Rita Alloro, Marta Marasà, Alberto Calandra, Claudia Costanza, Serena Cristofalo, Socrate Pallio, Marcello Maida, Ilaria Tarantino and Goffredo Arena
Life 2021, 11(12), 1415; https://doi.org/10.3390/life11121415 - 16 Dec 2021
Cited by 2 | Viewed by 2020
Abstract
The clinical course of Crohn’s disease (CD) is often complicated by intestinal strictures, which can be fibrotic, inflammatory, or mixed, therefore leading to stenosis and eventually symptomatic obstruction. We report two cases of subclinical CD diagnosed after fruit pit ingestion, causing bowel obstruction; [...] Read more.
The clinical course of Crohn’s disease (CD) is often complicated by intestinal strictures, which can be fibrotic, inflammatory, or mixed, therefore leading to stenosis and eventually symptomatic obstruction. We report two cases of subclinical CD diagnosed after fruit pit ingestion, causing bowel obstruction; additionally, we conducted a narrative review of the scientific literature on cases of intestinal obstruction secondary to impacted bezoars due to fruit pits. Symptoms of gastrointestinal bezoars in CD patients are not diagnostic; and the diagnosis should be based on a combined assessment of history, clinical presentation, imaging examination and endoscopy findings. This report corroborates the concept that CD patients are at a greater risk of bowel obstruction with bezoars generally and shows that accidental ingestion of fruit pits may lead to an unusual presentation of the disease. Therapeutic options in this group of patients differ from the usual approaches implemented in other patients with strictures secondary to CD. Full article
(This article belongs to the Topic Inflammation and Fibrosis in Digestive Diseases)
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14 pages, 6918 KiB  
Article
The Anti-Proliferative Activity of Secondary Metabolite from the Marine Streptomyces sp. against Prostate Cancer Cells
by Hung-Yu Lin, Yong-Shiou Lin, Shou-Ping Shih, Sung-Bau Lee, Mohamed El-Shazly, Ken-Ming Chang, Yu-Chen S. H. Yang, Yi-Lun Lee and Mei-Chin Lu
Life 2021, 11(12), 1414; https://doi.org/10.3390/life11121414 - 16 Dec 2021
Cited by 10 | Viewed by 2712
Abstract
Many active substances from marine organisms are produced by symbiotic microorganisms such as bacteria, fungi, and algae. Secondary metabolites from marine actinomycetes exhibited several biological activities and provided interesting drug leads. This study reported the isolation of Lu01-M, a secondary metabolite from the [...] Read more.
Many active substances from marine organisms are produced by symbiotic microorganisms such as bacteria, fungi, and algae. Secondary metabolites from marine actinomycetes exhibited several biological activities and provided interesting drug leads. This study reported the isolation of Lu01-M, a secondary metabolite from the marine actinomycetes Streptomyces sp., with potent anti-proliferative activity against prostate cancers. Lu01-M blocked cell proliferation with IC50 values of 1.03 ± 0.31, 2.12 ± 0.38, 1.27 ± 0.25 μg/mL in human prostate cancer PC3, DU145, and LNCaP cells, respectively. Lu01-M induced cytotoxic activity through multiple mechanisms including cell apoptosis, necroptosis, autophagy, ER stress, and inhibiting colony formation and cell migration. Lu01-M induced cell cycle arrest at the G2/M phase and DNA damage. However, the activity of autophagy induced survival response in cancer cells. Our findings suggested that Lu01-M holds the potential to be developed as an anti-cancer agent against prostate cancers. Full article
(This article belongs to the Collection Tumor Progression, Microenvironments, and Therapeutics)
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15 pages, 3168 KiB  
Article
Influence of Metal Ions on Model Protoamphiphilic Vesicular Systems: Insights from Laboratory and Analogue Studies
by Manesh Prakash Joshi, Luke Steller, Martin J. Van Kranendonk and Sudha Rajamani
Life 2021, 11(12), 1413; https://doi.org/10.3390/life11121413 - 16 Dec 2021
Cited by 6 | Viewed by 3424
Abstract
Metal ions strongly affect the self-assembly and stability of membranes composed of prebiotically relevant amphiphiles (protoamphiphiles). Therefore, evaluating the behavior of such amphiphiles in the presence of ions is a crucial step towards assessing their potential as model protocell compartments. We have recently [...] Read more.
Metal ions strongly affect the self-assembly and stability of membranes composed of prebiotically relevant amphiphiles (protoamphiphiles). Therefore, evaluating the behavior of such amphiphiles in the presence of ions is a crucial step towards assessing their potential as model protocell compartments. We have recently reported vesicle formation by N-acyl amino acids (NAAs), an interesting class of protoamphiphiles containing an amino acid linked to a fatty acid via an amide linkage. Herein, we explore the effect of ions on the self-assembly and stability of model N-oleoyl glycine (NOG)-based membranes. Microscopic analysis showed that the blended membranes of NOG and Glycerol 1-monooleate (GMO) were more stable than pure NOG vesicles, both in the presence of monovalent and divalent cations, with the overall vesicle stability being 100-fold higher in the presence of a monovalent cation. Furthermore, both pure NOG and NOG + GMO mixed systems were able to self-assemble into vesicles in natural water samples containing multiple ions that were collected from active hot spring sites. Our study reveals that several aspects of the metal ion stability of NAA-based membranes are comparable to those of fatty acid-based systems, while also confirming the robustness of compositionally heterogeneous membranes towards high metal ion concentrations. Pertinently, the vesicle formation by NAA-based systems in terrestrial hot spring samples indicates the conduciveness of these low ionic strength freshwater systems for facilitating prebiotic membrane-assembly processes. This further highlights their potential to serve as a plausible niche for the emergence of cellular life on the early Earth. Full article
(This article belongs to the Special Issue The Origin and Early Evolution of Life: Prebiotic Systems Chemistry Perspective)
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3 pages, 191 KiB  
Editorial
Radiotherapy in Current Neuro-Oncology: There Is Still Much to Reveal
by Gianluca Ferini and Giuseppe Emmanuele Umana
Life 2021, 11(12), 1412; https://doi.org/10.3390/life11121412 - 16 Dec 2021
Cited by 4 | Viewed by 1621
Abstract
Radiation therapy (RT) has a pivotal role in the treatment of Central Nervous System (CNS) neoplasms and is routinely employed for both benign and malignant lesions [...] Full article
(This article belongs to the Special Issue Innovative Technologies in Neuro-oncology)
10 pages, 1988 KiB  
Article
Multiscale Entropy of Resting-State Functional Magnetic Resonance Imaging Differentiates Progressive Supranuclear Palsy and Multiple System Atrophy
by Katsuhiko Kadota, Keiichi Onoda, Satoshi Abe, Chizuko Hamada, Shingo Mitaki, Hiroaki Oguro, Atsushi Nagai, Hajime Kitagaki and Shuhei Yamaguchi
Life 2021, 11(12), 1411; https://doi.org/10.3390/life11121411 - 16 Dec 2021
Viewed by 2053
Abstract
Distinguishing progressive supranuclear palsy (PSP) from multiple system atrophy (MSA) in the early clinical stages is challenging; few sensitive and specific biomarkers are available for their differential diagnosis. Resting-state functional magnetic resonance imaging (rs-fMRI) is used to study the fluctuations in blood oxygen [...] Read more.
Distinguishing progressive supranuclear palsy (PSP) from multiple system atrophy (MSA) in the early clinical stages is challenging; few sensitive and specific biomarkers are available for their differential diagnosis. Resting-state functional magnetic resonance imaging (rs-fMRI) is used to study the fluctuations in blood oxygen level-dependent (BOLD) signals at rest, which provides evidence for aberrant brain functional networks in neurodegenerative diseases. We aimed to examine whether rs-fMRI data could differentiate between PSP and MSA via a multiscale entropy (MSE) analysis of BOLD signals, which estimates the complexity of temporal fluctuations in brain activity. We recruited 14 and 18 patients with PSP and MSA, respectively, who underwent neuropsychological tests and rs-fMRI. PSP patients demonstrated greater cognitive function impairments, particularly in the frontal executive function. The bilateral prefrontal cortex revealed lower entropy BOLD signal values in multiple time scales for PSP, compared to the values observed in MSA patients; however, the functional connectivity of the representative brain networks was comparable between the diseases. The reduced complexity of BOLD signals in the prefrontal cortex was associated with frontal dysfunction. Thus, an MSE analysis of rs-fMRI could differentiate between PSP and MSA, and the reduced complexity of BOLD signals could be associated with cognitive impairment. Full article
(This article belongs to the Topic Brain Functional and Structural Connectivity and Cognition)
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15 pages, 1115 KiB  
Article
Measuring Proviral HIV-1 DNA: Hurdles and Improvements to an Assay Monitoring Integration Events Utilising Human Alu Repeat Sequences
by Eva Malatinkova, Jordan Thomas, Ward De Spiegelaere, Sofie Rutsaert, Anna Maria Geretti, Georgios Pollakis, William A. Paxton, Linos Vandekerckhove and Alessandra Ruggiero
Life 2021, 11(12), 1410; https://doi.org/10.3390/life11121410 - 16 Dec 2021
Cited by 6 | Viewed by 2915
Abstract
Integrated HIV-1 DNA persists despite antiretroviral therapy and can fuel viral rebound following treatment interruption. Hence, methods to specifically measure the integrated HIV-1 DNA portion only are important to monitor the reservoir in eradication trials. Here, we provide an up-to-date overview of the [...] Read more.
Integrated HIV-1 DNA persists despite antiretroviral therapy and can fuel viral rebound following treatment interruption. Hence, methods to specifically measure the integrated HIV-1 DNA portion only are important to monitor the reservoir in eradication trials. Here, we provide an up-to-date overview of the literature on the different approaches used to measure integrated HIV-1 DNA. Further, we propose an implemented standard-curve free assay to quantify integrated HIV-1 DNA, so-called Alu-5LTR PCR, which utilises novel primer combinations. We tested the Alu-5LTR PCR in 20 individuals on suppressive ART for a median of nine years; the results were compared to those produced with the standard-free Alu-gag assay. The numbers of median integrated HIV-1 DNA copies were 5 (range: 1–12) and 14 (5–26) with the Alu-gag and Alu-5LTR, respectively. The ratios between Alu-gag vs Alu-5LTR results were distributed within the cohort as follows: most patients (12/20, 60%) provided ratios between 2–5, with 3/20 (15%) and 5/20 (25%) being below or above this range, respectively. Alu-5LTR assay sensitivity was also determined using an “integrated standard”; the data confirmed the increased sensitivity of the assay, i.e., equal to 0.25 proviruses in 10,000 genomes. This work represents an improvement in the field of measuring proviral HIV-1 DNA that could be employed in future HIV-1 persistence and eradication studies. Full article
(This article belongs to the Section Epidemiology)
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