bluuebunny/crossref_metadata_2025 huggingface dataset:
Pressure Adaptations in Deep-Sea Moritella Dihydrofolate Reductases: Compressibility versus Stability
Authors: Penhallurick Ryan W. , Ichiye Toshiko
Published: November 2021

Proteins from “pressure-loving” piezophiles appear to adapt by greater compressibility via larger total cavity volume. However, larger cavities in proteins have been associated with lower unfolding pressures. Here, dihydrofolate reductase (DHFR) from a moderate piezophile Moritella profunda (Mp) isolated at ~2.9 km in depth and from a hyperpiezophile Moritella yayanosii (My) isolated at ~11 km in depth were compared using molecular dynamics simulations. Although previous simulations indicate that MpDHFR is more compressible than a mesophile DHFR, here the average properties and a quasiharmonic analysis indicate that MpDHFR and MyDHFR have similar compressibilities. A cavity analysis also indicates that the three unique mutations in MyDHFR are near cavities, although the cavities are generally similar in size in both. However, while a cleft overlaps an internal cavity, thus forming a pathway from the surface to the interior in MpDHFR, the unique residue Tyr103 found in MyDHFR forms a hydrogen bond with Leu78, and the sidechain separates the cleft from the cavity. Thus, while Moritella DHFR may generally be well suited to high-pressure environments because of their greater compressibility, adaptation for greater depths may be to prevent water entry into the interior cavities.
Quantitative Analysis of Factors Regulating Angiogenesis for Stem Cell Therapy
Authors: Shimazaki Takahiro , Noro Nobuhiro , Hagikura Kazuhiro , Matsumoto Taro , Yoshida-Noro Chikako
Published: November 2021

(1) Background: The control of angiogenesis is essential in disease treatment. We investigated angiogenesis-promoting or -suppressing factors and their molecular mechanisms. (2) Methods: Angiogenesis from HUVECs was quantitatively analyzed using the Angiogenesis Analysis Kit (Kurabo, Osaka, Japan). Human rAng-1-producing 107-35 CHO cells or mouse DFAT-D1 cells were co-cultured with HUVEC. Antioxidant polyphenols were added to the culture. Gene expression was analyzed by RT-PCR. (3) Results: The addition of rAng-1-producing cells, their culture supernatant, or commercially available rAng-1 showed a promoting effect on angiogenesis. The co-culture of DFAT-D1 cells promoted angiogenesis. Polyphenols showed a dose-dependent inhibitory effect on angiogenesis. Luteolin and quercetin showed remarkable anti-angiogenic effects. The expression of vWF, Flk1, and PECAM-1 was increased by adding rAng-1-producing cell culture supernatant. Polyphenols suppressed these genes. Apigenin and luteolin markedly suppressed α-SMA and Flk1. Resveratrol and quercetin enhanced the expression of PPARγ, and luteolin suppressed the expression of COX-1. The expression of endothelial nitric oxide synthase (eNOS), an oxidative stress-related gene, was slightly increased by luteolin. These results suggest that polyphenols induce ROS reduction. (4) Conclusions: We showed the promoting effect of Ang-1 or DFAT and the suppressing effect of polyphenols on angiogenesis and studied their molecular mechanisms. These results help control angiogenesis in regenerative therapy.
Impact of Cryopreservation on Motile Subpopulations and Tyrosine-Phosphorylated Regions of Ram Spermatozoa during Capacitating Conditions
Authors: Peris-Frau Patricia , Sánchez-Ajofrín Irene , Martín Maestro Alicia , Maside Carolina , Medina-Chávez Daniela Alejandra , García-Álvarez Olga , Fernández-Santos María del Rocío , Montoro Vidal , Garde José Julián , Ramón Manuel , Soler Ana Josefa
Published: November 2021

The heterogeneous nature of ejaculates highlights the relevance of studying the behavior of different sperm subpopulations. Changes in sperm motility and the increase in tyrosine phosphorylation are key events that usually occur during capacitation and can be modified by the cryopreservation process. However, the relationship between both events remains poorly defined throughout capacitation in the different sperm subpopulations. Fresh and frozen-thawed spermatozoa were incubated in capacitating (CAP) and non-capacitating (NC) media up to 240 min. Sperm kinematics, tyrosine phosphorylation and mitochondrial activity were measured by the CASA system and imaging flow cytometry. Four motile sperm subpopulations (SP) were identified in fresh and frozen-thawed ram semen after the cluster analysis. Incubation under CAP conditions over time led to greater changes in the percentage of spermatozoa included in each subpopulation compared to NC conditions, being different between fresh and frozen-thawed spermatozoa. The SP1, characterized by slow spermatozoa, progressively increased after 15 min in frozen-thawed samples incubated in both media but not in fresh ones. The SP4, characterized by fast and non-linear spermatozoa, showed a marked increase during CAP, but not under NC conditions, occurring more rapidly in frozen-thawed spermatozoa. This subpopulation (SP4) was also the only one positively and strongly correlated with mitochondrial activity and all phosphorylated sperm regions during capacitation, either in fresh or frozen-thawed samples. Our results indicated that in vitro capacitation induced significant changes in the distribution of motile sperm subpopulations, being affected by cryopreservation. Notwithstanding, the subpopulation which probably represents hyperactivated-like spermatozoa (SP4) also increased in frozen-thawed samples, occurring faster and simultaneously to the increment of mitochondrial activity and tyrosine phosphorylation of different sperm regions.
Transcriptomic Profile of New Gene Markers Encoding Proteins Responsible for Structure of Porcine Ovarian Granulosa Cells
Authors: Kulus Jakub , Kulus Magdalena , Kranc Wiesława , Jopek Karol , Zdun Maciej , Józkowiak Małgorzata , Jaśkowski Jędrzej M. , Piotrowska-Kempisty Hanna , Bukowska Dorota , Antosik Paweł , Mozdziak Paul , Kempisty Bartosz
Published: November 2021

The extracellular matrix (ECM) in granulosa cells is functionally very important, and it is involved in many processes related to ovarian follicle growth and ovulation. The aim of this study was to describe the expression profile of genes within granulosa cells that are associated with extracellular matrix formation, intercellular signaling, and cell–cell fusion. The material for this study was ovaries of sexually mature pigs obtained from a commercial slaughterhouse. Laboratory-derived granulosa cells (GCs) from ovarian follicles were cultured in a primary in vitro culture model. The extracted genetic material (0, 48, 96, and 144 h) were subjected to microarray expression analysis. Among 81 genes, 66 showed increased expression and only 15 showed decreased expression were assigned to 7 gene ontology groups “extracellular matrix binding”, “extracellular matrix structural constituent”, “binding, bridging”, “cadherin binding”, “cell adhesion molecule binding”, “collagen binding” and “cadherin binding involved in cell-cell adhesion”. The 10 genes with the highest expression (POSTN, ITGA2, FN1, LAMB1, ITGB3, CHI3L1, PCOLCE2, CAV1, DCN, COL14A1) and 10 of the most down-regulated (SPP1, IRS1, CNTLN, TMPO, PAICS, ANK2, ADAM23, ABI3BP, DNAJB1, IGF1) were selected for further analysis. The results were validated by RT-qPCR. The current results may serve as preliminary data for further analyses using in vitro granulosa cell cultures in assisted reproduction technologies, studies of pathological processes in the ovary as well as in the use of the stemness potential of GCs.
Effects of Ciliate Infection on the Activities of Two Antioxidant Enzymes (SOD and CAT) in Captive Coral (Goniopora columna) and Evaluation of Drug Therapy
Authors: Cheng Chiu-Min , Cheng Yu-Rong , Ding De-Sing , Chen Ya-Ting , Sun Wei-Ting , Pan Chih-Hung
Published: November 2021

Ciliate infection is a serious parasitic disease of coral. Infected coral rots and dies in a short time. In addition to killing corals by infecting them in the oceans, ciliate infection also poses a threat to corals farmed on a large scale. In this study, two antioxidant enzymes (SOD and CAT) were used to judge the stress response in Goniopora columna after infection, and KCl and H2O2 were used to evaluate the therapeutic effect. The results showed that SOD and CAT increased during the early stage of infection but decreased with the extension of infection time. In terms of drug therapy, it was found that the treatment of ciliate infection with 1.5% of KCl had no significant effect on SOD and CAT of G. columna. The morphological changes of zooxanthellae, chlorophyll a, and coral were not significant. H2O2 leads to a stress response and polyp contraction. In conclusion, 1.5% of KCl can be used in the selection of drugs to treat ciliate infection.
Pseudomonas fluorescens Showing Antifungal Activity against Macrophomina phaseolina, a Severe Pathogenic Fungus of Soybean, Produces Phenazine as the Main Active Metabolite
Authors: Castaldi Stefany , Masi Marco , Sautua Francisco , Cimmino Alessio , Isticato Rachele , Carmona Marcelo , Tuzi Angela , Evidente Antonio
Published: November 2021

Pseudomonas fluorescens 9 and Bacillus subtilis 54, proposed as biofungicides to control Macrophomina phaseolina, a dangerous pathogen of soybean and other crops, were grown in vitro to evaluate their ability to produce metabolites with antifungal activity. The aim of the manuscript was to identify the natural compounds responsible for their antifungal activity. Only the culture filtrates of P. fluorescens 9 showed strong antifungal activity against M. phaseolina. Its organic extract contained phenazine and mesaconic acid (1 and 2), whose antifungal activity was tested against M. phaseolina, as well as Cercospora nicotianae and Colletotrichum truncatum, other pathogens of soybean; however, only compound 1 exhibited activity. The antifungal activity of compound 1 was compared to phenazine-1-carboxylic acid (PCA, 3), 2-hydroxyphenazine (2-OH P, 4), and various semisynthetic phenazine nitro derivatives in order to perform a structure–activity relationship (SAR) study. PCA and phenazine exhibited the same percentage of growth inhibition in M. phaseolina and C. truncatum, whereas PCA (3) showed lower activity against C. nicotianae than phenazine. 2-Hydroxyphenazine (4) showed no antifungal activity against M. phaseolina. The results of the SAR study showed that electron attractor (COOH and NO2) or repulsor (OH) groups significantly affect the antifungal growth, as well as their α- or β-location on the phenazine ring. Both PCA and phenazine could be proposed as biopesticides to control the soybean pathogens M. phaseolina, C. nicotianae, and C. truncatum, and these results should prompt an investigation of their large-scale production and their suitable formulation for greenhouse and field applications.
Opposite Effects of Chronic Central Leptin Infusion on Activation of Insulin Signaling Pathways in Adipose Tissue and Liver Are Related to Changes in the Inflammatory Environment
Authors: Barrios Vicente , Campillo-Calatayud Ana , Guerra-Cantera Santiago , Canelles Sandra , Martín-Rivada Álvaro , Frago Laura M. , Chowen Julie A. , Argente Jesús
Published: November 2021

Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling.
Novel Bi-Modular GH19 Chitinase with Broad pH Stability from a Fibrolytic Intestinal Symbiont of Eisenia fetida, Cellulosimicrobium funkei HY-13
Authors: Bai Lu , Kim Jonghoon , Son Kwang-Hee , Chung Chung-Wook , Shin Dong-Ha , Ku Bon-Hwan , Kim Do , Park Ho-Yong
Published: November 2021

Endo-type chitinase is the principal enzyme involved in the breakdown of N-acetyl-d-glucosamine-based oligomeric and polymeric materials through hydrolysis. The gene (966-bp) encoding a novel endo-type chitinase (ChiJ), which is comprised of an N-terminal chitin-binding domain type 3 and a C-terminal catalytic glycoside hydrolase family 19 domain, was identified from a fibrolytic intestinal symbiont of the earthworm Eisenia fetida, Cellulosimicrobium funkei HY-13. The highest endochitinase activity of the recombinant enzyme (rChiJ: 30.0 kDa) toward colloidal shrimp shell chitin was found at pH 5.5 and 55 °C and was considerably stable in a wide pH range (3.5–11.0). The enzyme exhibited the highest biocatalytic activity (338.8 U/mg) toward ethylene glycol chitin, preferentially degrading chitin polymers in the following order: ethylene glycol chitin > colloidal shrimp shell chitin > colloidal crab shell chitin. The enzymatic hydrolysis of N-acetyl-β-d-chitooligosaccharides with a degree of polymerization from two to six and colloidal shrimp shell chitin yielded primarily N,N′-diacetyl-β-d-chitobiose together with a small amount of N-acetyl-d-glucosamine. The high chitin-degrading ability of inverting rChiJ with broad pH stability suggests that it can be exploited as a suitable biocatalyst for the preparation of N,N′-diacetyl-β-d-chitobiose, which has been shown to alleviate metabolic dysfunction associated with type 2 diabetes.
Design of α/β-Hybrid Peptide Ligands of α4β1 Integrin Equipped with a Linkable Side Chain for Chemoselective Biofunctionalization of Microstructured Materials
Authors: Anselmi Michele , Baiula Monica , Santino Federica , Zhao Junwei , Spampinato Santi , Calonghi Natalia , Gentilucci Luca
Published: November 2021

Arg-Gly-Asp (RGD)-binding integrins, e.g., αvβ3, αvβ1, αvβ5 integrins, are currently regarded as privileged targets for the delivery of diagnostic and theranostic agents, especially in cancer treatment. In contrast, scarce attention has been paid so far to the diagnostic opportunities promised by integrins that recognize other peptide motifs. In particular, α4β1 integrin is involved in inflammatory, allergic, and autoimmune diseases, therefore, it represents an interesting therapeutic target. Aiming at obtaining simple, highly stable ligands of α4β1 integrin, we designed hybrid α/β peptidomimetics carrying linkable side chains for the expedient functionalization of biomaterials, nano- and microparticles. We identified the prototypic ligands MPUPA-(R)-isoAsp(NHPr)-Gly-OH (12) and MPUPA-Dap(Ac)-Gly-OH (13) (MPUPA, methylphenylureaphenylacetic acid; Dap, 2,3-diamino propionic acid). Modification of 12 and 13 by introduction of flexible linkers at isoAsp or Dap gave 49 and 50, respectively, which allowed for coating with monolayers (ML) of flat zeolite crystals. The resulting peptide–zeolite MLs were able to capture selectively α4β1 integrin-expressing cells. In perspective, the α4β1 integrin ligands identified in this study can find applications for preparing biofunctionalized surfaces and diagnostic devices to control the progression of α4β1 integrin-correlated diseases.
Is “Fuel Reduction” Justified as Fire Management in Spotted Owl Habitat?
Authors: Hanson Chad T.
Published: November 2021

The California Spotted Owl is an imperiled species that selects mature conifer forests for nesting and roosting while actively foraging in the “snag forest habitat” created when fire or drought kills most of the trees in patches. Federal agencies believe there are excess surface fuels in both of these habitat conditions in many of California’s forests due to fuel accumulation from decades of fire suppression and recent drought-related tree mortality. Accordingly, agencies such as the U.S. Forest Service are implementing widespread logging in Spotted Owl territories. While they acknowledge habitat degradation from such logging, and risks to the conservation of declining Spotted Owl populations, agencies hypothesize that such active forest management equates to effective fuel reduction that is needed to curb fire severity for the overall benefit of this at-risk species. In an initial investigation, I analyzed this issue in a large 2020 fire, the Creek Fire (153,738 ha), in the southern Sierra Nevada mountains of California. I found that pre-fire snag density was not correlated with burn severity. I also found that more intensive forest management was correlated to higher fire severity. My results suggest the fuel reduction approach is not justified and provide indirect evidence that such management represents a threat to Spotted Owls.
Effects of Force Modulation on Large Muscles during Human Cycling
Authors: Costa-García Álvaro , Úbeda Andrés , Shimoda Shingo
Published: November 2021

Voluntary force modulation is defined as the ability to tune the application of force during motion. However, the mechanisms behind this modulation are not yet fully understood. In this study, we examine muscle activity under various resistance levels at a fixed cycling speed. The main goal of this research is to identify significant changes in muscle activation related to the real-time tuning of muscle force. This work revealed significant motor adaptations of the main muscles utilized in cycling as well as positive associations between the force level and the temporal and spatial inter-cycle stability in the distribution of sEMG activity. From these results, relevant biomarkers of motor adaptation could be extracted for application in clinical rehabilitation to increase the efficacy of physical therapy.
Prevalence of Individuals at Clinical High-Risk of Psychosis in the General Population and Clinical Samples: Systematic Review and Meta-Analysis
Authors: Salazar de Pablo Gonzalo , Woods Scott W. , Drymonitou Georgia , de Diego Héctor , Fusar-Poli Paolo
Published: November 2021

(1) The consistency and magnitude of the prevalence of Clinical High-Risk for Psychosis (CHR-P) individuals are undetermined, limiting efficient detection of cases. We aimed to evaluate the prevalence of CHR-P individuals systematically assessed in the general population or clinical samples. (2) PRISMA/MOOSE-compliant (PROSPERO: CRD42020168672) meta-analysis of multiple databases until 21/01/21: a random-effects model meta-analysis, heterogeneity analysis, publication bias and quality assessment, sensitivity analysis—according to the gold-standard CHR-P and pre-screening instruments—leave-one-study-out analyses, and meta-regressions were conducted. (3) 35 studies were included, with 37,135 individuals tested and 1554 CHR-P individuals identified (median age = 19.3 years, Interquartile range (IQR) = 15.8–22.1; 52.2% females, IQR = 38.7–64.4). In the general population (k = 13, n = 26,835 individuals evaluated), the prevalence of the CHR-P state was 1.7% (95% Confidence Interval (CI) = 1.0–2.9%). In clinical samples (k = 22, n = 10,300 individuals evaluated), the prevalence of the CHR-P state was 19.2% (95% CI = 12.9–27.7%). Using a pre-screening instrument was associated with false negatives (5.6%, 95% CI = 2.2–13.3%) and a lower CHR-P prevalence (11.5%, 95% CI = 6.2–20.5%) compared to using CHR-P instruments only (28.5%, 95% CI = 23.0–34.7%, p = 0.003). (4) The prevalence of the CHR-P state is low in the general population and ten times higher in clinical samples. The prevalence of CHR-P may increase with a higher proportion of females in the general population and with a younger population in clinical samples. The CHR-P state may be unrecognized in routine clinical practice. These findings can refine detection and preventive strategies.
Nonlinear Numerical Assessment of Exterior Beam-Column Connections with Low-Strength Concrete
Authors: Abdelwahed Basem , Kaloop Mosbeh , El-Demerdash Waleed
Published: November 2021

The ductility and capacity of reinforced concrete beam-column connections depend mainly on the concrete’s strength and the provided reinforcements. This study investigates numerically the role of low-strength concrete in beam-column joints utilizing ABAQUS software. In this simulation, a newly developed stress-inelastic strain relationship for both confined and unconfined low-strength concrete is used. This study recommended a specific value of the concrete dilation angle for both substandard and standard joints. Also, stirrups’ yield strength value was found to play an insignificant role in improving the shear resistance of such joints with low-strength. In addition, the joint shear strength prediction using empirical models that implicitly consider the stirrups contribution in improving joint resistance was found to be better than the prediction of other models that explicitly consider the stirrups’ presence. The numerical results also showed that the use of a diagonal steel haunch as a joint retrofitting technique significantly increases the joint shear capacity and changes its brittle shear failure into a ductile beam flexural failure.
Influence of Compressive Strength of Concrete on Shear Strengthening of Reinforced Concrete Beams with Near Surface Mounted Carbon Fiber-Reinforced Polymer
Authors: Abdel-Jaber Ma’en , Abdel-Jaber Mu’tasim , Katkhuda Hasan , Shatarat Nasim , El-Nimri Rola
Published: November 2021

This paper investigates the effect of using near-surface mounted carbon fiber-reinforced polymer (NSM-CFRP) on the shear strengthening of rectangle beams with low strength concrete (f′c = 17 MPa), medium strength concrete (f′c = 32 MPa), and high strength concrete (f′c = 47 MPa). The experimental program was performed by installing NSM-CFRP strips vertically in three different configurations: aligned with the internal stirrups, one vertical NSM-CFRP strip between every two internal stirrups, and two vertical NSM-CFRP strips between every two internal stirrups. All tested beams were simply supported beams and tested under a three-point loading test. The experimental results were compared with the theoretical capacities that were calculated according to the ACI 440.2R-17 and finite element analysis (FEA) that was conducted using ABAQUS software to simulate the behavior of all beams. The experimental results indicated that using NSM-CFRP limited the failure mode of all beams to pure shear failure with no debonding or rapture of the carbon strips. Moreover, the use of NSM-CFRP proved its efficiency by increasing the shear capacity of all beams by a range of 4% to 66%, in which the best enhancement was recorded for the case of using two unaligned NSM-CFRP strips. In general, the experimental shear capacities increased with the increase in the compressive strength of all beams. On the other hand, the ACI 440.2R-17 was conservative in predicting the theoretical shear capacities, and the FEA results agreed well with the experimental results.
Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis
Authors: Pagano Alessandra , Breuzard Gilles , Parat Fabrice , Tchoghandjian Aurélie , Figarella-Branger Dominique , De Bessa Tiphany Coralie , Garrouste Françoise , Douence Alexis , Barbier Pascale , Kovacic Hervé
Published: November 2021

The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau contributed to glioblastoma in vivo tumorigenicity and analyzed its function in a 3D model of multicellular spheroids (MCS). Tau depletion significantly increased median mouse survival in an orthotopic glioblastoma xenograft model. This was accompanied by the inhibition of MCS growth and cell evasion, as well as decreased MCS compactness, implying N-cadherin mislocalization. Intracellular Signaling Array analysis revealed a defective activation of the PI3K/AKT pathway in Tau-depleted cells. Such a defect in PI3K/AKT signaling was responsible for reduced MCS growth and cell evasion, as demonstrated by the inhibition of the pathway in control MCS using LY294002 or Perifosine, which did not significantly affect Tau-depleted MCS. Finally, analysis of the glioblastoma TCGA dataset showed a positive correlation between the amount of phosphorylated Akt-Ser473 and the expression of MAPT RNA encoding Tau, underlining the relevance of our findings in glioblastoma disease. We suggest a role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis.
Oligoprogression in Non-Small Cell Lung Cancer
Authors: Harada Daijiro , Takigawa Nagio
Published: November 2021

We reviewed the literature on oligoprogressive disease (OPD) and local ablative therapy (LAT) in patients with advanced non-small cell lung cancer (NSCLC). The frequency of OPD varies depending on its definition and is estimated to be between 15–47%. The implications of the strategy of continuing the same anticancer agents beyond progressive disease after LAT with radiation therapy for OPD are based on the concept of progression in which only a small number of lesions, not more than about four, proliferate after chemotherapy. In the case of OPD harboring driver mutations such as EGFR, prospective studies are underway. However, evidence from retrospective studies support this strategy, which is currently recommended in some guidelines. The prognosis in OPD cases during the administration of an immune checkpoint inhibitor (ICI) is relatively promising. Additionally, LAT with radiation for OPD after the first-line treatment of ICI with cytotoxic chemotherapy may overcome the resistance to the combination drug therapy due to an abscopal effect. To achieve long-term survival in advanced-stage NSCLC, it is important to verify the optimal method and timing of the therapy through prospective comparative studies as well as patient selection based on patient characteristics and biomarker levels.
Homologous Recombination Repair Gene Mutation Characterization by Liquid Biopsy: A Phase II Trial of Olaparib and Abiraterone in Metastatic Castrate-Resistant Prostate Cancer
Authors: Carr T. Hedley , Adelman Carrie , Barnicle Alan , Kozarewa Iwanka , Luke Sally , Lai Zhongwu , Hollis Sally , Dougherty Brian , Harrington Elizabeth A. , Kang Jinyu , Saad Fred , Sala Nuria , Thiery-Vuillemin Antoine , Clarke Noel W. , Hodgson Darren , Barrett J. Carl
Published: November 2021

Background: Phase III randomized trial data have confirmed the activity for olaparib in homologous recombination repair (HRR) mutated metastatic castration-resistant prostate cancer (mCRPC) post next-generation hormonal agent (NHA) progression. Preclinical data have suggested the potential for a combined effect between olaparib and NHAs irrespective of whether an HRR gene alteration was present. NCT01972217 was a randomised double-blind Phase II study which evaluated olaparib and abiraterone versus placebo and abiraterone in mCRPC patients who had received prior chemotherapy containing docetaxel. The study showed that radiologic progression was significantly delayed by the combination of olaparib and abiraterone regardless of homologous recombination repair mutation (HRRm) status. The study utilized tumour, blood (germline), and circulating tumour DNA (ctDNA) analysis to profile patient HRRm status, but tumour tissue provision was not mandated, leading to relatively low tissue acquisition and DNA sequencing success rates not representative of real-world testing. Patients and methods: Further analysis of germline and ctDNA samples has been performed for the trial to characterize HRRm status more fully and robustly analyse patient response to treatment. Results: Germline and plasma testing increased the HRRm characterized population from 27% to 68% of 142 randomized patients. Tumour-derived variants were detectable with high confidence in 78% of patients with a baseline plasma sample (71% of randomized patients). There was high concordance across methodologies (plasma vs. tumour; plasma vs. germline). The HR for the exploratory analysis of radiographic progression-free survival was 0.54 (95% CI: 0.32–0.93) in favour of olaparib and abiraterone in the updated HRR wild type (HRRwt) group (n = 73) and 0.62 (95% CI: 0.23–1.65) in the HRRm group (n = 23). Conclusion: Our results confirm the value of plasma testing for HRRm status when there is insufficient high-quality tissue for multi-gene molecular testing. We show that patients with mCRPC benefit from the combination of olaparib and abiraterone treatment regardless of HRRm status. The combination is currently being further investigated in the Phase III PROpel trial.
Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1
Authors: Paret Claudia , Lehmann Nadine , Bender Hannah , Sprang Maximilian , Sommer Clemens J. , Cana Denis , Seidmann Larissa , Wingerter Arthur , Neu Marie A. , El Malki Khalifa , Alt Francesca , Roth Lea , Marini Federico , Ottenhausen Malte , Glaser Martin , Knuf Markus , Russo Alexandra , Faber Joerg
Published: November 2021

Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8+ cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.
Hybrids of Reduced Graphene Oxide Aerogel and CNT for Electrochemical O2 Reduction
Authors: Hernández-Ferrer Javier , Benito Ana M. , Maser Wolfgang K. , García-Bordejé Enrique
Published: November 2021

Carbon nanotubes (CNTs), graphene aerogels (GAs), and their hybrid (CNT-GA) prepared by hydrothermal treatment were tested in the electrocatalytic oxygen reduction reaction (ORR). The importance of porous structure derived from the combination of mesoporosity coming from CNTs with macroporosity stemming from GAs was evidenced because the hybrid carbon material exhibited synergistic performance in terms of kinetic current and onset potential. Different electrocatalysts were prepared based on these hybrids doped with nitrogen using different precursors and also supporting Fe nanoparticles. N-doped carbon hybrids showed higher electrocatalytic activity than their undoped counterparts. Nevertheless, both doped and undoped materials provided a mixed two and four electron reduction. On the other hand, the addition of a Fe precursor and phenanthroline to the CNT-GA allowed preparing an N-doped hybrid containing Fe nanoparticles which favored the 4-electron oxygen reduction to water, thus being an excellent candidate as a structured cathode in fuel cells.
Halide-Doping Effect of Strontium Cobalt Oxide Electrocatalyst and the Induced Activity for Oxygen Evolution in an Alkaline Solution
Authors: Ghanem Mohamed A. , Amer Mabrook S. , Al-Mayouf Abdullah M. , Arunachalam Prabhakarn , Weller Mark T.
Published: November 2021

Perovskites of strontium cobalt oxyhalides having the chemical formulae Sr2CoO4-xHx (H = F, Cl, and Br; x = 0 and 1) were prepared using a solid-phase synthesis approach and comparatively evaluated as electrocatalysts for oxygen evolution in an alkaline solution. The perovskite electrocatalyst crystal phase, surface morphology, and composition were examined by X-ray diffraction, a scanning electron microscope, and energy-dispersive X-ray (EDX) mapping. The electrochemical investigations of the oxyhalides catalysts showed that the doping of F, Cl, or Br into the Sr2CoO4 parent oxide enhances the electrocatalytic activity for the oxygen evolution reaction (OER) with the onset potential as well as the potential required to achieve a current density of 10 mA/cm2 shifting to lower potential values in the order of Sr2CoO4 (1.64, 1.73) > Sr2CoO3Br (1.61, 1.65) > Sr2CoO3Cl (1.53, 1.60) > Sr2CoO3F (1.50, 1.56) V vs. HRE which indicates that Sr2CoO3F is the most active electrode among the studied catalysts under static and steady-state conditions. Moreover, Sr2CoO3F demonstrates long-term stability and remarkably less charge transfer resistance (Rct = 36.8 ohm) than the other oxyhalide counterparts during the OER. The doping of the perovskites with halide ions particularly the fluoride-ion enhances the surface oxygen vacancy density due to electron withdrawal away from the Co-atom which improves the ionic and electronic conductivity as well as the electrochemical activity of the oxygen evolution in alkaline solution.
Methanation of CO2 Using MIL-53-Based Catalysts: Ni/MIL-53–Al2O3 versus Ni/MIL-53
Authors: Grad Oana , Blanita Gabriela , Lazar Mihaela D. , Mihet Maria
Published: November 2021

MIL-53 and the MIL-53–Al2O3 composite synthesized by a solvothermal procedure, with water as the only solvent besides CrCl3 and benzene-1,4-dicarboxylic acid (BDC), were used as catalytic supports to obtain the novel MIL-53-based catalysts Ni(10 wt.%)/MIL-53 and Ni(10 wt.%)/MIL-53–Al2O3. Ni nanoparticle deposition by an adapted double-solvent method leads to the uniform distribution of metallic particles, both smaller (≤10 nm) and larger ones (10–30 nm). MIL-53–Al2O3 and Ni/MIL-53–Al2O3 show superior thermal stability to MIL-53 and Ni/MIL-53, while MIL-53–Al2O3 samples combine the features of both MIL-53 and alumina in terms of porosity. The investigation of temperature’s effect on the catalytic performance in the methanation process (CO2:H2 = 1:5.2, GHSV = 4650 h−1) revealed that Ni/MIL-53 is more active at temperatures below 300 °C, and Ni/MIL-53–Al2O3 above 300 °C. Both catalysts show maximum CO2 conversion at 350 °C: 75.5% for Ni/MIL-53 (methane selectivity of 93%) and 88.8% for Ni/MIL-53–Al2O3 (methane selectivity of 98%). Stability tests performed at 280 °C prove that Ni/MIL-53–Al2O3 is a possible candidate for the CO2 methanation process due to its high CO2 conversion and CH4 selectivity, corroborated by the preservation of the structure and crystallinity of MIL-53 after prolonged exposure in the reaction medium.
The Role of Fibroblast Growth Factor (FGF) Signaling in Tissue Repair and Regeneration
Authors: Farooq Mariya , Khan Abdul Waheed , Kim Moon Suk , Choi Sangdun
Published: November 2021

Fibroblast growth factors (FGFs) are a large family of secretory molecules that act through tyrosine kinase receptors known as FGF receptors. They play crucial roles in a wide variety of cellular functions, including cell proliferation, survival, metabolism, morphogenesis, and differentiation, as well as in tissue repair and regeneration. The signaling pathways regulated by FGFs include RAS/mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)–protein kinase B (AKT), phospholipase C gamma (PLCγ), and signal transducer and activator of transcription (STAT). To date, 22 FGFs have been discovered, involved in different functions in the body. Several FGFs directly or indirectly interfere with repair during tissue regeneration, in addition to their critical functions in the maintenance of pluripotency and dedifferentiation of stem cells. In this review, we summarize the roles of FGFs in diverse cellular processes and shed light on the importance of FGF signaling in mechanisms of tissue repair and regeneration.
The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target
Authors: Ye Lingxiao , Zhu Zhengxin , Chen Xiaochuan , Zhang Haoran , Huang Jiaqi , Gu Shengxian , Zhao Xiaoyin
Published: November 2021

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment.
Retinal Protection from LED-Backlit Screen Lights by Short Wavelength Absorption Filters
Authors: Sanchez-Ramos Celia , Bonnin-Arias Cristina , Blázquez-Sánchez Vanesa , Aguirre-Vilacoro Victoria , Cobo Teresa , García-Suarez Olivia , Perez-Carrasco María Jesús , Alvarez-Peregrina Cristina , Vega José A.
Published: November 2021

(1) Background: Ocular exposure to intense light or long-time exposure to low-intensity short-wavelength lights may cause eye injury. Excessive levels of blue light induce photochemical damage to the retinal pigment and degeneration of photoreceptors of the outer segments. Currently, people spend a lot of time watching LED screens that emit high proportions of blue light. This study aims to assess the effects of light emitted by LED tablet screens on pigmented rat retinas with and without optical filters. (2) Methods: Commercially available tablets were used for exposure experiments on three groups of rats. One was exposed to tablet screens, the other was exposed to the tablet screens with a selective filter and the other was a control group. Structure, gene expression (including life/death, extracellular matrix degradation, growth factors, and oxidative stress related genes), and immunohistochemistry in the retina were compared among groups. (3) Results: There was a reduction of the thickness of the external nuclear layer and changes in the genes involved in cell survival and death, extracellular matrix turnover, growth factors, inflammation, and oxidative stress, leading decrease in cell density and retinal damage in the first group. Modulation of gene changes was observed when the LED light of screens was modified with an optical filter. (4) Conclusions: The use of short-wavelength selective filters on the screens contribute to reduce LED light-induced damage in the rat retina.
Induced Pluripotent Stem Cells as a Tool for Modeling Hematologic Disorders and as a Potential Source for Cell-Based Therapies
Authors: Pratumkaew Ponthip , Issaragrisil Surapol , Luanpitpong Sudjit
Published: November 2021

The breakthrough in human induced pluripotent stem cells (hiPSCs) has revolutionized the field of biomedical and pharmaceutical research and opened up vast opportunities for drug discovery and regenerative medicine, especially when combined with gene-editing technology. Numerous healthy and patient-derived hiPSCs for human disease modeling have been established, enabling mechanistic studies of pathogenesis, platforms for preclinical drug screening, and the development of novel therapeutic targets/approaches. Additionally, hiPSCs hold great promise for cell-based therapy, serving as an attractive cell source for generating stem/progenitor cells or functional differentiated cells for degenerative diseases, due to their unlimited proliferative capacity, pluripotency, and ethical acceptability. In this review, we provide an overview of hiPSCs and their utility in the study of hematologic disorders through hematopoietic differentiation. We highlight recent hereditary and acquired genetic hematologic disease modeling with patient-specific iPSCs, and discuss their applications as instrumental drug screening tools. The clinical applications of hiPSCs in cell-based therapy, including the next-generation cancer immunotherapy, are provided. Lastly, we discuss the current challenges that need to be addressed to fulfill the validity of hiPSC-based disease modeling and future perspectives of hiPSCs in the field of hematology.
Hepatitis-D Virus Infection Is Not Impaired by Innate Immunity but Increases Cytotoxic T-Cell Activity
Authors: Altstetter Sebastian Maximilian , Quitt Oliver , Pinci Francesca , Hornung Veit , Lucko Aaron Michael , Wisskirchen Karin , Jung Stephanie , Protzer Ulrike
Published: November 2021

Approximately 70 million humans worldwide are affected by chronic hepatitis D, which rapidly leads to liver cirrhosis and hepatocellular carcinoma due to chronic inflammation. The triggers and consequences of this chronic inflammation, induced by co-infection with the hepatitis D virus (HDV) and the hepatitis B virus (HBV), are poorly understood. Using CRISPR technology, we characterized the recognition of HDV mono- and co-infection by intracellular innate immunity and determined its influence on the viral life cycle and effector T-cell responses using different HBV and HDV permissive hepatoma cell lines. We showed that HDV infection is detected by MDA5 and -after a lag phase -induces a profound type I interferon response in the infected cells. The type I interferon response, however, was not able to suppress HDV replication or spread, thus providing a persistent trigger. Using engineered T-cells directed against the envelope proteins commonly used by HBV and HDV, we found that HDV immune recognition enhanced T-cell cytotoxicity. Interestingly, the T-cell effector function was enhanced independently of antigen presentation. These findings help to explain immune mediated tissue damage in chronic hepatitis D patients and indicate that combining innate triggers with T-cell activating therapies might allow for a curative approach.
The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity
Authors: Karwi Qutuba G. , Sun Qiuyu , Lopaschuk Gary D.
Published: November 2021

Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic patients is cardiovascular disease including diabetic cardiomyopathy. Therefore, understanding how diabetes increases the incidence of diabetic cardiomyopathy and how it mediates the major perturbations in cell signaling and energy metabolism should help in the development of therapeutics to prevent these perturbations. One of the significant metabolic alterations in diabetes is a marked increase in cardiac fatty acid oxidation rates and the domination of fatty acids as the major energy source in the heart. This increased reliance of the heart on fatty acids in the diabetic has a negative impact on cardiac function and structure through a number of mechanisms. It also has a detrimental effect on cardiac efficiency and worsens the energy status in diabetes, mainly through inhibiting cardiac glucose oxidation. Furthermore, accelerated cardiac fatty acid oxidation rates in diabetes also make the heart more vulnerable to ischemic injury. In this review, we discuss how cardiac energy metabolism is altered in diabetic cardiomyopathy and the impact of cardiac insulin resistance on the contribution of glucose and fatty acid to overall cardiac ATP production and cardiac efficiency. Furthermore, how diabetes influences the susceptibility of the myocardium to ischemia/reperfusion injury and the role of the changes in glucose and fatty acid oxidation in mediating these effects are also discussed.
Advanced Glycation End Products Increase Salivary Gland Hypofunction in d-Galactose-Induced Aging Rats and Its Prevention by Physical Exercise
Authors: Jung Woo Kwon , Park Su-Bin , Kim Hyung Rae , Ryu Hwa Young , Kim Yong Hwan , Kim Junghyun
Published: November 2021

A declined salivary gland function is commonly observed in elderly people. Advanced glycation end products (AGEs) are believed to contribute to the pathogenesis of aging. Although physical exercise is shown to increase various organ functions in human and experimental models, it is not known whether it has a similar effect in the salivary glands. In the present study, we evaluated the AGEs burden in the salivary gland in the aging process and the protective effect of physical exercise on age-related salivary hypofunction. To accelerate the aging process, rats were peritoneally injected with D-galactose for 6 weeks. Young control rats and d-galactose-induced aging rats in the old group were not exercised. The rats in the physical exercise group ran on a treadmill (12 m/min, 60 min/day, 3 days/week for 6 weeks). The results showed that the salivary flow rate and total protein levels in the saliva of the d-galactose-induced aging rats were reduced compared to those of the young control rats. Circulating AGEs in serum and secreted AGEs in saliva increased with d-galactose-induced aging. AGEs also accumulated in the salivary glands of these aging rats. The salivary gland of aging rats showed increased reactive oxygen species (ROS) generation, loss of acinar cells, and apoptosis compared to young control mice. However, physical exercise suppressed all of these age-related salivary changes. Overall, physical exercise could provide a beneficial option for age-related salivary hypofunction.