bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxia and Ezrin Expression in Primary Melanoma Have High Prognostic Relevance
Authors: Maccio Umberto , Mihic Alanna , Lenggenhager Daniela , Kolm Isabel , Mittmann Christiane , Heikenwälder Mathias , Lorentzen Anna , Mihic-Probst Daniela
Published: September 2022

Hypoxia affects tumor aggressiveness and activates pathways associated with epithelial mesenchymal transition (EMT) which are crucial for tumor progress. In this study, the correlation of hypoxia and EMT with sentinel lymph node status and tumor-specific survival was investigated in primary melanomas. CD34 for capillary count and Hypoxia inducible factor-1α (HIF-1α) as hypoxia indicators as well as Ezrin and L1-Cell Adhesion Molecule (L1CAM), both critical proteins contributing to EMT, were analyzed using immunohistochemistry in 49 melanoma patients with long follow-up (F/U, mean 110 months; range 12–263 months). We found a significant correlation between Breslow tumor thickness and Ezrin expression (p = 0.018). L1CAM expression in primary melanoma was significantly associated with HIF-1α expression (p < 0.0001) and sentinel lymph node metastasis (p = 0.011). Furthermore, low capillary count, reflecting hypoxic condition, was significantly associated with Ezrin expression (p = 0.047) and decreased tumor-specific survival (p = 0.035). In addition, patients with high Ezrin expression in their primary melanoma had a dramatic loss of life early in their F/U period (mean survival time 29 months; range 15–44 month). Our results highlight the relevance of Ezrin, L1CAM and HIF-1α as prognostic markers in melanoma patients. Additionally, we demonstrate that hypoxia in primary melanoma affects EMT and is at least partly responsible for early metastatic dissemination.
Comparative Analysis of Serum microRNA in Diagnosed Ocular Sarcoidosis versus Idiopathic Uveitis with Ocular Manifestations of Sarcoidosis
Authors: Saito Shoko , Keino Hiroshi , Takasaki Ichiro , Abe Shinya , Kohno Hideo , Ichihara Kousuke , Hayashi Isami , Nakayama Makiko , Tsuboshita Yukihiro , Miyoshi Sawako , Okamoto Susumu , Okada Annabelle A.
Published: September 2022

“Idiopathic” is the most common category of uveitis, representing cases in which a specific diagnosis has not been established despite work-up. Sarcoidosis is a systemic granulomatous disorder affecting multiple organs including the lungs, skin, kidneys, and eyes. We used microRNA (miRNA) microarrays to investigate serum miRNA profiles of patients with ocular sarcoidosis as diagnosed by specific criteria (diagnosed ocular sarcoidosis), and patients with idiopathic uveitis characterized by ocular manifestations of sarcoidosis (suspected ocular sarcoidosis). Principal component analysis (PCA) and hierarchical clustering showed that serum miRNA profiles of diagnosed ocular sarcoidosis and suspected ocular sarcoidosis were both clearly distinguishable from healthy controls. Furthermore, comparative analysis of the miRNA profiles showed highly similar patterns between diagnosed ocular sarcoidosis and suspected ocular sarcoidosis. Pathway analysis revealed common pathways were involved in the two groups, including those of WNT signaling and TGF-beta signaling. Our study demonstrated a high overlap of differentially expressed serum miRNAs in patients with diagnosed ocular sarcoidosis and suspected ocular sarcoidosis, suggesting that these groups share a similar underlying pathology and may represent possible variants of the disease. Characterization of serum miRNA profiles may provide an opportunity for earlier diagnosis and treatment, and may inform more accurate clinical prognosis in patients with an ocular sarcoidosis phenotype.
Evaluation of Plant Ceramide Species-Induced Exosome Release from Neuronal Cells and Exosome Loading Using Deuterium Chemistry
Authors: Murai Yuta , Honda Takumi , Yuyama Kohei , Mikami Daisuke , Eguchi Koichi , Ukawa Yuichi , Usuki Seigo , Igarashi Yasuyuki , Monde Kenji
Published: September 2022

The extracellular accumulation of aggregated amyloid-β (Aβ) in the brain leads to the early pathology of Alzheimer’s disease (AD). The administration of exogenous plant-type ceramides into AD model mice can promote the release of neuronal exosomes, a subtype of extracellular vesicles, that can mediate Aβ clearance. In vitro studies showed that the length of fatty acids in mammalian-type ceramides is crucial for promoting neuronal exosome release. Therefore, investigating the structures of plant ceramides is important for evaluating the potential in releasing exosomes to remove Aβ. In this study, we assessed plant ceramide species with D-erythro-(4E,8Z)-sphingadienine and D-erythro-(8Z)-phytosphingenine as sphingoid bases that differ from mammalian-type species. Some plant ceramides were more effective than mammalian ceramides at stimulating exosome release. In addition, using deuterium chemistry-based lipidomics, most exogenous plant ceramides were confirmed to be derived from exosomes. These results suggest that the ceramide-dependent upregulation of exosome release may promote the release of exogenous ceramides from cells, and plant ceramides with long-chain fatty acids can effectively release neuronal exosomes and prevent AD pathology.
Stemazole Promotes Oligodendrocyte Precursor Cell Survival In Vitro and Remyelination In Vivo
Authors: Zhu Yizi , Chen Mingzhu , Zhang Yubo , Han Mei
Published: September 2022

Maintaining the normal function of oligodendrocyte precursor cells (OPCs) and protecting OPCs from damage is the basis of myelin regeneration in multiple sclerosis (MS). In this paper, we investigated the effect of stemazole, a novel small molecule, on the promotion of oligodendrocyte precursor cell survival and remyelination. The results show that stemazole enhanced the survival rate and the number of clone formation in a dose-dependent manner and decreased the percentage of cell apoptosis. In particular, the number of cell clones was increased up to 6-fold (p < 0.001) in the stemazole group compared with the control group. In vivo, we assessed the effect of stemazole on recovering the motor dysfunction and demyelination induced by cuprizone (CPZ). The results show that stemazole promoted the recovery of motor dysfunction and the repair of myelin sheaths. Compared with the CPZ group, the stemazole group showed a 30.46% increase in the myelin area (p < 0.001), a 37.08% increase in MBP expression (p < 0.01), and a 1.66-fold increase in Olig2 expression (p < 0.001). Histologically, stemazole had a better effect than the positive control drugs. In conclusion, stemazole promoted OPC survival in vitro and remyelination in vivo, suggesting that this compound may be used as a therapeutic agent against demyelinating disease.
In Vitro Rescue of the Bile Acid Transport Function of ABCB11 Variants by CFTR Potentiators
Authors: Mareux Elodie , Lapalus Martine , Ben Saad Amel , Zelli Renaud , Lakli Mounia , Riahi Yosra , Almes Marion , Banet Manon , Callebaut Isabelle , Decout Jean-Luc , Falguières Thomas , Jacquemin Emmanuel , Gonzales Emmanuel
Published: September 2022

ABCB11 is responsible for biliary bile acid secretion at the canalicular membrane of hepatocytes. Variations in the ABCB11 gene cause a spectrum of rare liver diseases. The most severe form is progressive familial intrahepatic cholestasis type 2 (PFIC2). Current medical treatments have limited efficacy. Here, we report the in vitro study of Abcb11 missense variants identified in PFIC2 patients and their functional rescue using cystic fibrosis transmembrane conductance regulator potentiators. Three ABCB11 disease-causing variations identified in PFIC2 patients (i.e., A257V, T463I and G562D) were reproduced in a plasmid encoding an Abcb11-green fluorescent protein. After transfection, the expression and localization of the variants were studied in HepG2 cells. Taurocholate transport activity and the effect of potentiators were studied in Madin–Darby canine kidney (MDCK) clones coexpressing Abcb11 and the sodium taurocholate cotransporting polypeptide (Ntcp/Slc10A1). As predicted using three-dimensional structure analysis, the three variants were expressed at the canalicular membrane but showed a defective function. Ivacaftor, GLP1837, SBC040 and SBC219 potentiators increased the bile acid transport of A257V and T463I and to a lesser extent, of G562D Abcb11 missense variants. In addition, a synergic effect was observed when ivacaftor was combined with SBC040 or SBC219. Such potentiators could represent new pharmacological approaches for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the function of the transporter.
Studies on Mapping Plant Genes That Confer Tolerance to Abiotic Stresses
Authors: Wang Richard R.-C.
Published: September 2022

Climate change is affecting the Earth’s environment through temperature fluctuation, rainfall patterns, wind, and radiation [...]
Increasing the Grain Yield and Grain Protein Content of Common Wheat (Triticum aestivum) by Introducing Missense Mutations in the Q Gene
Authors: Chen Qing , Guo Zhenru , Shi Xiaoli , Wei Meiqiao , Fan Yazhen , Zhu Jing , Zheng Ting , Wang Yan , Kong Li , Deng Mei , Cao Xinyou , Wang Jirui , Wei Yuming , Jiang Qiantao , Jiang Yunfeng , Chen Guoyue , Zheng Youliang , Qi Pengfei
Published: September 2022

Grain yield (GY) and grain protein content (GPC) are important traits for wheat breeding and production; however, they are usually negatively correlated. The Q gene is the most important domestication gene in cultivated wheat because it influences many traits, including GY and GPC. Allelic variations in the Q gene may positively affect both GY and GPC. Accordingly, we characterized two new Q alleles (Qs1 and Qc1-N8) obtained through ethyl methanesulfonate-induced mutagenesis. Compared with the wild-type Q allele, Qs1 contains a missense mutation in the sequence encoding the first AP2 domain, whereas Qc1-N8 has two missense mutations: one in the sequence encoding the second AP2 domain and the other in the microRNA172-binding site. The Qs1 allele did not significantly affect GPC or other processing quality parameters, but it adversely affected GY by decreasing the thousand kernel weight and grain number per spike. In contrast, Qc1-N8 positively affected GPC and GY by increasing the thousand kernel weight and grain number per spike. Thus, we generated novel germplasm relevant for wheat breeding. A specific molecular marker was developed to facilitate the use of the Qc1-N8 allele in breeding. Furthermore, our findings provide useful new information for enhancing cereal crops via non-transgenic approaches.
Hepatic Stellate Cell Modulates the Immune Microenvironment in the Progression of Hepatocellular Carcinoma
Authors: Wang Pei-Wen , Lin Tung-Yi , Yang Pei-Ming , Yeh Chau-Ting , Pan Tai-Long
Published: September 2022

Hepatocellular carcinoma (HCC) is a major cause of increases in the mortality rate due to cancer that usually develops in patients with liver fibrosis and impaired hepatic immunity. Hepatic stellate cells (HSCs) may directly or indirectly crosstalk with various hepatic cells and subsequently modulate extracellular remodeling, cell invasion, macrophage conversion, and cancer deterioration. In this regard, the tumor microenvironment created by activated HSC plays a critical role in mediating pathogenesis and immune escape during HCC progression. Herein, intermediately differentiated human liver cancer cell line (J5) cells were co-cultured with HSC-conditioned medium (HSC-CM); changes in cell phenotype and cytokine profiles were analyzed to assess the impact of HSCs on the development of hepatoma. The stage of liver fibrosis correlated significantly with tumor grade, and the administration of conditioned medium secreted by activated HSC (aHSC-CM) could induce the expression of N-cadherin, cell migration, and invasive potential, as well as the activity of matrix metalloproteinases in J5 cells, implying that aHSC-CM could trigger the epithelial-mesenchymal transition (EMT). Next, the HSC-CM was further investigated and network analysis indicated that specific cytokines and soluble proteins, such as activin A, released from activated HSCs could remarkably affect the tumor-associated immune microenvironment involved in macrophage polarization, which would, in turn, diminish a host’s immune surveillance and drive hepatoma cells into a more malignant phenotype. Together, our findings provide a novel insight into the integral roles of HSCs to enhance hepatocarcinogenesis through their immune-modulatory properties and suggest that HSC may serve as a potent target for the treatment of advanced HCC.
Effect of Heading Date on the Starch Structure and Grain Yield of Rice Lines with Low Gelatinization Temperature
Authors: Crofts Naoko , Hareyama Kaito , Miura Satoko , Hosaka Yuko , Oitome Naoko F. , Fujita Naoko
Published: September 2022

Early flowering trait is essential for rice cultivars grown at high latitude since delayed flowering leads to seed development at low temperature, which decreases yield. However, early flowering at high temperature promotes the formation of chalky seeds with low apparent amylose content and high starch gelatinization temperature, thus affecting grain quality. Deletion of starch synthase IIa (SSIIa) shows inverse effects of high temperature, and the ss2a mutant shows higher apparent amylose content and lower gelatinization temperature. Heading date 1 (Hd1) is the major regulator of flowering time, and a nonfunctional hd1 allele is required for early flowering. To understand the relationship among heading date, starch properties, and yield, we generated and characterized near-isogenic rice lines with ss2a Hd1, ss2a Hd1 hd1, and ss2a hd1 genotypes. The ss2a Hd1 line showed the highest plant biomass; however, its grain yield varied by year. The ss2a Hd1 hd1 showed higher total grain weight than ss2a hd1. The ss2a hd1 line produced the lowest number of premature seeds and showed higher gelatinization temperature and lower apparent amylose content than ss2a Hd1. These results highlight Hd1 as the candidate gene for developing high-yielding rice cultivars with the desired starch structure.
Structural Insights into the Phosphorylation-Enhanced Deubiquitinating Activity of UCHL3 and Ubiquitin Chain Cleavage Preference Analysis
Authors: Ren Yujing , Yu Beiming , Zhou Lihui , Wang Feng , Wang Yanfeng
Published: September 2022

Ubiquitin C-terminal hydrolase-L3 (UCHL3), an important member of the ubiquitin C-terminal hydrolase family, is involved in DNA repair and cancer development. UCHL3 can cleave only complexes of monoubiquitin and its conjugates, such as Ub-AMC, His, or small ubiquitin-like modifier, but not polyubiquitin chains. Phosphorylation of Ser75 promotes the cleavage activity of UCHL3 toward poly-ubiquitin chains in vivo, but biochemical evidence in vitro is still lacking. Here, we first analyzed the structure of simulated phosphorylated UCHL3S75E and the complex of UCHL3S75E with Ub-PA and preliminarily explained the structural mechanism of phosphorylation-enhanced UCHL3 deubiquitinating activity. Additionally, the cleavage activity of UCHL3 toward different types of synthesized poly-ubiquitin chains in vitro was tested. The results showed that purified UCHL3S75E enhanced the cleavage activity toward Ub-AMC compared to UCHL3WT. Meanwhile, UCHL3S75E and UCHL3WT did not show any cleavage activity for different types of di-ubiquitin and tri-ubiquitin chains. However, UCHL3 could hydrolyze the K48 tetra-ubiquitin chain, providing compelling in vitro evidence confirming previous in vivo results. Thus, this study shows that UCHL3 can hydrolyze and has a cleavage preference for polyubiquitin chains, which expands our understanding of the phosphorylation regulation of UCHL3 and lays a foundation for further elucidation of its physiological role.
Surgical Treatment of Glioblastoma: State-of-the-Art and Future Trends
Authors: Sales Arthur , Beck Jürgen , Schnell Oliver , Fung Christian , Meyer Bernhard , Gempt Jens
Published: September 2022

Glioblastoma (GBM) is a highly aggressive disease and is associated with poor prognosis despite treatment advances in recent years. Surgical resection of tumor remains the main therapeutic option when approaching these patients, especially when combined with adjuvant radiochemotherapy. In the present study, we conducted a comprehensive literature review on the state-of-the-art and future trends of the surgical treatment of GBM, emphasizing topics that have been the object of recent study.
Tocilizumab for the Treatment of Familial Mediterranean Fever—A Randomized, Double-Blind, Placebo-Controlled Phase II Study
Authors: Henes Joerg C. , Saur Sebastian , Kofler David M. , Kedor Claudia , Meisner Christoph , Schuett Marion , Krusche Martin , Koetter Ina , Xenitidis Theodoros , Schulze-Koops Hendrik , Feist Eugen
Published: September 2022

Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician’s global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial.
Is Brain Network Efficiency Reduced in Young Survivors of Acute Lymphoblastic Leukemia?—Evidence from Individual-Based Morphological Brain Network Analysis
Authors: Zhuang Ying , Qian Long , Wu Lin , Chen Linglong , He Fei , Zhang Shouhua , Cheung Gerald L. , Zhou Fuqing , Gong Honghan
Published: September 2022

Altered cerebral structure and function have been observed in young survivors of acute lymphoblastic leukemia (ALL). However, the topological organization of the morphological brain networks (MBNs) has not yet been investigated at the individual level. Twenty-three young survivors of ALL and twenty healthy controls (HCs) were recruited and underwent T1-weighted magnetic resonance imaging (MRI) scanning. After preprocessing and segmentation, individual-based MBNs were constructed based on the morphological similarity of gray matter using the combined Euclidean distance. Young survivors showed a significantly lower global clustering coefficient (p = 0.008) and local efficiency (p = 0.035) compared with HCs. In addition, ALL survivors exhibited bidirectional alterations (decreases and increases) in nodal centrality and efficiency around the Rolandic operculum and posterior occipital lobe (p < 0.05, false discovery rate (FDR) corrected). Altered nodal topological efficiencies were associated with off-therapy duration and verbal memory capacity in the digit span test (p < 0.05, FDR corrected). Network-based statistical analysis revealed decreased morphological connections mainly in the pallidum subnetwork, which was negatively correlated with off-therapy durations (p < 0.05). Overall, the topological organization of the individual-based MBNs was disrupted in the young survivors of ALL, which may play a crucial role in executive efficiency deficits.
Airway Management during Massive Gastric Regurgitation Using VieScope or Macintosh Laryngoscope—A Randomized, Controlled Simulation Trial
Authors: Ecker Hannes , Stranz Sebastian , Kolvenbach Simone , Herff Holger , Hellmich Martin , Wetsch Wolfgang A.
Published: September 2022

In this model of massive gastric aspiration, we compared two different laryngoscopes (VieScope and Macintosh) in a randomized, controlled simulation study. The primary endpoint was time to intubation; the secondary endpoints were intubation success (i.e., tracheal tube position) and amount of pulmonary aspiration. Thirty-four anesthetists performed endotracheal intubation using VieScope and Macintosh laryngoscopy in a randomized order on an airway manikin simulating massive regurgitation of gastric fluid. The primary endpoint “time until intubation” could be achieved significantly faster (mean −12.4 s [95% confidence intervals (CI) −19.7 s; −7.3 s]) with Macintosh compared to VieScope (p < 0.001). Concerning “correct tube position”, no statistical difference was found between the devices (p = 1.0). The mean time to first ventilation was −11.1 s [95% CI −18.3 s; −5.3 s] when using Macintosh (p = 0.001). The mean volume of aspirated gastric fluid was lower in the Macintosh group: −90.0 mL [95% CI −235.0 mL; −27.5 mL] (p = 0.011). Data from this simulation study suggest that in a model of massive gastric regurgitation, airway management can be achieved faster and with less gastric aspiration when using a Macintosh laryngoscope compared to a VieScope laryngoscope.
Radiological Features for Frailty Assessment in Patients Requiring Emergency Laparotomy
Authors: Kołodziejska Katarzyna , Witowski Jan , Tylec Piotr , Grochowska Anna , Przytuła Natalia , Lis Maciej , Pędziwiatr Michał , Rubinkiewicz Mateusz
Published: September 2022

Introduction: As the number of elderly patients requiring surgical intervention rises, it is believed that frailty syndrome has a greater impact on perioperative course than on chronological age. The aim of this study was to evaluate the efficacy of various imaging features for frailty assessment in patients undergoing emergency laparotomy. Methods: The study included all patients that qualified for emergency surgery with preoperative CT scans between 2016 and 2020 in the Second Department of General Surgery. Multiple trauma patients were excluded from the analysis. The modified frailty index and brief geriatric assessment were used in the analysis. CT images were reviewed for the assessment of osteopenia, sarcopenia, sarcopenic obesity, renal volume and abdominal aorta calcification rate. Results: A total of 261 patients were included in the analysis. Multivariate logistic regression identified every next ASA class (OR: 4.161, 95%CI: 1.672–10.355, p = 0.002), intraoperative adverse events (OR: 12.397, 95%CI: 2.166–70.969, p = 0.005) and osteopenia (OR: 4.213, 95%CI: 1.235–14.367, p = 0.022) as a risk factor for 30-day mortality. Our study showed that every next ASA class (OR: 1.952, 95%Cl: 1.171–3.256, p = 0.010) and every point of the BGA score (OR: 1.496, 95%Cl: 1.110–2.016, p = 0.008) are risk factors for major complications. Conclusions: Osteopenia was the best parameter for perioperative mortality risk stratification in patients undergoing emergency surgical intervention. Sarcopenia (measured as psoas muscle area), sarcopenic obesity, aortic calcifications and mean kidney volume do not predict poor outcomes in those patients. None of the radiological markers appeared to be useful for the prediction of perioperative morbidity.
The Expression of Follistatin-like 1 Protein Is Associated with the Activation of the EMT Program in Sjögren’s Syndrome
Authors: Sisto Margherita , Ribatti Domenico , Ingravallo Giuseppe , Lisi Sabrina
Published: September 2022

Background: The activation of the epithelial to mesenchymal transition (EMT) program is a pathological response of the Sjögren’s syndrome (SS) salivary glands epithelial cells (SGEC) to chronic inflammation. Follistatin-like 1 protein (FSTL1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1), actively involved in the modulation of EMT. However, the role of FSTL1 in the EMT program activation in SS has not yet been investigated. Methods: TGF-β1-stimulated healthy human SGEC, SS SGEC, and SS salivary glands (SGs) biopsies were used to assess the effect of FSTL1 on the activation of the EMT program. FSTL1 gene activity was inhibited by the siRNA gene knockdown technique. Results: Here we reported that FSTL1 is up-regulated in SS SGs tissue in a correlated manner with the inflammatory grade. Blockage of FSTL1 gene expression by siRNA negatively modulates the TGF-β1-induced EMT program in vitro. We discovered that these actions were mediated through the modulation of the SMAD2/3-dependent EMT signaling pathway. Conclusions: Our data suggest that the TGF-β1-FSTL1-SMAD2/3 regulatory circuit plays a key role in the regulation of EMT in SS and targeting FSTL1 may be a strategy for the treatment of SGs EMT-dependent fibrosis.
Fluoride Exposure and Salivary Glands: How Is Glandular Morphology Susceptible to Long-Term Exposure? A Preclinical Study
Authors: Matos-Sousa José Mário , Bittencourt Leonardo Oliveira , Ferreira Maria Karolina Martins , dos Santos Vinicius Ruan Neves , Balbinot Karolyny Martins , Alves-Júnior Sérgio , Pinheiro João de Jesus Viana , Charone Senda , Pessan Juliano Pelim , Lima Rafael Rodrigues
Published: September 2022

Despite a strong body of evidence attesting to the effectiveness of fluoride (F) in preventing and controlling caries, some studies have sought to investigate the influence of F exposure on the salivary glands, organs that are essential for the maintenance of cavity homeostasis through salivary production, finding that exposure to F can cause biochemical and proteomic changes. Thus, this study aimed to investigate the morphological effects of prolonged exposure to F on the salivary glands of mice, at concentrations that would correspond to optimally fluoridated water (suitable for human consumption) and to fluorosis-endemic regions. Twenty-four male mice (Mus musculus) were divided into three groups, according to F levels in the drinking water: 0 (control), 10, or 50 mg F/L, with an exposure period of 60 days. The glands were morphometrically analyzed for the total acinar area, parenchyma area, and stromal area, as well as for the immunohistochemical analysis of myoepithelial cells. The results showed that prolonged exposure to F at 10 mg F/L did not promote significant changes in the morphometry of the salivary glands of mice, which reinforces the safety of the chronic use of F in low doses.
Skin Hyperpigmentation Due to Post-Surgical Adrenal Insufficiency Regressed with the Dexamethasone Treatment
Authors: Shagjaa Tungalagtamir , Sanga Viola , Rossi Gian Paolo
Published: September 2022

Primary adrenal insufficiency (AI) due to bilateral adrenalectomy is not uncommon and causes skin hyperpigmentation, which worsens quality of life. Case description: A 50-year-old lady presented with skin hyperpigmentation after spare adrenalectomy for recurrent primary aldosteronism. In 2002 she has her first unilateral adrenalectomy and was cured at follow-up. After 16 years she developed primary aldosteronism, which was treated by spare adrenalectomy. She thereafter developed AI and started glucocorticoid replacing therapy, which did not prevent the development of full-blown skin hyperpigmentation. The addition of a low dose of dexamethasone (0.5 mg/day) to the ongoing adrenal replacement therapy normalized her plasma adrenocorticotropic hormone (ACTH) levels and regressed skin hyperpigmentation without causing Cushing-like symptoms or signs. Conclusions: This clinical case provides compelling evidence for a place for low-dose dexamethasone for regressing skin pigmentation in patients with primary AI.
Evolution of Radiation Therapy in Pancreas Cancer Management toward MRI-Guided Adaptive Radiation Therapy
Authors: Yalamanchili Amulya , Thomas Tarita O. , Dajani Salah , Hayes John P.
Published: September 2022

Pancreas cancer has a poor prognosis despite aggressive treatment and is the fourth leading cause of cancer death in the United States. At diagnosis, most patients have either metastatic or locally advanced disease. In this article, we review the evolution of treatments in locally advanced pancreas cancer (LAPC) and discuss the various radiation therapy fractionation schemes. Furthermore, we examine the data supporting dose escalation and the delivery of ablative biologically effective doses in the setting of LAPC. Finally, we review the role of MRI-guided radiation therapy in escalating dose while sparing organs at risk in the era of stereotactic magnetic resonance-guided adaptive radiation therapy.
A Numerical Study of Long-Return Period Near-Bottom Ocean Currents in Lower Cook Inlet, Alaska
Authors: Fissel David B. , Lin Yuehua
Published: September 2022

Lower Cook Inlet (LCI) is an important waterway with very large tides and high marine productivity. Oceanographic forcing in LCI is complex due to a combination of tides, seasonal winds, and large freshwater discharges, as well as inflow from the Alaska Coastal Current. From an analysis of historical current meter data sets, deeper ocean currents of LCI were found to have large differences resulting from the dominance of large tides in the northeast portion of LCI while subtidal contributions to the deeper currents are more important relative to the reduced tidal currents in central and western parts of LCI. To compute the largest values of the near-bottom currents of LCI, a 3D hydrodynamical model was developed over a large model domain extending over the full 300 km length of Cook Inlet as well as a large portion of the adjoining Alaska continental shelf region. At the open model boundaries, nine major tidal height constituents were specified based on National Oceanic and Atmospheric Administration (NOAA) tidal gauge data. The model was forced by the spatially varying winds and freshwater discharges for the six gauged rivers in Cook Inlet. The model was verified using available current meter data in the study area. Model runs were carried out for 21 case studies to derive the near-bottom currents for return periods of 1, 10, and 100 years. Within LCI, the extremal values for near bottom currents arise from quite different forcing regimes. Tidal currents are completely dominant in the northeast portion of LCI while for central and western portions, remote wind forcing over the Alaskan continental shelf current, which generates the Alaska Coastal Current, becomes more important.
Coastal Protection by Planted Mangrove Forest during Typhoon Mangkhut
Authors: Zhang Xiaoxia , Lin Pengzhi , Chen Xinping
Published: September 2022

Mangroves provide many ecosystem services, including coastal protection against storm surges and waves. As an adaptive method for coastal defense, mangroves were widely restored and planted in tropical and subtropical regions, such as the coastal regions in Southeast Asia. Field surveys were conducted to quantify the nature-based coastal protection provided by a planted mangrove forest along the coasts of Shanwei, Guangdong Province, China, under typhoon influence. The resilience of mangrove trees was assessed under the impact of Typhoon Mangkhut (2018), which induced a maximum storm surge of 1.74 m with a maximum wave height of 1.16 m in the study area. The pre- and post-typhoon surveys and hydrodynamic measurements were conducted at a mudflat with planted mangroves. The wave height reduction reached 77% over 100 m wide mangrove forest. Our results suggest that a six-year-old planted mangrove forest with a ~100 m width might withstand a super typhoon impact and provide substantial protection for the fish ponds and embankments behind the mangrove forest. No uproots or deadly breakage of stems were observed in the mangrove forest, while severe defoliation was spotted for a small portion of trees in the study area, mainly along the wind path, the windward edge of the forest, and among the taller plants. Obvious sedimentation in the mangrove front and the tidal flat was observed during the typhoon Mangkhut (2018) and the entire typhoon season of 2018.
Building Capacity for Implementation Science in Precision Health and Society: Development of a Course for Professional and Graduate Students in Pharmacy
Authors: Roberts Megan C. , McLaughlin Jacqueline E.
Published: September 2022

Training in the field of implementation science is critical for future pharmacists and pharmaceutical scientists to successfully implement precision health interventions in pharmacy practice. We developed an elective course for second- and third-year students at the UNC Eshelman School of Pharmacy to develop foundational knowledge in implementation science with a focus on precision health implementation. The eight-week course used a flipped classroom format featuring lecture videos, suggested readings, quizzes, guest lectures from experts, case studies, and a group project. We evaluated course quality through class participation, a pre- and post-test on course content, and a mixed-methods survey completed by the students. Overall engagement in in the course was high and students demonstrated significant improvement in understanding of implementation science and precision health. Strengths of the course as identified by students were the use of expert guest speakers, pre-class lectures, and case study exercises, while the ordering of content and improved connection between content and guest lectures were identified as areas for improvement. In conclusion, the elective course was well-received and meets a critical need in the field of pharmacy to build implementation science capacity. Future work is needed to expand and refine education for the implementation of precision health for pharmacy professionals.
Smart-Contract-Based Automation for OF-RAN Processes: A Federated Learning Use-Case
Authors: Jijin Jofina , Seet Boon-Chong , Chong Peter Han Joo
Published: September 2022

The opportunistic fog radio access network (OF-RAN) expands its offloading computation capacity on-demand by establishing virtual fog access points (v-FAPs), comprising user devices with idle resources recruited opportunistically to execute the offloaded tasks in a distributed manner. OF-RAN is attractive for providing computation offloading services to resource-limited Internet-of-Things (IoT) devices from vertical industrial applications such as smart transportation, tourism, mobile healthcare, and public safety. However, the current OF-RAN design is lacking a trusted and distributed mechanism for automating its processes such as v-FAP formation and service execution. Motivated by the recent emergence of blockchain, with smart contracts as an enabler of trusted and distributed systems, we propose an automated mechanism for OF-RAN processes using smart contracts. To demonstrate how our smart-contract-based automation for OF-RAN could apply in real life, a federated deep learning (DL) use-case where a resource-limited client offloads the resource-intensive training of its DL model to a v-FAP is implemented and evaluated. The results validate the DL and blockchain performances of the proposed smart-contract-enabled OF-RAN. The appropriate setting of process parameters to meet the often competing requirements is also demonstrated.
Integrated Modelling Approaches for Sustainable Agri-Economic Growth and Environmental Improvement: Examples from Greece, Canada and Ireland
Authors: Garcia Jorge Andres , Alamanos Angelos
Published: September 2022

Complex agricultural problems concern many countries, as a result of competing economic and environmental objectives. In this work we model three common agricultural problems through optimization techniques: a water-scarce area with overexploited surface and groundwater resources due to over-pumping for irrigation (Greece); an area facing water quality deterioration caused by agriculture (Canada); and an intensified animal farming area facing environmental degradation and increased greenhouse gases emissions (Ireland). Multiple goals are considered to optimize farmers’ welfare and environmental sustainability. The proposed approaches are new applications for each case-study, providing useful insights for most countries facing similar problems.
An Advanced Open Land Use Database as a Resource to Address Destination Earth Challenges
Authors: Kepka Michal , Hájek Pavel , Kožuch Dmitrij , Řezník Tomáš , Mildorf Tomáš , Charvát Karel , Kepka Vichrová Martina , Chytrý Jan
Published: September 2022

Land-use and land-cover (LULC) themes are important for many domains, especially when they process environmental and socio-economic phenomena. The evolution of a land-use database called Open Land Use (OLU) started in 2013 and was continued by adapting many user requirements. The goal of this study was to design a new version of the OLU database that would better fit the gathered user requirements collected by projects using LULC data. A formal definition of the developed data model through Unified Modeling Language (UML) class diagrams, a feature catalogue based on ISO 19110 and SQL scripts for setting up the OLU database, are the key achievements of the presented paper. The presented research provides a multi-scale open database of LULC information supporting the DestinE initiative to develop a very-high-precision digital model of the earth. The novel spatio-temporal thematic approach also lies in modular views of the OLU database.
Effects of Hydrologic Pulsing and Vegetation on Invertebrate Communities in Wetlands
Authors: Keljo Kurt S.
Published: September 2022

Constructed, mitigation wetlands in the midwestern United States are frequently dominated by a Typha spp. monoculture and their hydrologies are often determined by adjustable control structures. Wetlands provide habitat for multiple macroinvertebrate species, which in turn provide food for other organisms inhabiting the wetlands, such as waterfowl. This study examined the impacts of plant diversity and manipulated hydrology on macroinvertebrate communities. Forty 1-m2 wetland mesocosms were either planted with a monoculture of Typha spp. or with a more diverse plant community of Schoenoplectus tabernaemontani, Juncus effusus, and Sparganium eurycarpum. They were also assigned to one of four hydrologic regimes: steady state, pulsing, deep spring/shallow fall, and shallow spring/deep summer. After one year, macroinvertebrates were sampled in the mesocosms. Mesocosms with deep spring hydrologies were found to have greater taxon diversity than those with other hydrologies, but Chironomidae biomass was the lowest under the deep spring hydrology. Culicidae and Chironomidae were found in higher numbers in mixed vegetation than in Typha spp. Taxon richness and Chironomid biomass were significantly higher in mixed vegetation mesocosms than in Typha spp. monocultures. Results suggest vegetation diversity and hydrological regimes impact macroinvertebrate communities, with potential implications for constructed wetland design and management.
Enzymatic Hydrolysis of Textile and Cardboard Waste as a Glucose Source for the Production of Limonene in Escherichia coli
Authors: Zebec Žiga , Poberžnik Mojca , Lobnik Aleksandra
Published: September 2022

Cellulose containing textiles (cotton) and cardboard/carton waste represent a large reservoir of untapped organic carbon. These wastes have enormous potential for use as carbon feedstock in industrial biotechnological processes. Essentially, cotton/cardboard (CC) waste is pure cellulose (with some additives) in the form of polymerised glucose consisting of β-(1→4)-linked D-glucose subunits. One of the largest and most diverse classes of natural chemicals that can be produced from glucose are terpenes with a wide range of applications as flavours, fragrances, pharmaceuticals, biopesticides, and biofuels. Here we have investigated the bioconversion of CC waste into the exemplary terpene limonene as a proof of concept. Six different CC waste streams were enzymatically hydrolysed and used to produce limonene using the Escherichia coli (E. coli) microbial cell factory. The D-glucose content in the CC hydrolysate (glucose juice) was determined and then metabolised by E. coli via a manipulated heterogeneous biolipid synthesis pathway (the mevalonate pathway) to produce limonene. This study represents an important proof of concept for the production of terpenes from hydrolysed CC waste streams.
Intragenic L1 Insertion: One Possibility of Brain Disorder
Authors: Son Ji-Hoon , Do Hyunsu , Han Jinju
Published: September 2022

Long interspersed nuclear element 1 (LINE1, L1) is a retrotransposon comprising ~17% of the human genome. A subset of L1s maintains the potential to mobilize and alter the genomic landscape, consequently contributing to the change in genome integrity and gene expression. L1 retrotransposition occurs in the human brain regardless of disease status. However, in the brain of patients with various brain diseases, the expression level and copy number of L1 are significantly increased. In this review, we briefly introduce the methodologies applied to measure L1 mobility and identify genomic loci where new insertion of L1 occurs in the brain. Then, we present a list of genes disrupted by L1 transposition in the genome of patients with brain disorders. Finally, we discuss the association between genes disrupted by L1 and relative brain disorders.
Curcumin Modulates Oxidative Stress, Fibrosis, and Apoptosis in Drug-Resistant Cancer Cell Lines
Authors: Gabr Sami A. , Elsaed Wael M. , Eladl Mohamed Ahmed , El-Sherbiny Mohamed , Ebrahim Hasnaa Ali , Asseri Saad Mohamed , Eltahir Yasir A. M. , Elsherbiny Nehal , Eldesoqui Mamdouh
Published: September 2022

In cancer management, drug resistance remains a challenge that reduces the effectiveness of chemotherapy. Several studies have shown that curcumin resensitizes cancer cells to chemotherapeutic drugs to overcome resistance. In the present study, we investigate the potential therapeutic role of curcumin in regulating the proliferation of drug-resistant cancers. Six drug-sensitive (MCF7, HCT116, and A549) and -resistant (MCF7/TH, HCT116R, and A549/ADR) cancer cell lines were treated with curcumin followed by an analysis of cytotoxicity, LDH enzyme, total reactive oxygen species, antioxidant enzymes (SOD and CAT), fibrosis markers (TGF-β1 protein, fibronectin, and hydroxyproline), and expression of cellular apoptotic markers (Bcl-2, Bax, Bax/Bcl-2 ratio, Annexin V, cytochrome c, and caspase-8). Additionally, the expression of cellular SIRT1 was estimated by ELISA and RT-PCR analysis. Curcumin treatment at doses of 2.7–54.3 µM significantly reduced the growth of sensitive and resistant cells as supported with decreased viability and increased cellular LDH enzyme of treated cells compared to controls non-treated cells. Curcumin also at doses of 2.7 and 54.3 µM regulated the fibrogenesis by reducing the expression of fibrotic markers in treated cells. Analysis of apoptotic markers indicated increased Bax, Bax, Bax/Bcl-2 ratio, Annexin V, caspase-8, and cytochrome c expression, while Bcl-2 expressions were significantly reduced. In curcumin-treated cells at 2.7 μM, non-significant change in ROS with significant increase in SOD and CAT activity was observed, whereas an increase in ROS with a reduction in respective antioxidant enzymes were seen at higher concentrations along with significant upregulation of SIRT1. In conclusion, the present study shows that curcumin induces anticancer activity against resistant cancer cell lines in a concentration- and time-dependent manner. The protective activities of curcumin against the growth of cancer cells are mediated by modulating oxidative stress, regulating fibrosis, SIRT1 activation, and inducing cellular apoptosis. Therefore, curcumin could be tested as an auxiliary therapeutic agent to improve the prognosis in patients with resistant cancers.
Is There Any Improvement in Image Quality in Obese Patients When Using a New X-ray Tube and Deep Learning Image Reconstruction in Coronary Computed Tomography Angiography?
Authors: Pfeffer Anne-Sofie Brunebjerg , Mørup Svea Deppe , Andersen Thomas Rueskov , Mohamed Roda Abdulkadir , Lambrechtsen Jess
Published: September 2022

Deep learning image reconstruction (DLIR) is a technique that should reduce noise and improve image quality. This study assessed the impact of using both higher tube currents as well as DLIR on the image quality and diagnostic accuracy. The study consisted of 51 symptomatic obese (BMI > 30 kg/m2) patients with low to moderate risk of coronary artery disease (CAD). All patients underwent coronary computed tomography angiography (CCTA) twice, first with the Revolution CT scanner and then with the upgraded Revolution Apex scanner with the ability to increase tube current. Images were reconstructed using ASiR-V 50% and DLIR. The image quality was evaluated by an observer using a Likert score and by ROI measurements in aorta and the myocardium. Image quality was significantly improved with the Revolution Apex scanner and reconstruction with DLIR resulting in an odds ratio of 1.23 (p = 0.017), and noise was reduced by 41%. A total of 88% of the image sets performed with Revolution Apex + DLIR were assessed as good enough for diagnosis compared to 69% of the image sets performed with Revolution Apex/CT + ASiR-V. In obese patients, the combination of higher tube current and DLIR significantly improves the subjective image quality and diagnostic utility and reduces noise.
Ferrocenyl-bis-(1-(4-benzyl-5-morpholinooxazol-2-yl)-N-(4-(trifluoromethyl)benzyl)methanamine)
Authors: Blanco-Carapia Roberto E. , Aguilar-Rangel Enrique A. , Islas-Jácome Alejandro , González-Zamora Eduardo
Published: September 2022

The new bis-heterocyclic compound ferrocenyl-bis-(1-(4-benzyl-5-morpholinooxazol-2-yl)-N-(4-(trifluoromethyl)benzyl)methanamine) (1) was synthesized in 73% overall yield in 1.5 hours via a pseudo-repetitive Ugi-Zhu five-component reaction, starting from 1,1′-ferrocenedicarboxaldehyde, 4-(trifluoromethyl)benzylamine, and 2-isocyano-1-morpholino-3-phenylpropan-1-one, in 1:2.1:2.2 proportions, respectively, using scandium(III) triflate as a Lewis-acid catalyst, microwaves as a heat source, and toluene as a solvent. The synthesized compound was characterized by 1D (1H, 13C, and 19F) and 2D (COSY, HSQC, and HMBC) NMR, HRMS, and FT-IR.
Mechanical Performance and Corrosion Behaviour of Diffusion-Bonded A5083 Aluminium and A36 Mild Steel with Gallium Interlayer
Authors: Ismail Asmawi , Othman Nurul Husna , Mustapha Mazli , Mohamed Saheed Mohamed Shuaib , Abdullah Zaki , Muhammed Musa , Mohamed Saat Asmalina , Mustapha Faizal
Published: September 2022

This article investigated the mechanical performance and corrosion behaviour of a diffusion-bonded A5083 aluminium/A36 mild steel dissimilar joint with a Gallium (Ga) interlayer. The bonding parameters were the bonding temperature (525 and 550 °C), holding time (60 and 120 min) and surface roughness (800 and 1200 grit). Property characterisation was achieved using Scanning Electron Microscopy (SEM), Energy Dispersive X-ray (EDX) analysis, Vickers microhardness tester, Izod impact tester and potentiodynamic polarisation testing. The results revealed that the significance of the bonding parameters was in the order bonding temperature > surface roughness > holding time. Increasing the bonding temperature resulted in an increase in the impact strength and a corresponding reduction in the corrosion rate and microhardness. However, increasing the grit size decreased the microhardness and a corresponding increase in the impact strength and corrosion rate. The impact strength and corrosion rate decreased with the increasing holding time while the microhardness followed a reverse trend. It was also discovered that incorporating the Ga interlayer resulted in a 67.9% improvement in the degradation rate.