bluuebunny/crossref_metadata_2025 huggingface dataset:
The Performance of Three-Frequency GPS PPP-RTK with Partial Ambiguity Resolution
Authors: Yan Zhongbao , Zhang Xiaohong
Published: June 2022

The correct ambiguity resolution of real-time kinematic precise point positioning (PPP-RTK) plays an essential role in achieving fast, reliable, and high-precision positioning. However, the ambiguity of incorrect fixing will cause poor PPP-RTK positioning performance. Hence, it is essential to optimize the selected strategy of the ambiguity subset to obtain a more reliable ambiguity resolution performance for PPP-RTK. For this reason, a partial ambiguity resolution (PAR) method combining quality control and Schmidt orthogonalization (Gram–Schmidt) is proposed in this study. To investigate the performance of global positioning system (GPS) dual- and three-frequency PPP-RTK comprehensively, the PAR method based on the Gram–Schmidt method was analyzed and compared with the highest elevation angle method, which considered the satellite with the highest elevation angle as the reference satellite. The performance of ambiguity fixing, atmospheric corrections, and positioning were evaluated using five stations in Belgium and its surrounding area. The results showed average epoch fixing rates of 81.01%, 95.92%, 82.05%, and 97.93% in the dual-frequency highest elevation angle (F2-MAX), dual-frequency Gram–Schmidt (F2-ALT), three-frequency highest elevation angle (F3-MAX), and three–frequency Gram–Schmidt (F3-ALT), respectively. In terms of the time to first fix (TTFF), 89.02%, 94.25%, 90.24%, and 95.69% of the single-differenced (SD) narrow lane (NL) ambiguity fell within 3 min in F2-MAX, F2-ALT, F3-MAX, and F3-ALT, respectively. As far as the ionospheric corrections are concerned, the proportion of SD ionospheric residuals within ±0.25 total electron content units (TECU) were 95.08%, 95.93%, 95.68%, and 96.98% for the F2-MAX, F2-ALT, F3-MAX, and F3-ALT, respectively. The centimeter-level accuracy of both the horizontal and vertical positioning errors can be achieved almost instantaneously in F3-ALT. This is attributed to the accurate and reliable SD NL ambiguity fixing based on the Gram–Schmidt approach.
Determination of Internal Temperature Differences for Various Cylindrical Lithium-Ion Batteries Using a Pulse Resistance Approach
Authors: Ludwig Sebastian , Steinhardt Marco , Jossen Andreas
Published: June 2022

The temperature of lithium-ion batteries is crucial in terms of performance, aging, and safety. The internal temperature, which is complicated to measure with conventional temperature sensors, plays an important role here. For this reason, numerous methods exist in the literature for determining the internal cell temperature without sensors, which are usually based on electrochemical impedance spectroscopy. This study presents a method in the time domain, based on the pulse resistance, for determining the internal cell temperature by examining the temperature behavior for the cylindrical formats 18650, 21700, and 26650 in isothermal and transient temperature states for different states of charge (SOCs). A previously validated component-resolved 2D thermal model was used to analyze the location of the calculated temperature TR within the cell, which is still an unsolved question for pulse resistance-based temperature determination. The model comparison shows that TR is close to the average jelly roll temperature. The differences between surface temperature and TR depend on the SOC and cell format and range from 2.14K to 2.70K (18650), 3.07K to 3.85K (21700), and 4.74K to 5.45K (26650). The difference decreases for each cell format with increasing SOC and is linear dependent on the cell diameter.
Large-Scale Expansion of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Stirred Suspension Bioreactor Enabled by Computational Fluid Dynamics Modeling
Authors: Zhang Junhong , Peng Yan , Guo Meijin , Li Chao
Published: June 2022

Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) hold great potential to generate novel and curative cell therapy products. However, the current large-scale cultivation of hUCMSCs is based on empirical geometry-dependent methods, limiting the generation of high-quantity and high-quality hUCMSCs for clinical therapy. Herein, we develop a novel scale-up strategy based on computational fluid dynamics (CFD) to effectively expand the hUCMSCs in a 3D tank bioreactor. Using a standardized hUCMSCs line on microcarriers, we successfully translated and expanded the hUCMSCs from a 200 mL spinner flask to a 1.5 L computer-controlled bioreactor by matching the shear environment and suspending the microcarrier. Experimental results revealed that the batch-cultured hUCMSCs in bioreactors with an agitation speed of 40 rpm shared a more favorable growth and physiological state, similar to that run at 45 rpm in a 200 mL spinner flask, showing comparability in both culture systems. Notably, the maximum cell density reached up to 27.3 × 105 cells/mL in fed-batch culture, 2.9 folds of that of batch culture and 20.2 times of seeding cells. As such, efficient process optimization and scale-up expansion of hUCMSCs were achieved in the microcarrier-based bioreactor system by the developed CFD simulation strategy, which provided an alternative toolbox to generate massive and standardized curative cell therapy products.
Vitamin C Is Essential for the Maintenance of Skeletal Muscle Functions
Authors: Takisawa Shoko , Takino Yuka , Lee Jaewon , Machida Shuichi , Ishigami Akihito
Published: June 2022

Vitamin C (L-ascorbic acid, VC) is a water-soluble antioxidant essential for collagen polymerization. Previously, we reported that long-term VC deficiency causes muscle atrophy and deterioration in physical ability using female senescence marker protein-30 (SMP30)-deficient mice with a lack of VC synthesis, which is similar to that observed in humans. To determine whether these findings also hold true for male SMP30-deficient mice, two-month-old male SMP30-deficient mice were divided into two groups: the VC-treated group (VC(+)) was administered 1.5 g/L VC, and the VC-untreated group (VC(−)) was supplied water without VC. The VC level at four weeks in the gastrocnemius muscles from the VC(+) and VC(−) groups was 205.7 ± 8.5 nmol/g tissue and 13.1 ± 0.6 nmol/g tissue, respectively. Thus, four weeks was enough to reduce the VC level in the skeletal muscle in the VC-untreated group. On the other hand, muscle weights of the gastrocnemius, soleus, plantaris, tibialis anterior, and extensor digitorum longus in the VC(−) group were significantly reduced by VC deficiency after twelve weeks. The physical endurance of the VC(−) group at eight weeks was markedly lower than that of the VC(+) group. The grasping strength and activity in the cage in the nocturnal phases of the VC(−) group were markedly lower at twelve and sixteen weeks than those of the VC(+) group. Interestingly, muscle atrophy and declined physical ability were completely restored with VC supplementation for twelve weeks after VC deficiency. Thus, VC is essential for maintaining skeletal muscle function in both male and female SMP30-deficient mice with a lack of VC synthesis.
scEpiLock: A Weakly Supervised Learning Framework for cis-Regulatory Element Localization and Variant Impact Quantification for Single-Cell Epigenetic Data
Authors: Gong Yanwen , Srinivasan Shushrruth Sai , Zhang Ruiyi , Kessenbrock Kai , Zhang Jing
Published: June 2022

Recent advances in single-cell transposase-accessible chromatin using a sequencing assay (scATAC-seq) allow cellular heterogeneity dissection and regulatory landscape reconstruction with an unprecedented resolution. However, compared to bulk-sequencing, its ultra-high missingness remarkably reduces usable reads in each cell type, resulting in broader, fuzzier peak boundary definitions and limiting our ability to pinpoint functional regions and interpret variant impacts precisely. We propose a weakly supervised learning method, scEpiLock, to directly identify core functional regions from coarse peak labels and quantify variant impacts in a cell-type-specific manner. First, scEpiLock uses a multi-label classifier to predict chromatin accessibility via a deep convolutional neural network. Then, its weakly supervised object detection module further refines the peak boundary definition using gradient-weighted class activation mapping (Grad-CAM). Finally, scEpiLock provides cell-type-specific variant impacts within a given peak region. We applied scEpiLock to various scATAC-seq datasets and found that it achieves an area under receiver operating characteristic curve (AUC) of ~0.9 and an area under precision recall (AUPR) above 0.7. Besides, scEpiLock’s object detection condenses coarse peaks to only ⅓ of their original size while still reporting higher conservation scores. In addition, we applied scEpiLock on brain scATAC-seq data and reported several genome-wide association studies (GWAS) variants disrupting regulatory elements around known risk genes for Alzheimer’s disease, demonstrating its potential to provide cell-type-specific biological insights in disease studies.
Phycoremediation of Copper by Chlorella protothecoides (UTEX 256): Proteomics of Protein Biosynthesis and Stress Response
Authors: Andrade Lidiane Maria , Tito Caique Alves , Mascarenhas Camila , Lima Fabíola Aliaga , Dias Meriellen , Andrade Cristiano José , Mendes Maria Anita , Nascimento Claudio Augusto Oller
Published: June 2022

Phycoremediation is an eco-friendly treatment for mining wastes. Copper at high concentrations is toxic for microalgae growth (bioremediation). Proteomics is a modern approach that can assist in elucidating, in detail, the highly complex metabolic mechanisms related to phycoremediation. Therefore, this study aimed to evaluate the effect of copper ions (Cu2+) on the metabolism of Chlorella protothecoides (UTEX 256), particularly the proteome changes. The WC culture medium supplemented with Cu2+ at 0.3, 0.6, and 0.9 mg/L showed a strict correlation to Cu2+ removal of 40, 33, and 36% of the initial content, respectively. In addition, Cu2+ concentrations did not affect microalgae growth—a very traditional approach to measuring toxicity. However, the proteomics data indicated that when compared to the control, reductions in protein levels were observed, and the 10 most scored proteins were related to the light-harvesting complex. Interestingly, C. protothecoides cultivated at 0.9 mg of Cu2+/L biosynthesized the protein Ycf3-interacting chloroplastic isoform X1 to respond to the photooxidative stress and the DNA-directed RNA polymerase III subunit RPC5 was related to the Cu2+ binding. Pre-mRNA-processing factor 19 and cytochrome c peroxidase proteins were observed only in the copper-containing treatments indicating the activation of antioxidant mechanisms by reactive oxygen species, which are potential environmental pollutant biomarkers.
The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases
Authors: Ghezzi Laura , Cantoni Claudia , Rotondo Emanuela , Galimberti Daniela
Published: June 2022

The gut–brain axis (GBA) is a complex interactive network linking the gut to the brain. It involves the bidirectional communication between the gastrointestinal and the central nervous system, mediated by endocrinological, immunological, and neural signals. Perturbations of the GBA have been reported in many neurodegenerative diseases, suggesting a possible role in disease pathogenesis, making it a potential therapeutic target. The gut microbiome is a pivotal component of the GBA, and alterations in its composition have been linked to GBA dysfunction and CNS inflammation and degeneration. The gut microbiome might influence the homeostasis of the central nervous system homeostasis through the modulation of the immune system and, more directly, the production of molecules and metabolites. Small clinical and preclinical trials, in which microbial composition was manipulated using dietary changes, fecal microbiome transplantation, and probiotic supplements, have provided promising outcomes. However, results are not always consistent, and large-scale randomized control trials are lacking. Here, we give an overview of how the gut microbiome influences the GBA and could contribute to disease pathogenesis in neurodegenerative diseases.
P63 and P73 Activation in Cancers with p53 Mutation
Authors: Cai Bi-He , Hsu Yun-Chien , Yeh Fang-Yu , Lin Yu-Rou , Lu Rui-Yu , Yu Si-Jie , Shaw Jei-Fu , Wu Ming-Han , Tsai Yi-Zhen , Lin Ying-Chen , Bai Zhi-Yu , Shih Yu-Chen , Hsu Yi-Chiang , Liao Ruo-Yu , Kuo Wei-Hsin , Hsu Chao-Tien , Lien Ching-Feng , Chen Chia-Chi
Published: June 2022

The members of the p53 family comprise p53, p63, and p73, and full-length isoforms of the p53 family have a tumor suppressor function. However, p53, but not p63 or p73, has a high mutation rate in cancers causing it to lose its tumor suppressor function. The top and second-most prevalent p53 mutations are missense and nonsense mutations, respectively. In this review, we discuss possible drug therapies for nonsense mutation and a missense mutation in p53. p63 and p73 activators may be able to replace mutant p53 and act as anti-cancer drugs. Herein, these p63 and p73 activators are summarized and how to improve these activator responses, particularly focusing on p53 gain-of-function mutants, is discussed.
A Cross-Sectional Study of Attitudes toward Willingness to Use Enhancement Technologies: Implications for Technology Regulation and Ethics
Authors: Nakazawa Eisuke , Mori Katsumi , Udagawa Makoto , Akabayashi Akira
Published: June 2022

Neuroenhancement is rapidly re-emerging as a research topic because of the development of minimally invasive brain intervention technologies, including neurofeedback. However, public attitude toward enhancement technologies remains relatively unexplored. To fill this gap in the literature, we conducted an online survey of 1258 people in Japan who were presented with four scenarios depicting minimally and highly invasive enhancement interventions. Approximately 20% of the respondents stated that they were willing to use enhancement technologies, whereas 80% were not. Most respondents were cautious about using enhancement technologies. We used a generalized linear mixed-effects model to study the association between the type of intervention and participants’ willingness to use such technologies. Factors related to willingness to use these technologies included interventions’ degree of invasiveness, as well as participants’ gender, educational attainment, and limit or suppression experiences. We also examined the influence of others’ choices and behaviors, and participants’ tolerance toward others’ use of enhancement technologies. We explored important aspects of policymaking vis à vis enhancement technologies. This study could provide valuable insights for a debate on the ethics and regulation of enhancement technologies.
Development of a Multiprotein Classifier for the Detection of Early Stage Ovarian Cancer
Authors: Boylan Kristin L. M. , Petersen Ashley , Starr Timothy K. , Pu Xuan , Geller Melissa A. , Bast Robert C. , Lu Karen H. , Cavallaro Ugo , Connolly Denise C. , Elias Kevin M. , Cramer Daniel W. , Pejovic Tanja , Skubitz Amy P. N.
Published: June 2022

Background: Individual serum biomarkers are neither adequately sensitive nor specific for use in screening the general population for ovarian cancer. The purpose of this study was to develop a multiprotein classifier to detect the early stages of ovarian cancer, when it is most treatable. Methods: The Olink Proseek Multiplex Oncology II panel was used to simultaneously quantify the expression levels of 92 cancer-related proteins in sera. Results: In the discovery phase, we generated a multiprotein classifier that included CA125, HE4, ITGAV, and SEZ6L, based on an analysis of sera from 116 women with early stage ovarian cancer and 336 age-matched healthy women. CA125 alone achieved a sensitivity of 87.9% at a specificity of 95%, while the multiprotein classifier resulted in an increased sensitivity of 91.4%, while holding the specificity fixed at 95%. The performance of the multiprotein classifier was validated in a second cohort comprised of 192 women with early stage ovarian cancer and 467 age-matched healthy women. The sensitivity at 95% specificity increased from 74.5% (CA125 alone) to 79.2% with the multiprotein classifier. In addition, the multiprotein classifier had a sensitivity of 95.1% at 98% specificity for late stage ovarian cancer samples and correctly classified 80.5% of the benign samples using the 98% specificity cutpoint. Conclusions: The inclusion of the proteins HE4, ITGAV, and SEZ6L improved the sensitivity and specificity of CA125 alone for the detection of early stages of ovarian cancer in serum samples. Furthermore, we identified several proteins that may be novel biomarkers of early stage ovarian cancer.
No Impact of Seasonality of Diagnoses on Baseline Tumor Immune Infiltration, Response to Treatment, and Prognosis in BC Patients Treated with NAC
Authors: Grandal Beatriz , Aljehani Ashwaq , Dumas Elise , Daoud Eric , Jochum Floriane , Gougis Paul , Hotton Judicaël , Lemoine Amélie , Michel Sophie , Laas Enora , Laé Marick , Pierga Jean-Yves , Alaoui Ismaili Khaoula , Lerebours Florence , Reyal Fabien , Hamy Anne Sophie
Published: June 2022

Breast cancer (BC) is the most common cancer in women worldwide. Neoadjuvant chemotherapy (NAC) makes it possible to monitor in vivo response to treatment. Several studies have investigated the impact of the seasons on the incidence and detection of BC, on tumor composition, and on the prognosis of BC. However, no evidence is available on their association with immune infiltration and the response to treatment. The objective of this study was to analyze pre- and post-NAC immune infiltration as assessed by TIL levels, the response to treatment as assessed by pathological complete response (pCR) rates, and oncological outcomes as assessed by relapse-free survival (RFS) or overall survival (OS) according to the seasonality of BC diagnoses in a clinical cohort of patients treated with neoadjuvant chemotherapy. Out of 1199 patients, the repartition of the season at BC diagnosis showed that 27.2% were diagnosed in fall, 25.4% in winter, 24% in spring, and 23.4% in summer. Baseline patient and tumor characteristics, including notable pre-NAC TIL levels, were not significantly different in terms of the season of BC diagnosis. Similarly, the pCR rates were not different. No association for oncological outcome was identified. Our data do not support the idea that the seasonality of diagnoses has a major impact on the natural history of BC treated with NAC.
Haloperidol Instigates Endometrial Carcinogenesis and Cancer Progression by the NF-κB/CSF-1 Signaling Cascade
Authors: Chiang Jung-Ying , Lei Fu-Ju , Chang Huan-Jui , Wei Sung-Tai , Wang Chi-Chung , Huang Yen-Chih , Wang Hwai-Lee , Chuang Chi-Fen , Hu Shu-Yu , Hsieh Chia-Hung
Published: June 2022

Haloperidol is a routine drug for schizophrenia and palliative care of cancer; it also has antitumor effects in several types of cancer. However, the role of haloperidol in endometrial cancer (EC) development is still unclear. Here, we show that chronic haloperidol treatment in clinically relevant doses induced endometrial hyperplasia in normal mice and promoted tumor growth and malignancy in mice with orthotopic EC. The pharmacokinetic study indicated that haloperidol highly accumulated in the uterus of mice. In vitro studies revealed that haloperidol stimulated the cellular transformation of human endometrial epithelial cells (HECCs) and promoted the proliferation, migration, and invasion of human endometrial carcinoma cells (HECCs) by activating nuclear factor kappa B (NF-κB) and its downstream signaling target, colony-stimulating factor 1 (CSF-1). Gain of function of CSF-1 promotes the cellular transformation of HEECs and the malignant progression of HECCs. Moreover, blockade of CSF-1 inhibited haloperidol-promoted EC progression in vitro and in vivo. A population-based cohort study of EC patients further demonstrated that the use of haloperidol was associated with increased EC-specific mortality. Collectively, these findings indicate that clinical use of haloperidol could potentially be harmful to female patients with EC.
Postoperative Hormone Replacement Therapy and Survival in Women with Ovarian Cancer
Authors: Ji Eunjeong , Kim Kidong , Lee Banghyun , Hwang Sung Ook , Lee Hee Joong , Lee Kyungjin , Lee Minkyung , Kim Yong Beom
Published: June 2022

The effect of postoperative hormone replacement therapy (HRT) on survival in women with ovarian cancer remains unclear. This study aimed to investigate the impact of postoperative HRT on survival in women with ovarian cancer using the nationwide cohort study. Women aged ≤60 and diagnosed with ovarian cancer that received primary surgery were followed-up for 5.6 ± 2.9 years. Mean ages of women administered HRT (the HRT group; n = 263) or not administered HRT (the control group; n = 1521) were 41.5 ± 8.5 and 41.0 ± 11.4 years, respectively. After adjustment for covariables, OS was significantly greater in the HRT group (HR 0.618; 95% CI 0.414–0.922; p = 0.018). Kaplan–Meier curve analysis showed OS was significantly higher in the HRT group (85.3% vs. 76.6%; p = 0.016). The ratio of women with HRT to women without HRT increased significantly with time (restricted mean survival times for OS, p < 0.001). In addition, OS was significantly greater for those that received HRT for >5 years than for those that received HRT for ≤0.5 years (HR 0.234; 95% CI 0.059–0.936; p = 0.040). Postoperative HRT improved survival among women with ovarian cancer. The impact of HRT on survival increased with time and treatment duration.
Changing Epidemiological Trends of Hepatobiliary Carcinomas in Austria 2010–2018
Authors: Hucke Florian , Pinter Matthias , Hucke Miriam , Bota Simona , Bolf Dajana , Hackl Monika , Peck-Radosavljevic Markus
Published: June 2022

Using national registries, we investigated the epidemiological trends of hepatobiliary carcinomas in Austria between 2010 and 2018 and compared them to those reported for the periods of 1990–1999 and 2000–2009. In total, 12,577 patients diagnosed with hepatocellular carcinoma (n = 7146), intrahepatic cholangiocarcinoma (n = 1858), extrahepatic cholangiocarcinoma (n = 1649), gallbladder carcinoma (n = 1365), and ampullary carcinoma (n = 559), between 2010 and 2018, were included. The median overall survival of all patients was 9.0 months. The best median overall survival was observed in patients with ampullary carcinoma (28.5 months) and the worst median overall survival was observed in patients with intrahepatic carcinoma (5.6 months). The overall survival significantly improved in all entities over the period 2010–2018 as compared with over the periods of 2000–2009 and 1990–1999. Age-adjusted incidence and mortality rates remained stable for most entities in both, men and women; only in gallbladder carcinoma, the incidence and mortality rates significantly decreased in women, whereas, in men, the incidence rates remained stable and mortality rates showed a decreasing trend. We showed that age-adjusted incidence and mortality rates were stable in most entities, except in gallbladder carcinoma. The overall survival improved in almost all entities as compared with those during 1990–2009.
Pre-Diagnosis Diet and Physical Activity and Risk of Cardiovascular Disease Mortality among Female Cancer Survivors
Authors: Weikart Daphne , Lin Dan , Dhingra Radha , Al-Shaar Laila , Sturgeon Kathleen
Published: June 2022

Sub-optimal diet and physical activity (PA) levels have been associated with increased risk of cardiovascular disease (CVD) mortality. The relationship between pre-cancer diagnosis diet quality and PA level on CVD mortality risk in cancer survivors is unclear. We examined the association between pre-cancer diagnosis diet quality and leisure-time PA and their interaction on CVD mortality in cancer survivors. Diet quality was characterized by the Alternative Mediterranean Diet Index (aMED). Leisure-time PA was converted to a metabolic equivalent of task hours per week (MET-h/wk). During a median of 6.3 years of follow-up of 18,533 female cancer survivors, we identified 915 CVD deaths. aMED score was not associated with CVD mortality. PA level was inversely associated with CVD mortality (HRQ1-Q4 = 0.74; 95% CI: 0.61–0.88; Ptrend = 0.0014). Compared to cancer survivors with the lowest pre-diagnosis aMED score and PA level, cancer survivors with higher aMED scores and higher MET-hrs/wk were at a 33% lower risk of CVD mortality (HR = 0.67; 95% CI: 0.52–0.87). Overall, this study shows PA to be a strong predictor of CVD mortality in female cancer survivors. Our observations support the importance of PA throughout the lifecycle in lowering CVD mortality risk.
The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation
Authors: Farhoumand Lina S. , Fiorentzis Miltiadis , Kraemer Miriam M. , Sak Ali , Stuschke Martin , Rassaf Tienush , Hendgen-Cotta Ulrike , Bechrakis Nikolaos E. , Berchner-Pfannschmidt Utta
Published: June 2022

Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite local tumor control, no effective therapy has been found to prevent metastasis, resulting in a high mortality rate. In the present study, we evaluated the anti-tumor potential of non-selective ß-blockers in 3D tumor spheroids grown from UM cell lines. Of the various ß-blockers tested, carvedilol and its enantiomers were most potent in decreasing the viability of Mel270 spheroids. Carvedilol at a concentration of 10–50 µM significantly elicited cytotoxicity and induced apoptosis in spheroid cells. In result, carvedilol inhibited tumor spheroid growth and compactness, and furthermore prevented the long-term survival and repopulation of spreading spheroid cells. The drug sensitivity of the different spheroids grown from Mel270, 92-1, UPMD2, or UPMM3 cell lines was dependent on 3D morphology rather than on high-risk cytogenetic profile or adrenergic receptor expression levels. In fact, the monosomy-3-containing UPMM3 cell line was most responsive to carvedilol treatment compared to the other cell lines. The concurrent treatment of UPMM3 spheroids with carvedilol and 5 or 10 Gy irradiation revealed additive cytotoxic effects that provided tumor control. Collectively, our data demonstrate the anti-tumor properties of carvedilol and its enantiomers, which may serve as candidates for the co-adjuvant therapy of UM.
Facile Synthesis of Sulfate-Intercalated CoFe LDH Nanosheets Derived from Two-Dimensional ZIF-9(III) for Promoted Oxygen Evolution Reaction
Authors: Xiao Guolei , Chen Weibin , Cai Yaming , Zhang Shifan , Wang Di , Cai Dandan
Published: June 2022

Layered double hydroxide (LDH) has emerged as a promising electrocatalyst; however, the synthetic method usually requires high temperature and high pressure, and sulfate-intercalated LDH is rarely reported. Herein, the sulfate-intercalated CoFe LDH nanosheets were successfully fabricated at ambient temperature via a facile strategy, using two-dimensional ZIF-9(III) as a template and FeSO4 as both etchant and iron source. When the as-prepared sulfate-intercalated CoFe LDH acts as an electrocatalyst, it presents superior electrocatalytic performance for the oxygen evolution reaction (OER), requiring low overpotential (η@10 mA cm−2 = 218 mV) with a small Tafel slope of 59.9 mV dec−1 in 1.0 M KOH, which compares favorably with commercial RuO2 and most reported transition-metal electrocatalysts. The high catalytic activity of CoFe LDH might be ascribed to the large interlayer space distance originating from special SO42− ions and the strong synergistic effects between Fe and Co. This work provides a novel and feasible approach to designing highly efficient electrocatalysts based on advanced LDH materials for OER.
Some Preliminary Results to Eradicate Leukemic Cells in Extracorporeal Circulation by Actuating Doxorubicin-Loaded Nanochains of Fe3O4 Nanoparticles
Authors: Zheng Xiawen , Mai Xiaoli , Bao Siyuan , Wang Peng , Hong Yu , Han Yuexia , Sun Jianfei , Xiong Fei
Published: June 2022

Leukemia is a non-solid cancer which features the malignant proliferation of leukocytes. Excessive leukocytes of lesions in peripheral blood will infiltrate organs, resulting in intumescence and weakening treatment efficiency. In this study, we proposed a novel approach for targeted clearance of the leukocytes in the peripheral blood ex vivo, which employed magnetic nanochains to selectively destroy the leukocytes of the lesions. The nanochains were doxorubicin-loaded nanochains of Fe3O4 nanoparticles which were fabricated by the solvent exchange method combined with magnetic field-directed self-assembly. Firstly, the nanochains were added into the peripheral blood during extracorporeal circulation and subjected to a rotational magnetic field for actuation. The leukocytes of the lesion were then conjugated by the nanochains via folic acid (FA) targeting. Finally, the rotational magnetic field actuated the nanochains to release the drugs and effectively damage the cytomembrane of the leukocytes. This strategy was conceptually shown in vitro (K562 cell line) and the method’s safety was evaluated in a rat model. The preliminary results demonstrate that the nanochains are biocompatible and suitable as drug carriers, showing direct lethal action to the leukemic cells combined with a rotational magnetic field. More importantly to note is that the nanochains can be effectively kept from entry into the body. We believe this extracorporeal circulation-based strategy by activating nanochains magnetically could serve as a potential method for leukemia treatment in the future.
Narrow-Gap Rheometry: A Novel Method for Measuring Cell Mechanics
Authors: Bashir Khawaja Muhammad Imran , Lee Suhyang , Jung Dong Hee , Basu Santanu Kumar , Cho Man-Gi , Wierschem Andreas
Published: June 2022

The viscoelastic properties of a cell cytoskeleton contain abundant information about the state of a cell. Cells show a response to a specific environment or an administered drug through changes in their viscoelastic properties. Studies of single cells have shown that chemical agents that interact with the cytoskeleton can alter mechanical cell properties and suppress mitosis. This envisions using rheological measurements as a non-specific tool for drug development, the pharmacological screening of new drug agents, and to optimize dosage. Although there exists a number of sophisticated methods for studying mechanical properties of single cells, studying concentration dependencies is difficult and cumbersome with these methods: large cell-to-cell variations demand high repetition rates to obtain statistically significant data. Furthermore, method-induced changes in the cell mechanics cannot be excluded when working in a nonlinear viscoelastic range. To address these issues, we not only compared narrow-gap rheometry with commonly used single cell techniques, such as atomic force microscopy and microfluidic-based approaches, but we also compared existing cell monolayer studies used to estimate cell mechanical properties. This review provides insight for whether and how narrow-gap rheometer could be used as an efficient drug screening tool, which could further improve our current understanding of the mechanical issues present in the treatment of human diseases.
Piperine Derivatives Enhance Fusion and Axonal Transport of Mitochondria by Activating Mitofusins
Authors: Zhang Lihong , Dang Xiawei , Franco Antonietta , Zhao Haiyang , Dorn Gerald W.
Published: June 2022

Piperine (1-piperoylpiperidine) is the major pungent component of black pepper (Piper nigrum) and exhibits a spectrum of pharmacological activities. The molecular bases for many of piperine’s biological effects are incompletely defined. We noted that the chemical structure of piperine generally conforms to a pharmacophore model for small bioactive molecules that activate mitofusin (MFN)-mediated mitochondrial fusion. Piperine, but not its isomer chavicine, stimulated mitochondrial fusion in MFN-deficient cells with EC50 of ~8 nM. We synthesized piperine analogs having structural features predicted to optimize mitofusin activation and defined structure-activity relationships (SAR) in live-cell mitochondrial elongation assays. When optimal spacing was maintained between amide and aromatic groups the derivatives were potent mitofusin activators. Compared to the prototype phenylhexanamide mitofusin activator, 2, novel molecules containing the piperidine structure of piperine exhibited markedly enhanced passive membrane permeability with no loss of fusogenic potency. Lead compounds 5 and 8 enhanced mitochondrial motility in cultured murine Charcot-Marie-Tooth disease type 2A (CMT2A) neurons, but only 8 improved mitochondrial transport in sciatic nerve axons of CMT2A mice. Piperine analogs represent a new chemical class of mitofusin activators with potential pharmaceutical advantages.
High-Performance Liquid Chromatography–Diode Array Detection Combined with Chemometrics for Simultaneous Quantitative Analysis of Five Active Constituents in a Chinese Medicine Formula Wen-Qing-Yin
Authors: Chen Jun-Chen , Wu Hai-Long , Wang Tong , Dong Ming-Yue , Chen Yue , Yu Ru-Qin
Published: June 2022

In this work, a simple analytical strategy combining high-performance liquid chromatography–diode array detection (HPLC-DAD) and the chemometric method was developed for the simultaneous quantification of 5-hydroxymethyl-2-furfural (HMF), paeoniflorin (PAE), ferulic acid (FER), baicalin (BAI), and berberine (BER) in a Chinese medicine formula Wen-Qing-Yin (WQY). The alternating trilinear decomposition (ATLD) algorithm and alternating trilinear decomposition assisted multivariate curve resolution (ATLD-MCR) algorithm were used to realize the separation and rapid determination of five target analytes under the presence of time shifts, solvent peaks, peak overlaps, and unknown interferences. All analytes were eluted within 10 min and the linear correlation coefficients of calibration sets were between 0.9969 and 0.9996. In addition, the average recoveries of the five active compounds obtained by ATLD and ATLD-MCR analysis were in the range of 91.8–112.5% and 88.6–101.6%, respectively. For investigating the accuracy and reliability of the proposed method, figures of merit including limit of detection (LOD), limit of quantitation (LOQ), sensitivity (SEN), and selectivity (SEL) were calculated. The proposed analytical strategy has the advantages of being fast, simple, and sensitive, and can be used for the qualitative and quantitative analysis of WQY, providing a feasible option for the quality monitoring of the traditional Chinese medicine formula.
Relationship between Physiological Resorption of Primary Molars with Its Permanent Successors, Dental Age and Chronological Age
Authors: Caleya Antonia M. , Gallardo Nuria E. , Feijoo Gonzalo , Mourelle-Martínez M. Rosa , Martín-Vacas Andrea , Maroto Myriam
Published: June 2022

The aim of the present study was to analyse root resorption of the primary mandibular molars and their relationship with their permanent successors and the age of the patient. Methods: The sample consisted of 408 digital panoramic radiographs. The mesial and distal crown-to-root ratios (CRR) of #74 and #75 were calculated by dividing the measures of the length of each root by its coronal height. The Demirjian formation stage of the premolar was established, and dental age was determined. A descriptive and statistical analysis was performed using SPSS to determine the correlation between the variables (Pearson’s correlation coefficient) and to identify the differences between them (Student’s t-test), with a confidence level of 95%. Results: 723 molars were measured, and tables of CRR depending on dental and chronological age were obtained. The CRR decreased with increasing dental and chronological age, but not uniformly. The CRR of #74 and #75 decreased slightly when the successor premolar was in the initial stages of formation. Gender differences were obtained with respect to chronological age, mainly in girls, because the root resorption of #74 was always more advanced, and the formation of the #34 more advanced. Conclusions: Root resorption of the molar is slight and progressive when the successor premolar begins formation until stage D, and becomes higher starting at stage E. It is possible to determine the state of the child’s maturation and the CRR according to dental and chronological age.
Cardiac Rhabdoid Tumor—A Rare Foe—Case Report and Literature Review
Authors: Luca Alina Costina , Miron Ingrith Crenguța , Cojocaru Elena , Țarcă Elena , Curpan Alexandrina-Stefania , Mihăila Doina , Mihaela Trandafir Laura , Iordache Alin-Constantin , Lupu Vasile-Valeriu , Tazelaar Henry D. , Pădureț Ioana Alexandra
Published: June 2022

Intracardiac masses are unusual findings in infants, and most of them are benign. Nevertheless, they may be associated with a significant degree of hemodynamic instability and/or arrhythmias. Malignant tumors of the heart rarely occur in children. Rhabdoid tumors are aggressive tumors with a dismal prognosis even when diagnosed early. Although rhabdomyomas are common cardiac tumors in infants, they are mostly benign. The most common sites of involvement are the kidneys and central nervous system, but soft tissues, lungs, and ovaries may also be affected. The diagnosis can be challenging, particularly in sites where they do not usually occur. In the present paper, we report the case of a 2-year-old boy diagnosed with cardiac rhabdoid tumor highlighting the importance of molecular studies and recent genetic discoveries with the purpose of improving the management of such cases. The aim of this educational case report and literature review is to raise awareness of cardiac masses in children and to point out diagnostic hints toward a cardiac tumor on various imaging modalities. Given the rarity of all tumors involving the heart and the lack of symptom specificity, a high degree of suspicion is needed to arrive at the correct diagnosis.
Dinutuximab Beta in Children with High-Risk Neuroblastoma: Experience from a Single Center in Croatia
Authors: Giljević Jasminka Stepan , Rajačić Nada , Mikulić Danko , Batoš Ana Tripalo
Published: June 2022

To determine the potential benefits and feasibility of administering maintenance therapy with dinutuximab beta for high-risk neuroblastoma (HRNB) in clinical practice, a retrospective review of charts of patients with HRNB treated at a single center in Croatia (2012–2021) was undertaken. Of 23 patients with HRNB, 11 received up to five cycles of dinutuximab beta as part of multimodal therapy; 12 patients did not (i.e., no immunotherapy). In the no immunotherapy group, one patient had complete remission (8%), and 11 patients died of tumor progression (92%). In the dinutuximab beta group, eight patients had complete remission (73%; median duration of response 5 years and 2 months), one had stable disease (9%), and two died of disease (18%). Patients who received dinutuximab beta had a higher median event-free survival (40.0 months [range: 12.5–83.0]) and median overall survival (56.0 months [range: 16.2–101.0]) than those who did not (12.9 months [range: 3.3–126.0] and 20.7 months [3.3–126.0], respectively). Dinutuximab beta was generally well tolerated; adverse events were manageable and as reported in clinical studies. These results confirm the benefits and feasibility of maintenance therapy with dinutuximab beta as part of multimodal therapy for patients with HRNB in real-world clinical practice.
Stalagmite-Inferred Climate in the Western Mediterranean during the Roman Warm Period
Authors: Hu Hsun-Ming , Michel Véronique , Valensi Patricia , Mii Horng-Sheng , Starnini Elisabetta , Zunino Marta , Shen Chuan-Chou
Published: June 2022

The circum-Mediterranean region is the cradle of ancient civilizations that had their roots in the Holocene. Climate change has been considered a key element that contributed to their rise or fall. The Roman Warm Period (RWP), 200 B.C. to 400 A.D., was the warmest period in Europe during the last two thousand years. Hydroclimatic change at the end of the RWP has been suggested as a possible influence on the stability of the Roman political regime and the eventual collapse of the Roman Empire in 476 A.D. A lack of precise proxy records hampers our understanding of hydroclimatic variability over the RWP. Here we present a stalagmite-based climate record from 550 ± 10 B.C. to 950 ± 7 A.D. (2σ) from northern Italy, which reveals a climatic trend of warming and increased humidity throughout the RWP. By comparison with other proxy records in Europe and the circum-Mediterranean region, we argue that the warm, humid climate in southern Europe could be linked to the multi-centennial warming of the Mediterranean Sea. Our record further suggests a century-long rapid drying trend from the early-4th to early-5th century, followed by a 100-year-long drought event, which could have influenced the fall of the Roman Empire.
In Vitro Sensitive Skin Models: Review of the Standard Methods and Introduction to a New Disruptive Technology
Authors: Guichard Alexandre , Remoué Noëlle , Honegger Thibault
Published: June 2022

The skin is a protective organ, able to decode a wide range of tactile, thermal, or noxious stimuli. Some of the sensors belonging to the transient receptor potential (TRP) family, for example, TRPV1, can elicit capsaicin-induced heat pain or histamine-induced itching sensations. The sensory nerve fibers, whose soma is located in the trigeminal or the dorsal root ganglia, are able to carry signals from the skin’s sensory receptors toward the brain via the spinal cord. In some cases, in response to environmental factors, nerve endings might be hyper activated, leading to a sensitive skin syndrome (SSS). SSS affects about 50% of the population and is correlated with small-fiber neuropathies resulting in neuropathic pain. Thus, for cosmetical and pharmaceutical industries developing SSS treatments, the selection of relevant and predictive in vitro models is essential. In this article, we reviewed the different in vitro models developed for the assessment of skin and neuron interactions. In a second part, we presented the advantages of microfluidic devices and organ-on-chip models, with a focus on the first model we developed in this context.
In Whose Best Interest? Parental Hesitancy toward the COVID-19 Vaccine for Children in Japan: A Literature Survey Study
Authors: Takahashi Shizuko , Nakazawa Eisuke , Akabayashi Akira
Published: June 2022

In early February 2022, the Japanese government sent COVID-19 vaccine vouchers to children ages 5–11. Using keywords obtained from the voucher, the frequently asked questions section, and experts, we descriptively analyzed the advantages and disadvantages of vaccination for children and their parents through a web-based literature survey of media articles and government homepage statements in Japan. For children, vaccination helps prevent severe symptoms and may be particularly beneficial for children in low-income families by lowering the rate of suicide and at-home child abuse. For parents, not vaccinating their child allows them to fulfill a more traditional role as a parent (mothers in particular), reduces the gender gap for mothers, and provides greater peace of mind about their child’s future fertility. We also examined the governmental vaccination campaigns targeting children from public health perspectives. We argue that the letter accompanying the vaccine voucher should clearly emphasize that further transmission will be prevented, reducing domestic infection. In addition to the biological dimensions of COVID-19 in Japan, we emphasize cultural issues and hope that these can be useful for other countries as they create their own vaccination strategies. Public health in Japan could be promoted if all citizens, regardless of age, acquired fundamental knowledge and skills, the motivation to learn, and the ability to utilize knowledge and skills and think, judge, and express personal ideas.
Understanding the Plastic Deformation of Gradient Interstitial Free (IF) Steel under Uniaxial Loading Using a Dislocation-Based Multiscale Approach
Authors: Lyu Hao , Ruimi Annie
Published: June 2022

Gradient interstitial free (IF) steels have been shown to exhibit a superior combination of strength and ductility due to their multiscale microstructures. The novelty of the work resides in the implementation of a modified slip transmission and a back-stress quantity induced by a long-range dislocation interaction in the dislocation-based multiscale model. This is an improvement over the model we previously proposed. Simulations are performed on IF specimens with gradient structures and with homogeneous structures. The macroscopic behavior of the samples under tension and compression is studied. The evolution of the microstructure such as dislocations, geometrically necessary dislocations (GNDs), and the effects of grain orientation is analyzed. Results show that with our enhanced model, the simulations can successfully reproduce the stress-strain curves obtained experimentally on gradient nano IF steel specimens under tension. The simulations also capture the tension-compression asymmetry (TCA) in specimens with homogeneous and gradient microstructures. The initial texture is found to have a significant effect on the TCA of specimens with gradient microstructures.
Anticholinesterase Inhibition, Drug-Likeness Assessment, and Molecular Docking Evaluation of Milk Protein-Derived Opioid Peptides for the Control of Alzheimer’s Disease
Authors: Ji Dawei , Ma Jingying , Dai Junyi , Xu Min , Harris Paul W. R. , Brimble Margaret A. , Agyei Dominic
Published: June 2022

The drug-likeness and pharmacokinetic properties of 23 dairy-protein-derived opioid peptides were studied using SwissADME and ADMETlab in silico tools. All the opioid peptides had poor drug-like properties based on violations of Lipinski’s rule-of-five. Moreover, prediction of their pharmacokinetic properties showed that the peptides had poor intestinal absorption and bioavailability. Following this, two well-known opioid peptides (βb-casomorphin-5, βb-casomorphin-7) from A1 bovine milk and caffeine (positive control) were selected for in silico molecular docking and in vitro inhibition study with two cholinesterase enzyme receptors important for the pathogenesis of Alzheimer’s disease. Both peptides showed higher binding free energies and inhibitory activities to butyrylcholinesterase (BChE) than caffeine, but in vitro binding energy values were lower than those from the docking model. Moreover, the two casomorphins had lower inhibitory properties against acetylcholinesterase (AChE) than caffeine, although the docking model predicted the opposite. At 1 mg/mL concentrations, βb-casomorphin-5 and βb-casomorphin-7 showed promising results in inhibiting both cholinesterases (i.e., respectively 34% and 43% inhibition of AChE, and 67% and 81% inhibition of BChE). These dairy-derived opioid peptides have the potential to treat Alzheimer’s disease via cholinesterase inhibition. However, appropriate derivatization may be required to improve their poor predicted intestinal absorption and bioavailability.