bluuebunny/crossref_metadata_2025 huggingface dataset:
Winter Wheat Take-All Disease Index Estimation Model Based on Hyperspectral Data
Authors: Guo Wei , Yang Yifeng , Zhao Hengqian , Song Rui , Dong Ping , Jin Qian , Baig Muhammad Hasan Ali , Liu Zelong , Yang Zihan
Published: October 2021

Wheat take-all, caused by two variants of the fungus Gaeumannomyces gramnis (Sacc.) Arx & D. Olivier, was common in spring wheat areas in northwest and north China and occurred in winter wheat areas in north China. The yield of common disease areas was reduced by more than 20% and the yield of severe cases was reduced by more than 50%. Large-scale rapid and accurate estimation of the incidence of wheat take-all plays an important role in guiding field control and agricultural yield estimation. In this study, a portable ground spectrometer was used to collect the spectral reflectance in the 350–1050 nm band range of wheat canopy after take-all infection in the wheat grain filling stage and combined with the ground disease survey data.Then a winter wheat take-all disease index estimation model was proposed based on the spectral band division interval and selected band combination. According to the normalized difference spectral index (NDSI) and the determinative coefficient of the disease index formed by any two band combinations, the spectral index band combinations corresponding to the spectral index with high correlation in each region were screened by dividing spectral intervals. Partial least-squares regression was used to establish a binary and ternary disease index calibration model. The results showed that the model based on spectral indices of ternary variables had the highest coefficient of determination. Finally, the optimal regression model of wheat take-all disease condition index composed of NDSI(R590,R598), NDSI(R534,R742) and NDSI(R810,R834) was established: Y = 134.577 − 70.301 NDSI(R590,R598) − 223.533 NDSI(R534,R742) + 51.584 NDSI(R810,R834) (R2 = 0.743, RMSEP = 0.094, df = 15), which was the most suitable model for winter wheat take-all estimation. The construction of this model can provide new method and technical support for future evaluation and monitoring of wheat take-all disease on the field.
A Study on the Blue Coloration of Ao-ike Pond, Aomori Prefecture, Japan: Formulation of a Physical Model in Terms of Radiance and Image Analyses
Authors: Hanaishi Ryuji , Chikita Kazuhisa A.
Published: October 2021

The blue coloration model of a closed pond, Ao-ike Pond, Aomori Prefecture, Japan, was formulated in terms of radiance by applying a theory of observation devices proposed by Szirmay-Kalos (2008) and Hanaishi’s reverse ray tracing method. In this model, three potential contributions to the coloration were considered; irregular reflection at the Lambertian pond bottom, density fluctuation scattering by water, and Mie scattering by suspended solids. By utilizing model formulas for these mechanisms, some parameters were determined in order to duplicate the images of the pond surface without solar shading by tree leaves above the pond surface, in addition to the images with sunbeam trajectories by solar radiations passing through tree leaves, which are emitted from the water and visible on the surface. Simulating the pictures of the pond surface and the sun-beam-image analyses revealed that the blue colorations of Ao-ike Pond are mainly produced (1) by the density fluctuation scattering of water itself and the white Mie scattering by suspended solids and (2) by the red-light absorption by water in the optical paths before and after the two scatterings. Then, the density fluctuation scattering of water and the Mie scattering by suspended solids exhibited contributions of almost equal magnitude. The contribution of irregular reflections at the pond bottom was judged to be relatively small.
Automatic Blob Detection for Dental Caries
Authors: Majanga Vincent , Viriri Serestina
Published: October 2021

Dental Caries are one of the most prevalent chronic diseases around the globe. Detecting carious lesions is a challenging task. Conventional computer aided diagnosis and detection methods in the past have heavily relied on the visual inspection of teeth. These methods are only effective on large and clearly visible caries on affected teeth. Conventional methods have been limited in performance due to the complex visual characteristics of dental caries images, which consist of hidden or inaccessible lesions. The early detection of dental caries is an important determinant for treatment and benefits much from the introduction of new tools, such as dental radiography. In this paper, we propose a deep learning-based technique for dental caries detection namely: blob detection. The proposed technique automatically detects hidden and inaccessible dental caries lesions in bitewing radio-graphs. The approach employs data augmentation to increase the number of images in the data set to have a total of 11,114 dental images. Image pre-processing on the data set was through the use of Gaussian blur filters. Image segmentation was handled through thresholding, erosion and dilation morphology, while image boundary detection was achieved through active contours method. Furthermore, the deep learning based network through the sequential model in Keras extracts features from the images through blob detection. Finally, a convexity threshold value of 0.9 is introduced to aid in the classification of caries as either present or not present. The process of detection and classifying dental caries achieved the results of 97% and 96% for the precision and recall values, respectively.
Explosion-Suppression Characteristics of Nonmetallic Spherical Spacers on Propane-Air Mixtures in Confined Space
Authors: Yu Yangyang , Liu Lehai , Zhang Junhong , Wang Jun , Meng Xiangde , Wang Dan
Published: October 2021

The explosion-suppression effects of NSSs on overpressures, flame propagation and flame tip velocities were explored under the initial pressures of 0.2 MPa, 0.3 MPa and 0.4 MPa. All experiments tested in a constant volume combustion bomb (CVCB). Explosion reaction of premixed propane–air gas in a new designed CVCB filled with nonmetallic spherical spacers (NSSs) was analyzed. The results showed that overpressures decreased under the different initial pressures. With the increase of filling density, the overpressure decreased, the time to reach explosion overpressure decreased, and the decay rate of explosion overpressure increased. It was also found that the explosion-suppression effects of NSSs on pressures. Flame front could be captured by high-speed schlieren photography. Combustion phenomena were captured including flame propagation, corrugated laminar flame, jet flame, corrugated turbulent flame as well as tulip flame under different initial pressures. Flame tip velocities also were captured. The results demonstrate that flame tip velocities decreased with the increase of filling densities. However, compared with unfilled CVCB, flame tip velocities increased after filling NSSs in CVCB under different initial pressures. NSSs suppressed the explosion overpressure in the cylinder, and promoted the flame propagation. In both cases, NSSs played a dual role. The suppression effect of NSSs was affected by both its suppression and promotion effect on the explosion. This work provides a scientific basis for the effective prevention of explosion accidents with propane–air premixtures and the development of explosion-suppression products.
Consideration of the Heating of High-Performance Concretes during Cyclic Tests in the Evaluation of Results
Authors: Deutscher Melchior
Published: October 2021

Material-efficient, highly load-bearing members made of high-performance compressive concretes are often exposed to cyclical loads because of their slender construction, which can be relevant to the design. When investigating the fatigue behaviour of high-performance concretes in pressure swell tests, however, the specimen temperature rises strongly owing to the elevated loading rate at frequencies higher than 3 Hz. This leads to a negative influence on the achieved number of load cycles compared to tests carried out at slow speeds and calculated values, for example, according to fib Model Code 2010. This phenomenon, which was already observed, must be considered when generating design formulae or Wöhler lines for component design, as the test conditions with high constant load frequencies as well as sample storage in a climate chamber at constant conditions are prerequisites that cannot be expected in real material applications. Therefore, laboratory testing influences must be eliminated in order to avoid underestimating the material. Instead of adjusting the test conditions to prevent or control temperature development, as was the case in previous approaches, this article shows how the temperature effects can be corrected when analysing the results, considering both the applied stress and the maximum temperature reached. For this purpose, a calculation method was developed that was validated on the basis of a large number of fatigue tests. Thus, in the future, the application of one temperature sensor to the test specimen can effectively advance the extraction of values for Wöhler curves, even with high test frequencies.
The Imprint of the Southern Annular Mode on Black Carbon AOD in the Western Cape Province
Authors: Ibebuchi Chibuike Chiedozie , Paeth Heiko
Published: October 2021

This study examines the relationship between variations of the Southern Annular Mode (SAM) and black carbon (BC) at 550 nm aerosol optical depth (AOD) in the Western Cape province (WC). Variations of the positive (negative) phase of the SAM are found to be related to regional circulation types (CTs) in southern Africa, associated with suppressed (enhanced) westerly wind over the WC through the southward (northward) migration of Southern Hemisphere mid-latitude cyclones. The CTs related to positive (negative) SAM anomalies induce stable (unstable) atmospheric conditions over the southwestern regions of the WC, especially during the austral winter and autumn seasons. Through the control of CTs, positive (negative) SAM phases tend to contribute to the build-up (dispersion and dilution) of BC in the study region because they imply dry (wet) conditions which favor the build-up (washing out) of pollutant particles in the atmosphere. Indeed, recent years with an above-average frequency of CTs related to positive (negative) SAM anomalies are associated with a high (low) BC AOD over southwesternmost Africa.
Impacts of Aerosol Loading in the Hindu Kush Himalayan Region Based on MERRA-2 Reanalysis Data
Authors: Ningombam Shantikumar S. , Dumka Umesh Chandra , Mugil Sivasamy Kalamani , Kuniyal Jagdish Chandra , Hooda Rakesh K. , Gautam Alok Sagar , Tiwari Suresh
Published: October 2021

The impacts of climate change have severely affected geosphere, biosphere and cryosphere ecosystems in the Hindu Kush Himalayan (HKH) region. The impact has been accelerating further during the last few decades due to rapid increase in anthropogenic activities such as modernization, industrialization and urbanization, along with energy demands. In view of this, the present work attempts to examine aerosol optical depth (AOD) over the HKH region using the long-term homogeneous MERRA-2 reanalysis data from January, 1980 to December, 2020. The AOD trends are examined statistically with student’s t-test (t). Due to a vast landmass, fragile topography and harsh climatic conditions, we categorized the HKH region into three sub-regions, namely, the northwestern and Karakoram (HKH1), the Central (HKH2) and the southeastern Himalaya and Tibetan Plateau (HKH3). Among the sub-regions, the significant enhancement of AOD is observed at several potential sites in the HKH2 region, namely, Pokhara, Nainital, Shimla and Dehradun by 55.75 × 10−4 ± 3.76 × 10−4, 53.15 × 10−4 ± 3.94 × 10−4, 51.53 × 10−4 ± 4.99 × 10−4 and 39.16 × 10−4 ± 4.08 × 10−4 AOD year−1 (550 nm), respectively, with correlation coefficients (Rs) of 0.86 to 0.93. However, at a sub-regional scale, HKH1, HKH2 and HKH3 exhibit 23.33 × 10−4 ± 2.28 × 10−4, 32.20 × 10−4 ± 2.58 × 10−4 and 9.48 × 10−4 ± 1.21 × 10−4 AOD year−1, respectively. The estimated trends are statistically significant (t > 7.0) with R from 0.81 to 0.91. Seasonally, the present study also shows strong positive AOD trends at several potential sites located in the HKH2 region, such as Pokhara, Nainital, Shimla and Dehradun, with minimum 19.81 × 10−4 ± 3.38 × 10−4 to maximum 72.95 × 10−4 ± 4.89 × 10−4 AOD year−1 with statistical significance. In addition, there are also increasing AOD trends at all the high-altitude background sites in all seasons.
Review of User-Friendly Models to Improve the Urban Micro-Climate
Authors: Jänicke Britta , Milošević Dragan , Manavvi Suneja
Published: October 2021

Various micro-scale models for comparing alternative design concepts have been developed in recent decades. The objective of this study is to provide an overview of current user-friendly micro-climate models. In the results, a vast majority of models identified were excluded from the review because the models were not micro-scale, lacking a user-interface, or were not available. In total, eight models met the seven-point inclusion criteria. These models were ADMS Temperature and Humidity model, advanced SkyHelios model, ANSYS FLUENT, ENVI-met, RayMan, SOLWEIG, TownScope, and UMEP. These models differ in their complexity and their widespread use in the scientific community, ranging from very few to thousands of citations. Most of these models simulate air temperature, global radiation, and mean radiant temperature, which helps to evaluate outdoor thermal comfort in cities. All of these models offer a linkage to CAD or GIS software and user support systems at various levels, which facilitates a smooth integration to planning and design. We detected that all models have been evaluated against observations. A wider model comparison, however, has only been performed for fewer models. With this review, we aim to support the finding of a reliable tool, which is fit for the specific purpose.
Applications of Optimal Spline Approximations for the Solution of Nonlinear Time-Fractional Initial Value Problems
Authors: Pellegrino Enza , Pitolli Francesca
Published: October 2021

Nonlinear fractional differential equations are widely used to model real-life phenomena. For this reason, there is a need for efficient numerical methods to solve such problems. In this respect, collocation methods are particularly attractive for their ability to deal with the nonlocal behavior of the fractional derivative. Among the variety of collocation methods, methods based on spline approximations are preferable since the approximations can be represented by local bases, thereby reducing the computational load. In this paper, we use a collocation method based on spline quasi-interpolant operators to solve nonlinear time-fractional initial value problems. The numerical tests we performed show that the method has good approximation properties.
Transcriptome and Metabolome Analysis Revealed the Freezing Resistance Mechanism in 60-Year-Old Overwintering Camellia sinensis
Authors: Wu Hui , Wu Zixian , Wang Yuanheng , Ding Jie , Zheng Yalin , Tang Heng , Yang Long
Published: October 2021

Freezing stress in winter is the biggest obstacle to the survival of C. sinensis in mid-latitude and high-latitude areas, which has a great impact on the yield, quality, and even life of C. sinensis every year. In this study, transcriptome and metabolome were used to clarify the freezing resistance mechanism of 60-year-old natural overwintering C. sinensis under freezing stress. Next, 3880 DEGs and 353 DAMs were obtained. The enrichment analysis showed that pathways of MAPK and ABA played a key role in the signal transduction of freezing stress, and Pyr/PYL-PP2C-SnRK2 in the ABA pathway promoted stomatal closure. Then, the water holding capacity and the freezing resistance of C. sinensis were improved. The pathway analysis showed that DEGs and DAMs were significantly enriched and up-regulated in the three-related pathways of phenylpropanoid biosynthesis, flavone and flavonol biosynthesis, and flavonoid biosynthesis. In addition, the carbohydrate and fatty acid synthesis pathways also had a significant enrichment, and the synthesis of these substances facilitated the freezing resistance. These results are of great significance to elucidate the freezing resistance mechanism and the freezing resistance breeding of C. sinensis.
Can Symbiotic Bacteria (Xenorhabdus and Photorhabdus) Be More Efficient than Their Entomopathogenic Nematodes against Pieris rapae and Pentodon algerinus Larvae?
Authors: Elbrense Hanaa , Elmasry Amr M. A. , Seleiman Mahmoud F. , AL-Harbi Mohammad S. , Abd El-Raheem Ahmed M.
Published: October 2021

Pieris rapae and Pentodon algerinus are considered a global threat to agricultural crops and food security; hence, their control is a critical issue. Heterorhabditid and Steinernematid nematodes, along with their symbiotic bacteria, can achieve the optimal biocontrol agent criterion. Therefore, this study aimed to evaluate the efficacy of Heterorhabditis bacteriophora, Steinernema riobravis, and their symbiotic bacteria (Xenorhabdus and Photorhabdus) against P. rapae and P. algerinus larvae. The virulence of entomopathogenic nematodes (EPNs) was determined at different infective juvenile concentrations and exposure times, while the symbiotic bacteria were applied at the concentration of 3 × 107 colony-forming units (CFU)/mL at different exposure times. Gas chromatography–mass spectrophotometry (GC-MS) analysis and the cytotoxic effect of Photorhabdus sp. and Xenorhabdus sp. were determined. The results indicated that H. bacteriophora, S. riobravis, and their symbiotic bacteria significantly (p ≤ 0.001) induced mortality in both insect species. However, H. bacteriophora and its symbiont, Photorhabdus sp., were more virulent. Moreover, the data clarified that both symbiotic bacteria outperformed EPNs against P. rapae but the opposite was true for P. algerinus. GC-MS analysis revealed the main active compounds that have insecticidal activity. However, the results revealed that there was no significant cytotoxic effect. In conclusion, H. bacteriophora, S. riobravis, and their symbiotic bacteria can be an optimal option for bio-controlling both insect species. Furthermore, both symbiotic bacteria can be utilized independently on EPNs for the management of both pests, and, hence, they can be safely incorporated into biocontrol programs and tested against other insect pests.
Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways
Authors: Whitaker Robert H. , Cook Jeanette Gowen
Published: October 2021

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways.
Distinctive CD26 Expression on CD4 T-Cell Subsets
Authors: Cordero Oscar J. , Rafael-Vidal Carlos , Varela-Calviño Rubén , Calviño-Sampedro Cristina , Malvar-Fernández Beatriz , García Samuel , Viñuela Juan E. , Pego-Reigosa José M.
Published: October 2021

Immune system CD4 T-cells with high cell-surface CD26 expression show anti-tumoral properties. When engineered with a chimeric antigen receptor (CAR), they incite strong responses against solid cancers. This subset was originally associated to human CD4 T helper cells bearing the CD45R0 effector/memory phenotype and later to Th17 cells. CD26 is also found in soluble form (sCD26) in several biological fluids, and its serum levels correlate with specific T cell subsets. However, the relationship between glycoprotein sCD26 and its dipeptidyl peptidase 4 (DPP4) enzymatic activity, and cell-surface CD26 expression is not well understood. We have studied ex vivo cell-surface CD26 and in vitro surface and intracellular CD26 expression and secretome’s sCD26 in cultured CD4 T cells under different polarization conditions. We show that most human CD26negative CD4 T cells in circulating lymphocytes are central memory (TCM) cells while CD26high expression is present in effector Th1, Th2, Th17, and TEM (effector memory) cells. However, there are significant percentages of Th1, Th2, Th17, and Th22 CD26 negative cells. This information may help to refine the research on CAR-Ts. The cell surface CD45R0 and CD26 levels in the different T helper subsets after in vitro polarization resemble those found ex vivo. In the secretomes of these cultures there was a significant amount of sCD26. However, in all polarizations, including Th1, the levels of sCD26 were lower (although not significantly) compared to the Th0 condition (activation without polarization). These differences could have an impact on the various physiological functions proposed for sCD26/DPP4.
Characterization of Phosphorylation Status and Kinase Activity of Src Family Kinases Expressed in Cell-Based and Cell-Free Protein Expression Systems
Authors: Kinoshita-Kikuta Emiko , Kinoshita Eiji , Suga Misaki , Higashida Mana , Yamane Yuka , Nakamura Tomoka , Koike Tohru
Published: October 2021

The production of heterologous proteins is an important procedure for biologists in basic and applied sciences. A variety of cell-based and cell-free protein expression systems are available to achieve this. The expression system must be selected carefully, especially for target proteins that require post-translational modifications. In this study, human Src family kinases were prepared using six different protein expression systems: 293 human embryonic kidney cells, Escherichia coli, and cell-free expression systems derived from rabbit reticulocytes, wheat germ, insect cells, or Escherichia coli. The phosphorylation status of each kinase was analyzed by Phos-tag SDS-PAGE. The kinase activities were also investigated. In the eukaryotic systems, multiple phosphorylated forms of the expressed kinases were observed. In the rabbit reticulocyte lysate system and 293 cells, differences in phosphorylation status between the wild-type and kinase-dead mutants were observed. Whether the expressed kinase was active depended on the properties of both the kinase and each expression system. In the prokaryotic systems, Src and Hck were expressed in autophosphorylated active forms. Clear differences in post-translational phosphorylation among the protein expression systems were revealed. These results provide useful information for preparing functional proteins regulated by phosphorylation.
Synthesis and Spectroscopic Investigations of Schiff Base Ligand and Its Bimetallic Ag(I) Complex as DNA and BSA Binders
Authors: Szymańska Martyna , Pospieszna-Markiewicz Izabela , Mańka Martyna , Insińska-Rak Małgorzata , Dutkiewicz Grzegorz , Patroniak Violetta , Fik-Jaskółka Marta A.
Published: October 2021

Generation of well-defined potential metallotherapeutics for cancer treatment, one of the most population-threatening diseases, is challenging and an active area of modern research in view of their unique properties and thus multiple possible pathways of action in cells. Specifically, Schiff base ligands were recognized as very promising building blocks for the construction of stable and active complexes of numerous geometries and topologies. Incorporation of Ag(I) ions allows for the formation of flat complexes with potential unoccupied coordination sites, thus giving rise to specific interactions between the metallotherapeutic and biomolecule of interest. Herein, we present the design, synthesis and characterization of new Schiff base ligand L and its Ag(I) bimetallic complex [Ag2L2]2+ with two planar moieties formed around the metal ions and connected through cyclohexane rings, confirmed by X-ray measurements. The compounds were described in context of their potential use as anticancer drugs through DNA and BSA binding pathways by several spectroscopic methods (CD, UV-Vis, fluorescence). We revealed that both, L and [Ag2L2]2+, interact with similar affinity with CT-DNA (Kb~106 M−1), while they differ in the type and strength of interactions with the model albumin–BSA. [Ag2L2]2+ binds BSA in both a dynamic and static manner with the Ksv = 8.8 × 104 M−1 in the Trp-134 and Trp-213 sites, whereas L interacts with BSA only dynamically (KSV = 2.4 × 104 M−1). This found further confirmation in the CD studies which revealed a reduction in α-helix content in the albumin of 16% in presence of [Ag2L2]2+.
Comparison of Isotonic Activation of Cell Volume Regulation in Rat Peritoneal Mesothelial Cells and in Kidney Outer Medullary Collecting Duct Principal Cells
Authors: Baturina Galina S. , Katkova Liubov E. , Schmitt Claus Peter , Solenov Evgeniy I. , Zarogiannis Sotirios G.
Published: October 2021

In disease states, mesothelial cells are exposed to variable osmotic conditions, with high osmotic stress exerted by peritoneal dialysis (PD) fluids. They contain unphysiologically high concentrations of glucose and result in major peritoneal membrane transformation and PD function loss. The effects of isotonic entry of urea and myo-inositol in hypertonic (380 mOsm/kg) medium on the cell volume of primary cultures of rat peritoneal mesothelial cells and rat kidney outer medullary collecting duct (OMCD) principal cells were studied. In hypertonic medium, rat peritoneal mesothelial cells activated a different mechanism of cell volume regulation in the presence of isotonic urea (100 mM) in comparison to rat kidney OMCD principal cells. In kidney OMCD cells inflow of urea into the shrunken cell results in restoration of cell volume. In the shrunken peritoneal mesothelial cells, isotonic urea inflow caused a small volume increase and activated regulatory volume decrease (RVD). Isotonic myo-inositol activated RVD in hypertonic medium in both cell types. Isotonic application of both osmolytes caused a sharp increase of intracellular calcium both in peritoneal mesothelial cells and in kidney OMCD principal cells. In conclusion, peritoneal mesothelial cells exhibit RVD mechanisms when challenged with myo-inositol and urea under hyperosmolar isotonic switch from mannitol through involvement of calcium-dependent control. Myo-inositol effects were identical with the ones in OMCD principal cells whereas urea effects in OMCD principal cells led to no RVD induction.
Antioxidant and Anti-Inflammatory Properties of Bioavailable Protein Hydrolysates from Lupin-Derived Agri-Waste
Authors: Montserrat-de la Paz Sergio , Villanueva Alvaro , Pedroche Justo , Millan Francisco , Martin Maria E. , Millan-Linares Maria C.
Published: October 2021

Agri-food industries generate several by-products, including protein-rich materials currently treated as waste. Lupine species could be a sustainable alternative source of protein compared to other crops such as soybean or chickpea. Protein hydrolysates contain bioactive peptides that may act positively in disease prevention or treatment. Inflammatory responses and oxidative stress underlie many chronic pathologies and natural treatment approaches have gained attention as an alternative to synthetic pharmaceuticals. Recent studies have shown that lupin protein hydrolysates (LPHs) could be an important source of biopeptides, especially since they demonstrate anti-inflammatory properties. However, due to their possible degradation by digestive and brush-border enzymes, it is not clear whether these peptides can resist intestinal absorption and reach the bloodstream, where they may exert their biological effects. In this work, the in vitro cellular uptake/transport and the anti-inflammatory and antioxidant properties of LPH were investigated in a co-culture system with intestinal epithelial Caco-2 cells and THP-1-derived macrophages. The results indicate that the LPH crosses the human intestinal Caco-2 monolayer and exerts anti-inflammatory activity in macrophages located in the basement area by decreasing mRNA levels and the production of pro-inflammatory cytokines. A remarkable reduction in nitric oxide and ROS in the cell-based system by peptides from LPH was also demonstrated. Our preliminary results point to underexplored protein hydrolysates from food production industries as a novel, natural source of high-value-added biopeptides.
Fecal Microbial Transplantation in Critically Ill Patients—Structured Review and Perspectives
Authors: Cibulková Ivana , Řehořová Veronika , Hajer Jan , Duška František
Published: October 2021

The human gut microbiota consists of bacteria, archaea, fungi, and viruses. It is a dynamic ecosystem shaped by several factors that play an essential role in both healthy and diseased states of humans. A disturbance of the gut microbiota, also termed “dysbiosis”, is associated with increased host susceptibility to a range of diseases. Because of splanchnic ischemia, exposure to antibiotics, and/or the underlying disease, critically ill patients loose 90% of the commensal organisms in their gut within hours after the insult. This is followed by a rapid overgrowth of potentially pathogenic and pro-inflammatory bacteria that alter metabolic, immune, and even neurocognitive functions and that turn the gut into the driver of systemic inflammation and multiorgan failure. Indeed, restoring healthy microbiota by means of fecal microbiota transplantation (FMT) in the critically ill is an attractive and plausible concept in intensive care. Nonetheless, available data from controlled studies are limited to probiotics and FMT for severe C. difficile infection or severe inflammatory bowel disease. Case series and observational trials have generated hypotheses that FMT might be feasible and safe in immunocompromised patients, refractory sepsis, or severe antibiotic-associated diarrhea in ICU. There is a burning need to test these hypotheses in randomized controlled trials powered for the determination of patient-centered outcomes.
Machine Learning Algorithms to Predict Mortality of Neonates on Mechanical Intubation for Respiratory Failure
Authors: Hsu Jen-Fu , Yang Chi , Lin Chun-Yuan , Chu Shih-Ming , Huang Hsuan-Rong , Chiang Ming-Chou , Wang Hsiao-Chin , Liao Wei-Chao , Fu Rei-Huei , Tsai Ming-Horng
Published: October 2021

Background: Early identification of critically ill neonates with poor outcomes can optimize therapeutic strategies. We aimed to examine whether machine learning (ML) methods can improve mortality prediction for neonatal intensive care unit (NICU) patients on intubation for respiratory failure. Methods: A total of 1734 neonates with respiratory failure were randomly divided into training (70%, n = 1214) and test (30%, n = 520) sets. The primary outcome was the probability of NICU mortality. The areas under the receiver operating characteristic curves (AUCs) of several ML algorithms were compared with those of the conventional neonatal illness severity scoring systems including the NTISS and SNAPPE-II. Results: For NICU mortality, the random forest (RF) model showed the highest AUC (0.939 (0.921–0.958)) for the prediction of neonates with respiratory failure, and the bagged classification and regression tree model demonstrated the next best results (0.915 (0.891–0.939)). The AUCs of both models were significantly better than the traditional NTISS (0.836 (0.800–0.871)) and SNAPPE-II scores (0.805 (0.766–0.843)). The superior performances were confirmed by higher accuracy and F1 score and better calibration, and the superior and net benefit was confirmed by decision curve analysis. In addition, Shapley additive explanation (SHAP) values were utilized to explain the RF prediction model. Conclusions: Machine learning algorithms increase the accuracy and predictive ability for mortality of neonates with respiratory failure compared with conventional neonatal illness severity scores. The RF model is suitable for clinical use in the NICU, and clinicians can gain insights and have better communication with families in advance.
New Insights into the Activities of D-Chiro-Inositol: A Narrative Review
Authors: Gambioli Riccardo , Montanino Oliva Mario , Nordio Maurizio , Chiefari Alfonsina , Puliani Giulia , Unfer Vittorio
Published: October 2021

D-chiro-inositol (DCI) is a natural compound detectable in cell membranes, which is highly conserved as a biological signaling molecule. In mammals, its function is primarily characterized in the intracellular transduction cascade of insulin. In particular, insulin signal promotes the release of pivotal DCI-containing molecules. In fact, impaired release of DCI is a common feature of insulin-resistant tissues, and insulin-sensitizing pharmaceuticals induce higher concentrations of free DCI. Moreover, it also plays important roles in several other processes. DCI is involved in the regulation of steroidogenesis, due to its regulatory effects on steroidogenic enzymes, including 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and aromatase. Such regulation of various enzymes indicates a mechanism by which the body regulates different processes via a single molecule, depending on its concentration. DCI also reduces the expression of integrin β3, which is an adhesion molecule involved in embryo implantation and cellular phenomena such as survival, stemness, and invasiveness. In addition, DCI seems to have important anti-inflammatory activities, like its 3-O-methyl-ether, called pinitol. In vitro evidence demonstrates that treatment with both compounds induces a reduction in pro-inflammatory factors—such as Nf-κB—and cytokines—such as TNF-α. DCI then plays important roles in several fundamental processes in physiology. Therefore, research on such molecule is of primary importance.
A UHPLC–MS/MS Method for Therapeutic Drug Monitoring of Aciclovir and Ganciclovir in Plasma and Dried Plasma Spots
Authors: Pigliasco Federica , Cafaro Alessia , Simeoli Raffaele , Barco Sebastiano , Magnasco Alberto , Faraci Maura , Tripodi Gino , Goffredo Bianca Maria , Cangemi Giuliana
Published: October 2021

The role of therapeutic drug monitoring (TDM) of valaciclovir (VA)/aciclovir (A) and valganciclovir/ganciclovir (VG/G) in critically ill patients is still a matter of debate. More data on the dose–concentration relationship might therefore be useful, especially in pediatrics where clinical practice is not adequately supported by robust PK studies. We developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) micro-method to simultaneously quantify A and G from plasma and dried plasma spots (DPS). The method was based on rapid organic extraction from DPS and separation on a reversed-phase C-18 UHPLC column after addition of deuterated internal standards. Accurate analyte quantification using SRM detection was then obtained using a Thermo Fisher Quantiva triple-quadrupole MS coupled to an Ultimate 3000 UHPLC. It was validated following international (EMA) guidelines for bioanalytical method validation and was tested on samples from pediatric patients treated with A, VG, or G for cytomegalovirus infection following solid organ or hematopoietic stem cell transplantation. Concentrations obtained from plasma and DPS were compared using Passing–Bablok and Bland–Altman statistical tests. The assay was linear over wide concentration ranges (0.01–20 mg/L) in both plasma and DPS for A and G, suitable for the expected therapeutic ranges for both Cmin and Cmax, accurate, and reproducible in the absence of matrix effects. The results obtained from plasma and DPS were comparable. Using an LC-MS/MS method allowed us to obtain a very specific, sensitive, and rapid quantification of these antiviral drugs starting from very low volumes (50 μL) of plasma samples and DPS. The stability of analytes for at least 30 days allows for cost-effective shipment and storage at room temperature. Our method is suitable for TDM and could be helpful for improving knowledge on PK/PD targets of antivirals in critically ill pediatric patients.
Evaluation of the Antioxidant, Antidiabetic, and Antiplasmodial Activities of Xanthones Isolated from Garcinia forbesii and Their In Silico Studies
Authors: Wairata Johanis , Sukandar Edwin Risky , Fadlan Arif , Purnomo Adi Setyo , Taher Muhammad , Ersam Taslim
Published: October 2021

This study aimed to isolate xanthones from Garcinia forbesii and evaluated their activity in vitro and in silico. The isolated compounds were evaluated for their antioxidant activity by DPPH, ABTS and FRAP methods. The antidiabetic activity was performed against α-glucosidase and α-amylase enzymes. The antiplasmodial activity was evaluated using Plasmodium falciparum strain 3D7 sensitive to chloroquine. Molecular docking analysis on the human lysosomal acid-alpha-glucosidase enzyme (5NN8) and P. falciparum lactate dehydrogenase enzyme (1CET) and prediction of ADMET for the active compound, were also studied. For the first time, lichexanthone (1), subelliptenone H (2), 12b-hydroxy-des-D-garcigerrin A (3), garciniaxanthone B (4) and garcigerin A (5) were isolated from the CH2Cl2 extract of the stem bark of G. forbesii. Four xanthones (Compounds 2–5) showed strong antioxidant activity. In vitro α-glucosidase test showed that Compounds 2 and 5 were more active than the others, while Compound 4 was the strongest against α-amylase enzymes. In vitro antiplasmodial evaluation revealed that Compounds 2 and 3 showed inhibitory activity on P. falciparum. Molecular docking studies confirmed in vitro activity. ADMET predictions suggested that Compounds 1–5 were potential candidates for oral drugs. The isolated 2–5 can be used as promising phytotherapy in antidiabetic and antiplasmodial treatment.
Discovery, Optimization, and Clinical Application of Natural Antimicrobial Peptides
Authors: Rodríguez Armando A. , Otero-González Anselmo , Ghattas Maretchia , Ständker Ludger
Published: October 2021

Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and anticancer activities. During the last 30 years, technological advances have boosted the research on antimicrobial peptides, which have also attracted great interest as an alternative to tackling the antimicrobial resistance scenario mainly provoked by some bacterial and fungal pathogens. However, the introduction of natural AMPs in clinical trials faces challenges such as proteolytic digestion, short half-lives, and cytotoxicity upon systemic and oral application. Therefore, some strategies have been implemented to improve the properties of AMPs aiming to be used as effective therapeutic agents. In the present review, we summarize the discovery path of AMPs, focusing on preclinical development, recent advances in chemical optimization and peptide delivery systems, and their introduction into the market.
Introducing Fluorescence-Guided Surgery for Pediatric Ewing, Osteo-, and Rhabdomyosarcomas: A Literature Review
Authors: Rijs Zeger , Jeremiasse Bernadette , Shifai Naweed , Gelderblom Hans , Sier Cornelis F. M. , Vahrmeijer Alexander L. , van Leeuwen Fijs W. B. , van der Steeg Alida F. W. , van de Sande Michiel A. J.
Published: October 2021

Sarcomas are a rare heterogeneous group of malignant neoplasms of mesenchymal origin which represent approximately 13% of all cancers in pediatric patients. The most prevalent pediatric bone sarcomas are osteosarcoma (OS) and Ewing sarcoma (ES). Rhabdomyosarcoma (RMS) is the most frequently occurring pediatric soft tissue sarcoma. The median age of OS and ES is approximately 17 years, so this disease is also commonly seen in adults while non-pleiomorphic RMS is rare in the adult population. The mainstay of all treatment regimens is multimodal treatment containing chemotherapy, surgical resection, and sometimes (neo)adjuvant radiotherapy. A clear resection margin improves both local control and overall survival and should be the goal during surgery with a curative intent. Real-time intraoperative fluorescence-guided imaging could facilitate complete resections by visualizing tumor tissue during surgery. This review evaluates whether non-targeted and targeted fluorescence-guided surgery (FGS) could be beneficial for pediatric OS, ES, and RMS patients. Necessities for clinical implementation, current literature, and the positive as well as negative aspects of non-targeted FGS using the NIR dye Indocyanine Green (ICG) were evaluated. In addition, we provide an overview of targets that could potentially be used for FGS in OS, ES, and RMS. Then, due to the time- and cost-efficient translational perspective, we elaborate on the use of antibody-based tracers as well as their disadvantages and alternatives. Finally, we conclude with recommendations for the experiments needed before FGS can be implemented for pediatric OS, ES, and RMS patients.
Does Chemotherapy-Induced Gastrointestinal Mucositis Affect the Bioavailability and Efficacy of Anti-Infective Drugs?
Authors: da Silva Ferreira Ana Rita , Märtson Anne-Grete , de Boer Alyse , Wardill Hannah R. , Alffenaar Jan-Willem , Harmsen Hermie J. M. , Tissing Wim J. E.
Published: October 2021

Antimicrobial prophylaxis is increasingly being used in patients with hematological malignancies receiving high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT). However, few studies have focused on the potential impact of gastrointestinal mucositis (GI-M), a frequently observed side effect of chemotherapy in patients with cancer that affects the gastrointestinal microenvironment, on drug absorption. In this review, we discuss how chemotherapy leads to an overall loss of mucosal surface area and consequently to uncontrolled transport across the barrier. The barrier function is depending on intestinal luminal pH, intestinal motility, and diet. Another factor contributing to drug absorption is the gut microbiota, as it modulates the bioavailability of orally administrated drugs by altering the gastrointestinal properties. To better understand the complex interplay of factors in GI-M and drug absorption we suggest: (i) the longitudinal characterization of the impact of GI-M severity on drug exposure in patients, (ii) the development of tools to predict drug absorption, and (iii) strategies that allow the support of the gut microbiota. These studies will provide relevant data to better design strategies to reduce the severity and impact of GI-M in patients with cancer.
Novel Biodegradable Composite of Calcium Phosphate Cement and the Collagen I Mimetic P-15 for Pedicle Screw Augmentation in Osteoporotic Bone
Authors: Krenzlin Harald , Foelger Andrea , Mailänder Volker , Blase Christopher , Brockmann Marc , Düber Christoph , Ringel Florian , Keric Naureen
Published: October 2021

Osteoporotic vertebral fractures often necessitate fusion surgery, with high rates of implant failure. We present a novel bioactive composite of calcium phosphate cement (CPC) and the collagen I mimetic P-15 for pedicle screw augmentation in osteoporotic bone. Methods involved expression analysis of osteogenesis-related genes during osteoblastic differentiation by RT-PCR and immunostaining of osteopontin and Ca2+ deposits. Untreated and decalcified sheep vertebrae were utilized for linear pullout testing of pedicle screws. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA). Expression of ALPI II (p < 0.0001), osteopontin (p < 0.0001), RUNX2 (p < 0.0001), and osteocalcin (p < 0.0001) was upregulated after co-culture of MSC with CPC-P-15. BMD was decreased by 28.75% ± 2.6%. Pullout loads in untreated vertebrae were 1405 ± 6 N (p < 0.001) without augmentation, 2010 ± 168 N (p < 0.0001) after augmentation with CPC-P-15, and 2112 ± 98 N (p < 0.0001) with PMMA. In decalcified vertebrae, pullout loads were 828 ± 66 N (p < 0.0001) without augmentation, 1324 ± 712 N (p = 0.04) with PMMA, and 1252 ± 131 N (p < 0.0078) with CPC-P-15. CPC-P-15 induces osteoblastic differentiation of human MES and improves pullout resistance of pedicle screws in osteoporotic and non-osteoporotic bone.
Macrophage Identification In Situ
Authors: Nikovics Krisztina , Favier Anne-Laure
Published: October 2021

Understanding the processes of inflammation and tissue regeneration after injury is of great importance. For a long time, macrophages have been known to play a central role during different stages of inflammation and tissue regeneration. However, the molecular and cellular mechanisms by which they exert their effects are as yet mostly unknown. While in vitro macrophages have been characterized, recent progress in macrophage biology studies revealed that macrophages in vivo exhibited distinctive features. Actually, the precise characterization of the macrophages in vivo is essential to develop new healing treatments and can be approached via in situ analyses. Nowadays, the characterization of macrophages in situ has improved significantly using antigen surface markers and cytokine secretion identification resulting in specific patterns. This review aims for a comprehensive overview of different tools used for in situ macrophage identification, reporter genes, immunolabeling and in situ hybridization, discussing their advantages and limitations.
A DNA Methylation-Based Gene Signature Can Predict Triple-Negative Breast Cancer Diagnosis
Authors: Mendaza Saioa , Guerrero-Setas David , Monreal-Santesteban Iñaki , Ulazia-Garmendia Ane , Cordoba Iturriagagoitia Alicia , De la Cruz Susana , Martín-Sánchez Esperanza
Published: October 2021

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype and lacks targeted treatment. It is diagnosed by the absence of immunohistochemical expression of several biomarkers, but this method still displays some interlaboratory variability. DNA methylome aberrations are common in BC, thereby methylation profiling could provide the identification of accurate TNBC diagnosis biomarkers. Here, we generated a signature of differentially methylated probes with class prediction ability between 5 non-neoplastic breast and 7 TNBC tissues (error rate = 0.083). The robustness of this signature was corroborated in larger cohorts of additional 58 non-neoplastic breast, 93 TNBC, and 150 BC samples from the Gene Expression Omnibus repository, where it yielded an error rate of 0.006. Furthermore, we validated by pyrosequencing the hypomethylation of three out of 34 selected probes (FLJ43663, PBX Homeobox 1 (PBX1), and RAS P21 protein activator 3 (RASA3) in 51 TNBC, even at early stages of the disease. Finally, we found significantly lower methylation levels of FLJ43663 in cell free-DNA from the plasma of six TNBC patients than in 15 healthy donors. In conclusion, we report a novel DNA methylation signature with potential predictive value for TNBC diagnosis.