bluuebunny/crossref_metadata_2025 huggingface dataset:
The synergistic interference effect of silica nanoparticles concentration and the wavelength of ELISA on the colorimetric assay of cell toxicity
Authors: Abbasi Fariba , Hashemi Hassan , Samaei Mohammad Reza , SavarDashtaki Amir , Azhdarpoor Abooalfazl , Fallahi Mohammad Javad
Published: July 2021

The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay is the most common method for the determination of cell toxicity, but some factors limit the sensitivity of this method, such as pH. Less attention had been paid to the interference effect of optical and plasmonic properties of SiO2 nanoparticles (NPs) in the wavelength range assigned to MTT. This study investigated the synergistic interference effect of SiO2 NPs and wavelength on MTT assay for the first time. The examined variables included the type of SiO2 NPs concentrations (1, 10, and 100 mM) and different wavelengths (470, 490, 520, and 570 nm). The results showed that optical density (OD) increased (p < 0.05) when wavelength and the concentration of crystalline SiO2 NPs increased. So, the maximum OD at 10 and 100 mM were attributed to crystalline SiO2 NPs (p < 0.05) due to the functional group, whereas it was related to amorphous at 1 mM (p > 0.05). According to polynomial regression modeling (PRM), the maximum interference effect was predicted at crystalline SiO2 NPs and wavelength > 550 nm. Besides, the synergistic effects of SiO2 NPs, wavelength, and concentration of NPs had been a good fitting with first-order PRM. Thus, the concentration of SiO2 NPs had a confounder factor in colorimetric for MTT assay. The best artificial neural network (ANN) structure was related to the 3:7:1 network (Rall = 0.936, MSE = 0.0006, MAPE = 0.063). The correlation between the actual and predicted data was 0.88. As SiO2 NPs presence is an interfering factor in MTT assay concerning wavelength, it is suggested wavelength use with minimum confounding effect for MTT assay.
Elevated cellular PpIX potentiates sonodynamic therapy in a mouse glioma stem cell-bearing glioma model by downregulating the Akt/NF-κB/MDR1 pathway
Authors: Shono Kenji , Mizobuchi Yoshifumi , Yamaguchi Izumi , Nakajima Kohei , Fujiwara Yuri , Fujihara Toshitaka , Kitazato Keiko , Matsuzaki Kazuhito , Uto Yoshihiro , Sampetrean Oltea , Saya Hideyuki , Takagi Yasushi
Published: July 2021

Glioblastoma (GBM) has high mortality rates because of extreme therapeutic resistance. During surgical resection for GBM, 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is conventionally applied to distinguish GBM. However, surgical intervention is insufficient for high invasive GBM. Sonodynamic therapy (SDT) combined with low-intensity ultrasonication (US) and PpIX, as a sonosensitizer, is an emerging and promising approach, although its efficacy is limited. Based on our previous study that down-regulation of multidrug resistant protein (MDR1) in GBM augmented the anti-tumor effects of chemotherapy, we hypothesized that elevation of cellular PpIX levels by down-regulation of MDR1 enhances anti-tumor effects by SDT. In high invasive progeny cells from mouse glioma stem cells (GSCs) and a GSC-bearing mouse glioma model, we assessed the anti-tumor effects of SDT with a COX-2 inhibitor, celecoxib. Down-regulation of MDR1 by celecoxib increased cellular PpIX levels, as well as valspodar, an MDR1 inhibitor, and augmented anti-tumor effects of SDT. MDR1 down-regulation via the Akt/NF-κB pathway by celecoxib was confirmed, using an NF-κB inhibitor, CAPÉ. Thus, elevation of cellar PpIX by down-regulation of MDR1 via the Akt/NF-κB pathway may be crucial to potentiate the efficacy of SDT in a site-directed manner and provide a promising new therapeutic strategy for GBM.
Validation of a self-report questionnaire for periodontitis in a Japanese population
Authors: Iwasaki Masanori , Usui Michihiko , Ariyoshi Wataru , Nakashima Keisuke , Nagai-Yoshioka Yoshie , Inoue Maki , Kobayashi Kaoru , Borgnakke Wenche S. , Taylor George W. , Nishihara Tatsuji
Published: July 2021

We aimed to assess the validity of the self-report questionnaire for periodontitis in a Japanese population. A Japanese 9-item self-report questionnaire, developed by translating English-version questions that were used to detect periodontitis, was validated against full-mouth clinically-assessed periodontitis in 949 Japanese adults (average age = 43.2 years). Multivariable logistic regression modeling was used to calculate the area under the receiver operating characteristic curve (AUC), wherein the periodontitis case definition of the Centers for Disease Control and Prevention/American Academy of Periodontology was considered the gold standard. Severe, moderate, and mild periodontitis were identified in 6.2%, 30.0%, and 6.7% of the study population, respectively. Self-reported oral health questions combined with socio-demographic and health-related variables had an AUC > 0.70 (range, 0.71–0.87) for any periodontitis category. Four oral health questions (“have gum disease,” “loose tooth,” “lost bone,” and “bleeding gums”) were selected in the parsimonious model for severe periodontitis. The periodontitis screening score generated by the responses to these four questions had an AUC, sensitivity, and specificity of 0.82, 73.1%, and 74.3%, respectively, where the cut-off was set at 2 points. In conclusion, a locally adapted version of the self-report questionnaire had an acceptable diagnostic capacity for the detection of periodontitis in this study population.
Genomic evolution of antimicrobial resistance in Escherichia coli
Authors: Leekitcharoenphon Pimlapas , Johansson Markus Hans Kristofer , Munk Patrick , Malorny Burkhard , Skarżyńska Magdalena , Wadepohl Katharina , Moyano Gabriel , Hesp Ayla , Veldman Kees T. , Bossers Alex ,   EFFORT Consortium, Graveland Haitske , van Essen Alieda , Battisti Antonio , Caprioli Andrea , Blaha Thomas , Hald Tine , Daskalov Hristo , Saatkamp Helmut W. , Stärk Katharina D. C. , Luiken Roosmarijn E. C. , Van Gompel Liese , Hansen Rasmus Borup , Dewulf Jeroen , Duarte Ana Sofia Ribeiro , Zając Magdalena , Wasyl Dariusz , Sanders Pascal , Gonzalez-Zorn Bruno , Brouwer Michael S. M. , Wagenaar Jaap A. , Heederik Dick J. J. , Mevius Dik , Aarestrup Frank M.
Published: July 2021

The emergence of antimicrobial resistance (AMR) is one of the biggest health threats globally. In addition, the use of antimicrobial drugs in humans and livestock is considered an important driver of antimicrobial resistance. The commensal microbiota, and especially the intestinal microbiota, has been shown to have an important role in the emergence of AMR. Mobile genetic elements (MGEs) also play a central role in facilitating the acquisition and spread of AMR genes. We isolated Escherichia coli (n = 627) from fecal samples in respectively 25 poultry, 28 swine, and 15 veal calf herds from 6 European countries to investigate the phylogeny of E. coli at country, animal host and farm levels. Furthermore, we examine the evolution of AMR in E. coli genomes including an association with virulence genes, plasmids and MGEs. We compared the abundance metrics retrieved from metagenomic sequencing and whole genome sequenced of E. coli isolates from the same fecal samples and farms. The E. coli isolates in this study indicated no clonality or clustering based on country of origin and genetic markers; AMR, and MGEs. Nonetheless, mobile genetic elements play a role in the acquisition of AMR and virulence genes. Additionally, an abundance of AMR was agreeable between metagenomic and whole genome sequencing analysis for several AMR classes in poultry fecal samples suggesting that metagenomics could be used as an indicator for surveillance of AMR in E. coli isolates and vice versa.
$$\mu PT$$ statistical ensemble: systems with fluctuating energy, particle number, and volume
Authors: Marzolino Ugo
Published: July 2021

Within the theory of statistical ensemble, the so-called $$\mu PT$$

μ
P
T

ensemble describes equilibrium systems that exchange energy, particles, and volume with the surrounding. General, model-independent features of volume and particle number statistics are derived. Non-analytic points of the partition function are discussed in connection with divergent fluctuations and ensemble equivalence. Quantum and classical ideal gases, and a model of Bose gas with mean-field interactions are discussed as examples of the above considerations.
A network approach to the five-facet model of mindfulness
Authors: Heeren Alexandre , Lannoy Séverine , Coussement Charlotte , Hoebeke Yorgo , Verschuren Alice , Blanchard M. Annelise , Chakroun-Baggioni Nadia , Philippot Pierre , Gierski Fabien
Published: July 2021

Despite the large-scale dissemination of mindfulness-based interventions, debates persist about the very nature of mindfulness. To date, one of the dominant views is the five-facet approach, which suggests that mindfulness includes five facets (i.e., Observing, Describing, Nonjudging, Nonreactivity, and Acting with Awareness). However, uncertainty remains regarding the potential interplay between these facets. In this study, we investigated the five-facet model via network analysis in an unselected sample (n = 1704). We used two distinct computational network approaches: a Gaussian graphical model (i.e., undirected) and a directed acyclic graph, with each model determining the relations between the facets and their relative importance in the network. Both computational approaches pointed to the facet denoting Acting with Awareness as playing an especially potent role in the network system. Altogether, our findings offer novel data-driven clues for the field's larger quest to ascertain the very foundations of mindfulness.
Cascading effects of moth outbreaks on subarctic soil food webs
Authors: Calderón-Sanou Irene , Münkemüller Tamara , Zinger Lucie , Schimann Heidy , Yoccoz Nigel Gilles , Gielly Ludovic , Foulquier Arnaud , Hedde Mickael , Ohlmann Marc , Roy Mélanie , Si-Moussi Sara , Thuiller Wilfried
Published: July 2021

The increasing severity and frequency of natural disturbances requires a better understanding of their effects on all compartments of biodiversity. In Northern Fennoscandia, recent large-scale moth outbreaks have led to an abrupt change in plant communities from birch forests dominated by dwarf shrubs to grass-dominated systems. However, the indirect effects on the belowground compartment remained unclear. Here, we combined eDNA surveys of multiple trophic groups with network analyses to demonstrate that moth defoliation has far-reaching consequences on soil food webs. Following this disturbance, diversity and relative abundance of certain trophic groups declined (e.g., ectomycorrhizal fungi), while many others expanded (e.g., bacterivores and omnivores) making soil food webs more diverse and structurally different. Overall, the direct and indirect consequences of moth outbreaks increased belowground diversity at different trophic levels. Our results highlight that a holistic view of ecosystems improves our understanding of cascading effects of major disturbances on soil food webs.
Seasonality and landscape characteristics impact species community structure and temporal dynamics of East African butterflies
Authors: Schmitt Thomas , Ulrich Werner , Delic Andjela , Teucher Mike , Habel Jan Christian
Published: July 2021

Species community structures respond strongly to habitat changes. These are either driven by nature or human activities. The biota of East African drylands responds highly sensitively to natural and anthropogenic impacts. Thus, seasonality strongly influences resource availability in a cyclic manner during the year, with cyclic appearance of the different developmental stages of invertebrates, while man-made landscape transformations profoundly and permanently modify habitat structures and, as a consequence, species communities. Butterflies are an excellent model group for the study of the effects of seasonality, and to test for biodiversity responses to anthropogenic activities such as habitat modification, degradation and destruction. We performed transect counts of adult butterflies in riparian forests and their adjoining areas, either dry savannahs with occasional pasturing (i.e. near-natural status) or farmland areas with fields, gardens and settlements (i.e. highly degraded status with lack of original vegetation). Transects were set along the river beds as well as at 250 m and 500 m distances parallel to these rivers, with eight transects per distance class and site (i.e. 48 transects in total). We recorded habitat structures for each transect. Counts were conducted during the dry and the rainy season, with 16 repetitions for each single transect, i.e. eight per season and transect. We compiled trait data on morphology, geographic distribution, ecology, behaviour, and life-history for all butterfly species encountered. Our results show higher species richness and numbers of individuals in farmland transects compared with the savannah region. Seasonal fluctuations of the detectable species abundances between the rainy and dry season were severe. These fluctuations were much more pronounced for the savannah than the farmland area, i.e. was buffered by human activities. Farmland and savannah support two distinct butterfly communities, with generalist species being more common in the farmland communities. Strict habitat associations were comparatively weak and typical dry savannah and riparian forest species were not clearly restricted to the near natural landscape.
Quasilinearization numerical technique for dual slip MHD Newtonian fluid flow with entropy generation in thermally dissipating flow above a thin needle
Authors: Khan Sohaib , Ali Farhad , Khan Waqar A. , Imtiaz Anees , Khan Ilyas , Abdeljawad Thabet
Published: July 2021

In the present article, we investigate the dual slip effect namely the velocity slip and thermal slip conditions on MHD flow past a thin needle. The entropy generation for the incompressible fluids that’s water and acetone that flowing above the thin needle is discussed. The energy dissipating term and the magnetic effect is included in the axial direction. The leading partial differential equations are transformed to ODE by an appropriate similarity transformation and solved using a numerical technique that is the Quasilinearization method. The terms for the rate of entropy generation, the Bejan number, and the irreversibility distribution ratio are discussed. Each dimensionless number is shown with velocity slip and also with the magnetic parameter is presented in graphical form. In the result, we conclude that the entropy generation rate is increasing with the increase in thermal slip parameter also some increasing effect is found as the size of the needle increases
Prognostic significance of pre-treatment ALBI grade in advanced non-small cell lung cancer receiving immune checkpoint therapy
Authors: Matsukane Ryosuke , Watanabe Hiroyuki , Hata Kojiro , Suetsugu Kimitaka , Tsuji Toshikazu , Egashira Nobuaki , Nakanishi Yoichi , Okamoto Isamu , Ieiri Ichiro
Published: July 2021

The liver is an essential organ for regulating innate and acquired immunity. We hypothesized that the pre-treatment hepatic function affects the clinical outcome of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We analyzed 140 patients with NSCLC who received ICIs. We investigated the association between pre-treatment liver function, assessed using the albumin–bilirubin (ALBI) grade, and clinical outcomes in univariate, multivariate, and propensity score matching analyses. Patients were divided into four grades according to pre-treatment liver function. Eighty-eight patients had good hepatic reserve (ALBI grade 1 or 2a), whereas 52 patients had poor hepatic reserve (ALBI grade 2b or 3). In the univariate Kaplan–Meier analysis, the ALBI grade 1, 2a group had a significantly prolonged progression-free survival (PFS, 5.3 versus 2.5 months, p = 0.0019) and overall survival (OS, 19.6 vs. 6.2 months, p = 0.0002). These results were consistent, regardless of whether the analysis was performed in patients with a performance status of 0 or 1 at pre-treatment (N = 124) or in those selected using propensity score matching (N = 76). In the multivariate analysis, pre-treatment ALBI grade was an independent prognostic factor for both PFS (hazard ratio [HR] 0.57, 95% confidence interval [95% CI] 0.38–0.86, p = 0.007) and OS (HR 0.45, 95% CI 0.29–0.72, p = 0.001). Our results suggest that pre-treatment hepatic function assessed by ALBI grade could be an essential biomarker for predicting the efficacy of treatment with ICIs in NSCLC.
QCBCT-NET for direct measurement of bone mineral density from quantitative cone-beam CT: a human skull phantom study
Authors: Yong Tae-Hoon , Yang Su , Lee Sang-Jeong , Park Chansoo , Kim Jo-Eun , Huh Kyung-Hoe , Lee Sam-Sun , Heo Min-Suk , Yi Won-Jin
Published: July 2021

The purpose of this study was to directly and quantitatively measure BMD from Cone-beam CT (CBCT) images by enhancing the linearity and uniformity of the bone intensities based on a hybrid deep-learning model (QCBCT-NET) of combining the generative adversarial network (Cycle-GAN) and U-Net, and to compare the bone images enhanced by the QCBCT-NET with those by Cycle-GAN and U-Net. We used two phantoms of human skulls encased in acrylic, one for the training and validation datasets, and the other for the test dataset. We proposed the QCBCT-NET consisting of Cycle-GAN with residual blocks and a multi-channel U-Net using paired training data of quantitative CT (QCT) and CBCT images. The BMD images produced by QCBCT-NET significantly outperformed the images produced by the Cycle-GAN or the U-Net in mean absolute difference (MAD), peak signal to noise ratio (PSNR), normalized cross-correlation (NCC), structural similarity (SSIM), and linearity when compared to the original QCT image. The QCBCT-NET improved the contrast of the bone images by reflecting the original BMD distribution of the QCT image locally using the Cycle-GAN, and also spatial uniformity of the bone images by globally suppressing image artifacts and noise using the two-channel U-Net. The QCBCT-NET substantially enhanced the linearity, uniformity, and contrast as well as the anatomical and quantitative accuracy of the bone images, and demonstrated more accuracy than the Cycle-GAN and the U-Net for quantitatively measuring BMD in CBCT.
A transitional fossil mite (Astigmata: Levantoglyphidae fam. n.) from the early Cretaceous suggests gradual evolution of phoresy-related metamorphosis
Authors: Klimov Pavel B. , Vorontsov Dmitry D. , Azar Dany , Sidorchuk Ekaterina A. , Braig Henk R. , Khaustov Alexander A. , Tolstikov Andrey V.
Published: July 2021

Metamorphosis is a key innovation allowing the same species to inhabit different environments and accomplish different functions, leading to evolutionary success in many animal groups. Astigmata is a megadiverse lineage of mites that expanded into a great number of habitats via associations with invertebrate and vertebrate hosts (human associates include stored food mites, house dust mites, and scabies). The evolutionary success of Astigmata is linked to phoresy-related metamorphosis, namely the origin of the heteromorphic deutonymph, which is highly specialized for phoresy (dispersal on hosts). The origin of this instar is enigmatic since it is morphologically divergent and no intermediate forms are known. Here we describe the heteromorphic deutonymph of Levantoglyphus sidorchukae n. gen. and sp. (Levantoglyphidae fam. n.) from early Cretaceous amber of Lebanon (129 Ma), which displays a transitional morphology. It is similar to extant phoretic deutonymphs in its modifications for phoresy but has the masticatory system and other parts of the gnathosoma well-developed. These aspects point to a gradual evolution of the astigmatid heteromorphic morphology and metamorphosis. The presence of well-developed presumably host-seeking sensory elements on the gnathosoma suggests that the deutonymph was not feeding either during phoretic or pre- or postphoretic periods.
BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory
Authors: Nash A. , Gijsen H. J. M. , Hrupka B. J. , Teng K. S.-L. , Lichtenthaler S. F. , Takeshima H. , Gunnersen J. M. , Munro K. M.
Published: July 2021

BACE inhibitors, which decrease BACE1 (β-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer’s disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function. Mice were treated with an in-diet BACE inhibitor for 4–8 weeks to achieve a clinically-relevant level of amyloid-β40 reduction in the brain. Mice underwent behavioural testing and postmortem analysis of dendritic spine number and morphology with Golgi-Cox staining. Sez6 family triple knockout mice were tested alongside wild-type mice to identify whether any effects of the treatment were due to altered cleavage of Sez6 family proteins. Wild-type mice treated with BACE inhibitor displayed hyperactivity on the elevated open field, as indicated by greater distance travelled, but this effect was not observed in treated Sez6 triple knockout mice. BACE inhibitor treatment did not lead to significant changes in spatial or fear learning, reference memory, cognitive flexibility or anxiety in mice as assessed by the Morris water maze, context fear conditioning, or light–dark box tests. Chronic BACE inhibitor treatment reduced the density of mushroom-type spines in the somatosensory cortex, regardless of genotype, but did not affect steady-state dendritic spine density or morphology in the CA1 region of the hippocampus. Chronic BACE inhibition for 1–2 months in mice led to increased locomotor output but did not alter memory or cognitive flexibility. While the mechanism underlying the treatment-induced hyperactivity is unknown, the absence of this response in Sez6 triple knockout mice indicates that blocking ectodomain shedding of Sez6 family proteins is a contributing factor. In contrast, the decrease in mature spine density in cortical neurons was not attributable to lack of shed Sez6 family protein ectodomains. Therefore, other BACE1 substrates are implicated in this effect and, potentially, in the cognitive decline in longer-term chronically treated patients.
Randomized clinical trial shows no substantial modulation of empathy-related neural activation by intranasal oxytocin in autism
Authors: Mayer Annalina V. , Wermter Anne-Kathrin , Stroth Sanna , Alter Peter , Haberhausen Michael , Stehr Thomas , Paulus Frieder M. , Krach Sören , Kamp-Becker Inge
Published: July 2021

Evidence suggests that intranasal application of oxytocin facilitates empathy and modulates its underlying neural processes, which are often impaired in individuals with autism spectrum disorders (ASD). Oxytocin has therefore been considered a promising candidate for the treatment of social difficulties in ASD. However, evidence linking oxytocin treatment to social behavior and brain function in ASD is limited and heterogeneous effects might depend on variations in the oxytocin-receptor gene (OXTR). We examined 25 male ASD patients without intellectual disability in a double-blind, cross-over, placebo-controlled fMRI-protocol, in which a single dose of oxytocin or placebo was applied intranasally. Patients performed three experiments in the MRI examining empathy for other’s physical pain, basic emotions, and social pain. All participants were genotyped for the rs53576 single-nucleotide polymorphism of the OXTR. Oxytocin increased bilateral amygdala responsiveness during the physical pain task for both painful and neutral stimuli. Other than that, there were no effects of oxytocin treatment. OXTR genotype did not significantly interact with oxytocin treatment. Our results contribute to the growing body of empirical literature suggesting heterogenous effects of oxytocin administration in ASD. To draw clinically relevant conclusions regarding the usefulness of oxytocin treatment, however, empirical studies need to consider methods of delivery, dose, and moderating individual factors more carefully in larger samples.
A rational design of multimodal asymmetric nanoshells as efficient tunable absorbers within the biological optical window
Authors: Souri Somayeh , Hadilou Naby , Navid H. A. , Sadighi Bonabi Rasoul , Anvari Abbas
Published: July 2021

In this work, the optical properties of asymmetric nanoshells with different geometries are comprehensively investigated in the quasi-static regime by applying the dipolar model and effective medium theory. The plasmonic behaviors of these nanostructures are explained by the plasmon hybridization model. Asymmetric hybrid nanoshells, composed of off-center core or nanorod core surrounded by a spherical metallic shell layer possess highly geometrically tunable optical resonances in the near-infrared regime. The plasmon modes of this nanostructures arise from the hybridization of the cavity and solid plasmon modes at the inner and outer surfaces of the shell. The results reveal that the symmetry breaking drastically affects the strength of hybridization between plasmon modes, which ultimately affects the absorption spectrum by altering the number of resonance modes, their wavelengths and absorption efficiencies. Therefore, offsetting the spherical core as well as changing the internal geometry of the nanoparticle to nanorod not only shift the resonance frequencies but can also strongly modify the relative magnitudes of the absorption efficiencies. Furthermore, higher order multipolar plasmon modes can appear in the spectrum of asymmetric nanoshell, especially in nanoegg configuration. The results also indicate that the strength of hybridization strongly depends on the metal of shell, material of core and the filling factor. Using Au-Ag alloy as a material of the shell can provide red-shifted narrow resonance peak in the near-infrared regime by combining the specific features of gold and silver. Moreover, inserting a high permittivity core in a nanoshell corresponds to a red-shift, while a core with small dielectric constant results in a blue-shift of spectrum. We envision that this research offers a novel perspective and provides a practical guideline in the fabrication of efficient tunable absorbers in the nanoscale regime.
Ly6G deficiency alters the dynamics of neutrophil recruitment and pathogen capture during Leishmania major skin infection
Authors: Kleinholz Corinna L. , Riek-Burchardt Monika , Seiß Elena A. , Amore Jonas , Gintschel Patricia , Philipsen Lars , Bousso Philippe , Relja Borna , Schraven Burkhart , Handschuh Juliane , Mohr Juliane , Müller Andreas J.
Published: July 2021

Neutrophils represent one of the first immune cell types recruited to sites of infection, where they can control pathogens by phagocytosis and cytotoxic mechanisms. Intracellular pathogens such asLeishmania majorcan hijack neutrophils to establish an efficient infection. However the dynamic interactions of neutrophils with the pathogen and other cells at the site of the infection are incompletely understood. Here, we have investigated the role of Ly6G, a homolog of the human CD177 protein, which has been shown to interact with cell adhesion molecules, and serves as a bona fide marker for neutrophils in mice. We show that Ly6G deficiency decreases the initial infection rate of neutrophils recruited to the site of infection. Although the uptake ofL. majorby subsequently recruited monocytes was tightly linked with the concomitant uptake of neutrophil material, this process was not altered by Ly6G deficiency of the neutrophils. Instead, we observed by intravital 2-photon microscopy that Ly6G-deficient neutrophils entered the site of infection with delayed initial recruitment kinetics. Thus, we conclude that by promoting neutrophils’ ability to efficiently enter the site of infection, Ly6G contributes to the early engagement of intracellular pathogens by the immune system.
Locomotion and disaggregation control of paramagnetic nanoclusters using wireless electromagnetic fields for enhanced targeted drug delivery
Authors: Nguyen Kim Tien , Go Gwangjun , Zhen Jin , Hoang Manh Cuong , Kang Byungjeon , Choi Eunpyo , Park Jong-Oh , Kim Chang-Sei
Published: July 2021

Magnetic nanorobots (MNRs) based on paramagnetic nanoparticles/nanoclusters for the targeted therapeutics of anticancer drugs have been highlighted for their efficiency potential. Controlling the locomotion of the MNRs is a key challenge for effective delivery to the target legions. Here, we present a method for controlling paramagnetic nanoclusters through enhanced tumbling and disaggregation motions with a combination of rotating field and gradient field generated by external electromagnets. The mechanism is carried out via an electromagnetic actuation system capable of generating MNR motions with five degrees of freedom in a spherical workspace without singularity. The nanocluster swarm structures can successfully pass through channels to the target region where they can disaggregate. The results show significantly faster response and higher targeting rate by using rotating magnetic and gradient fields. The mean velocities of the enhanced tumbling motion are twice those of the conventional tumbling motion and approximately 130% higher than the gradient pulling motion. The effects of each fundamental factor on the locomotion are investigated for further MNR applications. The locomotion speed of the MNR could be predicted by the proposed mathematical model and agrees well with experimental results. The high access rate and disaggregation performance insights the potentials for targeted drug delivery application.
The relationship between vitamin C or thiamine levels and outcomes for severe sepsis patients admitted to the ICU
Authors: Prasad Nandan , Grossestreuer Anne V. , Meyer Nuala J. , Perman Sarah M. , Mikkelsen Mark E. , Hollander Judd , Gaieski David F.
Published: July 2021

Preliminary data have produced conflicting results regarding whether initial vitamin C levels in patients with severe sepsis correlate with mortality outcomes. We hypothesized that low plasma ascorbic acid or thiamine levels in severe sepsis patients admitted from the Emergency Department (ED) to the Intensive Care Unit (ICU) would be associated with increased mortality and an increased incidence of shock. Retrospective analysis of a prospective database of severe sepsis patients admitted to the ICU at an urban, academic medical center. Ascorbic acid and thiamine levels were analyzed in relation to survivors vs. non-survivors and shock vs. non-shock patients. 235 patients were included; mean age, 59.4 years ± 16.8 years; male, 128 (54.5%); in-hospital mortality, 16.6% (39/235); mean APACHE3 score, 61.8 ± 22.8; mean ascorbic acid level (reference range 0.40–2.10 mg/dL), 0.23 mg/dL (95% CI 0.07–4.02); and the mean thiamine level (reference range 14.6–29.5 nmol/L), 6.0 nmol/L (95% CI 4.0–9.5). When survivors were compared to non-survivors, survivors were more likely to be male (57.7% [113/196] vs. 38.5% [15/39]) and have lower APACHE3 scores (58.2 ± 22.6 vs. 79.9 ± 16.0). For the total cohort of 235 patients, there was no statistically significant relationship between a patient’s initial ascorbic acid or thiamine level and either survival or development of shock. In this analysis of early plasma samples from patients with severe sepsis admitted from the ED to the ICU, we found that mean ascorbic acid and thiamine levels were lower than normal range but that there was no relationship between these levels and outcomes, including 28 day mortality and development of shock.
Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model
Authors: Sta Maria Naomi S. , Khawli Leslie A. , Pachipulusu Vyshnavi , Lin Sharon W. , Zheng Long , Cohrs Daniel , Liu Xiaodan , Hu Peisheng , Epstein Alan L. , Jacobs Russell E.
Published: July 2021

Quantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial 89Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgammanull (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following 89Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 106 cells), middle (7.14 ± 0.45 × 106 cells), or high (16.83 ± 0.41 × 106 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3–5 h and then migrate to the liver and spleen for up to 2–3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with 89Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.
Changes in the use patterns of bDMARDs in patients with rheumatic diseases over the past 13 years
Authors: Sánchez-Piedra Carlos , Sueiro-Delgado Diana , García-González Javier , Ros-Vilamajo Inmaculada , Prior-Español Agueda , Moreno-Ramos Manuel José , Garcia-Magallon Blanca , Calvo-Gutiérrez Jerusalen , Perez-Vera Yanira , Martín-Domenech Raquel , Ruiz-Montesino Dolores , Vela-Casasempere Paloma , Expósito Lorena , Sánchez-Alonso Fernando , González-Davila Enrique , Díaz-González Federico
Published: July 2021

The better understanding of the safety of biologic DMARDs (bDMARDs), as well as the emergence of new bDMARDs against different therapeutic targets and biosimilars have likely influenced the use patterns of these compounds over time. The aim of this study is to assess changes in demographic characteristics, disease activity and treatment patterns in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) who started a first- or second-line biologic between 2007 and mid-2020. Patients diagnosed with RA, PsA or AS included in the BIOBADASER registry from January 2007 to July 2020 were included. According to the start date of a first- or second-line biologic therapy, patients were stratified into four time periods: 2007–2009; 2010–2013; 2014–2017; 2018–2020 and analyzed cross-sectionally in each period. Demographic and clinical variables, as well as the type of biologic used, were assessed. Generalized linear models were applied to study the evolution of the variables of interest over time periods, the diagnosis, and the interactions between them. A total of 4543 patients initiated a first biologic during the entire time frame of the study. Over the four time periods, disease evolution at the time of biologic initiation (p < 0.001), disease activity (p < 0.001), retention rate (p < 0.001) and the use of tumor necrosis factor inhibitors as a first-line treatment (p < 0.001) showed a significant tendency to decrease. Conversely, comorbidities, as assessed by the Charlson index (p < 0.001), and the percentage of patients using bDMARDs in monotherapy (p < 0.001), and corticosteroids (p < 0.001) tended to increase over time. Over the entire period of the study's analysis, 3289 patients started a second biologic. The following trends were observed: decreased DAS28 at switching (p < 0.001), lower retention rates (p = 0.004), and incremental changes to the therapeutic target between the first and second biologic (p < 0.001). From 2007 until now rheumatic patients who started a biologic were older, exhibited less clinical activity, presented more comorbidities, and switched to a different biologic more frequently and earlier.
Neutralization of the induced VEGF-A potentiates the therapeutic effect of an anti-VEGFR2 antibody on gastric cancer in vivo
Authors: Mashima Tetsuo , Wakatsuki Takeru , Kawata Naomi , Jang Myung-Kyu , Nagamori Akiko , Yoshida Haruka , Nakamura Kenichi , Migita Toshiro , Seimiya Hiroyuki , Yamaguchi Kensei
Published: July 2021

The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.
Disentangling the syntrophic electron transfer mechanisms of Candidatus geobacter eutrophica through electrochemical stimulation and machine learning
Authors: Yuan Heyang , Wang Xuehao , Lin Tzu-Yu , Kim Jinha , Liu Wen-Tso
Published: July 2021

Interspecies hydrogen transfer (IHT) and direct interspecies electron transfer (DIET) are two syntrophy models for methanogenesis. Their relative importance in methanogenic environments is still unclear. Our recent discovery of a novel species Candidatus Geobacter eutrophica with the genetic potential of IHT and DIET may serve as a model species to address this knowledge gap. To experimentally demonstrate its DIET ability, we performed electrochemical enrichment of Ca. G. eutrophica-dominating communities under 0 and 0.4 V vs. Ag/AgCl based on the presumption that DIET and extracellular electron transfer (EET) share similar metabolic pathways. After three batches of enrichment, Geobacter OTU650, which was phylogenetically close to Ca. G. eutrophica, was outcompeted in the control but remained abundant and active under electrochemical stimulation, indicating Ca. G. eutrophica’s EET ability. The high-quality draft genome further showed high phylogenomic similarity with Ca. G. eutrophica, and the genes encoding outer membrane cytochromes and enzymes for hydrogen metabolism were actively expressed. A Bayesian network was trained with the genes encoding enzymes for alcohol metabolism, hydrogen metabolism, EET, and methanogenesis from dominant fermentative bacteria, Geobacter, and Methanobacterium. Methane production could not be accurately predicted when the genes for IHT were in silico knocked out, inferring its more important role in methanogenesis. The genomics-enabled machine learning modeling approach can provide predictive insights into the importance of IHT and DIET.
Superficial peroneal nerve entrapment in ankle sprain in childhood and adolescence
Authors: Falciglia Francesco , Basiglini Luca , Aulisa Angelo G. , Toniolo Renato M.
Published: July 2021

Traumatic injuries of the ankle are the most common injuries in sports. Up to 40% of patients who have undergone inversion ankle sprain report residual symptoms. The primary purpose of the study is to evaluate the incidence of SPN entrapment as consequence of acute severe inversion ankle sprain in children and adolescents; the secondary is to report the diagnostic pathway and the results after surgical treatment. From 2000 to 2015 were reviewed to summarize patients under the age of 15 years treated for a first episode of severe inversion ankle sprain. Cases with persistent symptoms (more than 3 months) indicative for SPN neuropathy were then identified. Instrumental investigations were recovered and a pre-operative assessment of pain (VAS) was recorded. Patients were evaluated at minimum of 1-year post-operative follow-up. 981 acute ankle sprains have been evaluated. 122 were considered severe according to van Dijk criteria. 5 patients were considered affected by neuropathy of the SPN. All patients underwent surgery consisting in neurolysis and capsular retention and ligament reconstruction. At 25 months of follow-up AOFAS moved from 57.6 to 98.6. The study highlights a previously unreported condition of perineural fibrosis of the superficial peroneal nerve at the level of the ankle following first acute severe inversion ankle sprain in children.
Oxidative stress parameters as biomarkers of bladder cancer development and progression
Authors: Wigner Paulina , Szymańska Beata , Bijak Michał , Sawicka Ewa , Kowal Paweł , Marchewka Zofia , Saluk-Bijak Joanna
Published: July 2021

The epidemiological studies confirm that the overproduction of free radical is an important factor of cancer induction as well as development, and loss of antioxidant systems efficiency is associated with an increased risk of carcinogenesis. While bladder cancer is the fourth most common type of cancer all over the world, there is little evidence of the advancing changes in oxidative/nitrative stress during the progression of bladder cancer. Our study aimed to investigate the plasma levels of typical markers of oxidative/nitrative stress depending on the clinical classification of bladder cancer differentiation and infiltration degree. We examined 40 patients with newly diagnosed bladder cancer and 20 healthy volunteers as a control group. We analysed the plasma levels of protein carbonyls, thiol groups, 3-nitrotyrosine, lipid peroxidation, as well as non-enzymatic plasma antioxidant capacity using DPPH·and ABTS·+radicals. We confirmed that all analysed biomarkers are higher in enrolled BC patients than in healthy subjects. Furthermore, our findings demonstrate a positive correlation between the degree of bladder cancer progression and the level of oxidative stress, but no correlation in the case of NT-3. Based on obtained results, we might conclude that during carcinogenesis of the bladder increased oxidative damage of biomolecules is manifested. This indicates the participation of oxidative stress in the development of bladder cancer, and it is important the ensure the proper antioxidant protection.
Computed tomography angiography scoring systems and the role of skull defects in the confirmation of brain death
Authors: Zampakis Petros , Panagiotopoulos Vasilios , Kalogeropoulou Christina , Karachaliou Maria , Aretha Diamanto , Sioulas Nektarios , Dimoulia Sofia , Karnabatidis Dimitrios , Fligou Fotini
Published: July 2021

To assess and compare all current computed tomography angiography (CTA) scoring systems for the diagnostic workup of brain death (BD) to digital subtraction angiography (DSA) and clinical tests. Fifty-two patients with a clinical suspicion of BD underwent CTA and subsequently DSA. The diagnostic performance of all current CTA scoring systems was compared to that of DSA, in all patients with a suspicion of BD. A comparison to clinical tests was made only in DSA-positive for BD patients (n = 49), since in DSA-negative BD patients (n = 3) clinical tests were not performed. Further subgroup analysis was performed in relation to skull defects (SDs) stratification. Statistical analysis was conducted by applying statistics-contingency tables, Cochran’s-Q test and McNemar’s test. The CTA -10, and -7- and all 4-point scoring systems, showed overall sensitivities of 81,6%, 87.8% and 95.9% respectively and 100% specificity, when compared to DSA. In patients with a clinical verification of BD, the CTA -10 and -7-point scoring systems were significantly inferior to clinical tests (p = 0.004 and p = 0.031), while the 4-point scoring systems showed no such difference (p = 0.5). All 4-point scoring systems showed 100% sensitivity in patients with a minor SD or no SD. In patients with a major SD, all CTA scoring systems (− 10, − 7- and all 4-point) were less sensitive (62.5%, 62.5% and 75% respectively). The presence of a major SD was associated with an 8 × relative risk for false negative results in all 4-point scoring systems. CTA showed excellent diagnostic performance in patients with a suspicion of BD. The 4-point CTA scoring systems are the most sensitive for the diagnosis of BD, although in patients with a major SD patient, the role of CTA is ambiguous.
Overview of Injectable Hydrogels for 3D Bioprinting and Tissue Regeneration
Authors: Janarthanan Gopinathan , Noh Insup
Published: July 2021

Recently, 3D bioprinting for complex tissues and organ regeneration has received noticeable attention in the aging society worldwide, and it has progressed vastly with the advancing cell-containing injectable biomaterials and biomedical technologies such as additive manufacturing. The development of injectable hydrogel is a critical factor for the successful engineering of large and complex tissue/organs by 3D bioprinting in terms of encapsulating and protecting the live cells during printing as well as regenerating the complex tissues with hierarchical structure after bioprinting.
Introduction to Hydrogel Synthesis and Crosslinking Methods for Developing Bioinks for 3D Bioprinting
Authors: Janarthanan Gopinathan , Thavasyappan Thambi , Hong SeongYeon , Noh Insup
Published: July 2021

Hydrogels are three-dimensional networks formed from crosslinked polymer systems and are mainly used as biomaterials in biomedical fields including 3D bioprinting for tissue engineering applications. These are generally developed from natural and synthetic sources and are classified into various types based on their crosslinking strategies and functional properties. For instance, chemically crosslinked hydrogels and physically crosslinked hydrogels are the two broad categories of hydrogels. Chemical crosslinking methods mainly involve the use of chemical agents (zero and non-zero length crosslinkers), followed by photo-polymerization and other reactions such as Schiff's base reaction, hydrazone bond formation, Diels–Alder reactions, azide–alkyne cycloaddition reactions, enzyme-driven reactions, etc. In physical crosslinking methods, ionic and coordination bonds crosslinking, hydrogen bonding crosslinking, host–guest interactions crosslinking and self-assembling peptide crosslinking are reported for developing hydrogels. The applications of such hydrogel biomaterials as bioinks in 3D bioprinting are discussed and elaborated in this chapter.