bluuebunny/crossref_metadata_2025 huggingface dataset:
Studying and mitigating the effects of data drifts on ML model performance at the example of chemical toxicity data
Authors: Morger Andrea , Garcia de Lomana Marina , Norinder Ulf , Svensson Fredrik , Kirchmair Johannes , Mathea Miriam , Volkamer Andrea
Published: May 2022

Machine learning models are widely applied to predict molecular properties or the biological activity of small molecules on a specific protein. Models can be integrated in a conformal prediction (CP) framework which adds a calibration step to estimate the confidence of the predictions. CP models present the advantage of ensuring a predefined error rate under the assumption that test and calibration set are exchangeable. In cases where the test data have drifted away from the descriptor space of the training data, or where assay setups have changed, this assumption might not be fulfilled and the models are not guaranteed to be valid. In this study, the performance of internally valid CP models when applied to either newer time-split data or to external data was evaluated. In detail, temporal data drifts were analysed based on twelve datasets from the ChEMBL database. In addition, discrepancies between models trained on publicly-available data and applied to proprietary data for the liver toxicity and MNT in vivo endpoints were investigated. In most cases, a drastic decrease in the validity of the models was observed when applied to the time-split or external (holdout) test sets. To overcome the decrease in model validity, a strategy for updating the calibration set with data more similar to the holdout set was investigated. Updating the calibration set generally improved the validity, restoring it completely to its expected value in many cases. The restored validity is the first requisite for applying the CP models with confidence. However, the increased validity comes at the cost of a decrease in model efficiency, as more predictions are identified as inconclusive. This study presents a strategy to recalibrate CP models to mitigate the effects of data drifts. Updating the calibration sets without having to retrain the model has proven to be a useful approach to restore the validity of most models.
Fast evaluation technique for the shear viscosity and ionic conductivity of electrolyte solutions
Authors: Baba Takeshi , Kajita Seiji , Shiga Tohru , Ohba Nobuko
Published: May 2022

With the growing need to obtain ideal materials for various applications, there is an increasing interest in computational methods to rapidly and accurately search for materials. Molecular dynamics simulation is one of the successful methods used to investigate liquid electrolytes with high transport properties applied in lithium-ion batteries. However, further reduction in computational cost is required to find a novel material with the desired properties from a large number of combinations. In this study, we demonstrate an effective fast evaluation technique for shear viscosity and ionic conductivity by molecular dynamics simulation for an exhaustive search of electrolyte materials with high transport properties. The proposed model was combined with a short-time correlation function of the stress tensor and empirical relationships to address the issues of inefficient and uncertain evaluation by conventional molecular dynamics methods. Because we focus on liquid electrolytes consisting of organic solvents and lithium salts, our model requires dissociation ratio and effective diffusion size of lithium salts. Our method is applied to search for the compositional combinations of electrolytes with superior transport properties even at low temperatures. These results correlate well with experimental results.
Seasonal dynamics of ammonia-oxidizing bacteria but not archaea influence soil nitrogen cycling in a semi-arid agricultural soil
Authors: Fisk L. M. , Barton L. , Maccarone L. D. , Jenkins S. N. , Murphy D. V.
Published: May 2022

Nitrification, a key pathway of nitrogen (N) loss from agricultural soils, is performed by ammonia-oxidizing bacteria (AOB) and archaea (AOA). We examined the seasonal dynamics (2 years) of ammonia oxidizer gene abundances across a gradient of soil carbon (C) and N in a semi-arid soil after 8 years of tillage and crop residue treatments. AOB was more dominant than AOA in the surface soil, as AOA were undetected in 96% of samples. Seasonal variation in AOB abundance was related to substrate availability; AOB gene copy numbers increased at the end of the growing season (during summer fallow) following higher concentrations in dissolved organic matter soil water. This suggests increased co-location between AOB and substrate resources in pores still filled with water as the soils dried. AOB was however not statistically related to soil ammonium concentrations, soil water content, rainfall or temperature. Organic matter inputs enhanced AOB abundance independent of seasonal variation. AOB abundance was greatest in autumn and immediately preceding the start of the growing season, and coincided with elevated soil nitrate concentrations. The growth of the AOB population is likely to contribute to increased risk of N loss through leaching and/or denitrification at the start of the crop growing season following summer fallow.
Biochemical and molecular characterization of three serologically different Vibrio harveyi strains isolated from farmed Dicentrarchus labrax from the Adriatic Sea
Authors: Pavlinec Željko , Zupičić Ivana Giovanna , Oraić Dražen , Lojkić Ivana , Fouz Belén , Zrnčić Snježana
Published: May 2022

Vibrio harveyi is recognized as one of the major causes of vibriosis, a disease that threatens the long-term sustainability of aquaculture. Current research shows that the Mediterranean strains of V. harveyi are serologically heterogeneous, though research comparing the traits of different strains is scarce. This study aims to describe the biochemical, physiological and genetic characteristics of three serologically different strains of V. harveyi isolated from farmed European Sea bass (Dicentrarchus labrax) from the Adriatic Sea. A total of 32 morphological and biochemical markers were examined and, the susceptibility to 13 antimicrobials tested, and then compared the results of high-throughput sequencing and in silico analyses. This study also presents the first whole genome sequences of V. harveyi isolated from European sea bass. A large number of nonsynonymous variations were detected among sequences of the three strains. The prediction analysis of resistance genes did not correspond with the in vitro antimicrobial susceptibility tests. Six virulence genes previously unrelated to virulence of vibrios were detected in all three studied strains. The results show that differences were detected at every level of comparison among the three studied strains isolated from the same fish species originating from a small geographic area.
Mosaic attenuation in non-fibrotic areas as a predictor of non-usual interstitial pneumonia pathologic diagnosis
Authors: Gayá García-Manso Ignacio , Arenas-Jiménez Juan , García-Sevila Raquel , Ruiz-Alcaraz Sandra , Sirera-Matilla Marina , García-Garrigós Elena , Martínez-García María Ángeles , Hernández-Blasco Luis
Published: May 2022

The new radiological diagnostic criteria for diagnosing idiopathic pulmonary fibrosis (IPF) seek to optimize the indications for surgical lung biopsy (SLB). We applied the new criteria to a retrospective series of patients with interstitial lung disease (ILD) who underwent SLB in order to analyse the correlation between the radiological findings suggestive of another diagnosis (especially mosaic attenuation and its location with respect to fibrotic areas) and the usual interstitial pneumonia (UIP) pathologic diagnosis. Two thoracic radiologists reviewed the HRCT images of 83 patients with ILD and SLB, describing the radiological findings and patterns based on the new criteria. The association of each radiological finding with radiological patterns and histology was analysed. Mosaic attenuation is highly prevalent in both the UIP and non-UIP pathologic diagnosis and with similar frequency (80.0% vs. 78.6%). However, the presence of significant mosaic attenuation (≥ 3 lobes) only in non-fibrotic areas was observed in 60.7% of non-UIP pathologic diagnosis compared to 20.0% in UIP. This finding was associated with other diagnoses different from IPF, mostly connective tissue disease-associated interstitial lung disease (CTD-ILD) and hypersensitivity pneumonitis (HP). In our series of pathologically confirmed ILD, mosaic attenuation in non-fibrotic areas was a predictor of non-UIP pathologic diagnosis, and was associated with other diagnoses different from UIP, mostly CTD-ILD and HP. If confirmed in larger series, this finding could constitute a valuable tool for improving the interpretation of radiological patterns.
Giant nonlinear self-phase modulation of large-amplitude spin waves in microscopic YIG waveguides
Authors: Merbouche H. , Divinskiy B. , Nikolaev K. O. , Kaspar C. , Pernice W. H. P. , Gouéré D. , Lebrun R. , Cros V. , Ben Youssef J. , Bortolotti P. , Anane A. , Demokritov S. O. , Demidov V. E.
Published: May 2022

Nonlinear self-phase modulation is a universal phenomenon responsible, for example, for the formation of propagating dynamic solitons. It has been reported for waves of different physical nature. However its direct experimental observation for spin waves has been challenging. Here we show that exceptionally strong phase modulation can be achieved for spin waves in microscopic waveguides fabricated from nanometer-thick films of magnetic insulator, which support propagation of spin waves with large amplitudes corresponding to angles of magnetization precession exceeding 10°. At these amplitudes, the nonstationary nonlinear dynamic response of the spin system causes an extreme broadening of the spectrum of spin-wave pulses resulting in a strong spatial variation of the spin-wave wavelength and a temporal variation of the spin-wave phase across the pulse. Our findings demonstrate great complexity of nonlinear wave processes in microscopic magnetic structures and importance of their understanding for technical applications of spin waves in integrated devices.
Taxonomic and functional trait-based approaches suggest that aerobic and anaerobic soil microorganisms allow the natural attenuation of oil from natural seeps
Authors: Cébron Aurélie , Borreca Adrien , Beguiristain Thierry , Biache Coralie , Faure Pierre
Published: May 2022

Natural attenuation, involving microbial adaptation, helps mitigating the effect of oil contamination of surface soils. We hypothesized that in soils under fluctuating conditions and receiving oil from seeps, aerobic and anaerobic bacteria as well as fungi could coexist to efficiently degrade hydrocarbons and prevent the spread of pollution. Microbial community diversity was studied in soil longitudinal and depth gradients contaminated with petroleum seeps for at least a century. Hydrocarbon contamination was high just next to the petroleum seeps but this level drastically lowered from 2 m distance and beyond. Fungal abundance and alpha-diversity indices were constant along the gradients. Bacterial abundance was constant but alpha-diversity indices were lower next to the oil seeps. Hydrocarbon contamination was the main driver of microbial community assemblage. 281 bacterial OTUs were identified as indicator taxa, tolerant to hydrocarbon, potentially involved in hydrocarbon-degradation or benefiting from the degradation by-products. These taxa belonging to lineages of aerobic and anaerobic bacteria, have specific functional traits indicating the development of a complex community adapted to the biodegradation of petroleum hydrocarbons and to fluctuating conditions. Fungi are less impacted by oil contamination but few taxa should contribute to the metabolic complementary within the microbial consortia forming an efficient barrier against petroleum dissemination.
Course of disease and risk factors for hospitalization in outpatients with a SARS-CoV-2 infection
Authors: Schäfer Eik , Scheer Christian , Saljé Karen , Fritz Anja , Kohlmann Thomas , Hübner Nils-Olaf , Napp Matthias , Fiedler-Lacombe Lizon , Stahl Dana , Rauch Bernhard , Nauck Matthias , Völker Uwe , Felix Stephan , Lucchese Guglielmo , Flöel Agnes , Engeli Stefan , Hoffmann Wolfgang , Hahnenkamp Klaus , Tzvetkov Mladen V.
Published: May 2022

We analyzed symptoms and comorbidities as predictors of hospitalization in 710 outpatients in North-East Germany with PCR-confirmed SARS-CoV-2 infection. During the first 3 days of infection, commonly reported symptoms were fatigue (71.8%), arthralgia/myalgia (56.8%), headache (55.1%), and dry cough (51.8%). Loss of smell (anosmia), loss of taste (ageusia), dyspnea, and productive cough were reported with an onset of 4 days. Anosmia or ageusia were reported by only 18% of the participants at day one, but up to 49% between days 7 and 9. Not all participants who reported ageusia also reported anosmia. Individuals suffering from ageusia without anosmia were at highest risk of hospitalization (OR 6.8, 95% CI 2.5–18.1). They also experienced more commonly dyspnea and nausea (OR of 3.0, 2.9, respectively) suggesting pathophysiological connections between these symptoms. Other symptoms significantly associated with increased risk of hospitalization were dyspnea, vomiting, and fever. Among basic parameters and comorbidities, age > 60 years, COPD, prior stroke, diabetes, kidney and cardiac diseases were also associated with increased risk of hospitalization. In conclusion, due to the delayed onset, ageusia and anosmia may be of limited use in differential diagnosis of SARS-CoV-2. However, differentiation between ageusia and anosmia may be useful for evaluating risk for hospitalization.
Sleep enhances reconsolidation-based strengthening of visuospatial memories
Authors: Jones Bethany J. , Chen Margaret E. , Simoncini Lindsey , Spencer Rebecca M. C.
Published: May 2022

Consolidated memories can be returned to a labile state upon reactivation. The re-stabilization of reactivated memories, or reconsolidation, can allow for change in previously established memories. Given the role of sleep in the initial consolidation of memories, sleep may be important for reconsolidation as well. However, effects of sleep on reconsolidation and specific aspects of sleep that may contribute are unclear. Here, participants learned 30 picture-location pairs. After overnight sleep, initial consolidation was tested. Following either one day (Experiment 1) or one week (Experiment 2), participants were tested again to reactivate their memory and then learned 30 novel picture-location pairs. Control groups (Experiment 1) received no reactivation prior to new learning. Twelve hours later, after daytime wakefulness or overnight sleep, participants completed a final memory test. Sleep participants underwent polysomnography between reactivation and final tests. In Experiment 1, reactivation led to preservation of memory compared to no reactivation. Sleep was associated with less post-reactivation memory decline than waking, with memory preservation positively related to time spent in non-rapid-eye movement sleep. In Experiment 2, sleep was associated with greater post-reactivation memory improvement than waking, with improvement positively related to sigma activity. These results suggest sleep enhances reconsolidation-based strengthening of episodic memories.
Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia
Authors: Godbole Nimish , Nyholm Iiris , Hukkinen Maria , Davidson Joseph R. , Tyraskis Athanasios , Lohi Jouko , Heikkilä Päivi , Eloranta Katja , Pihlajoki Marjut , Davenport Mark , Heikinheimo Markku , Kyrönlahti Antti , Pakarinen Mikko P.
Published: May 2022

Biliary atresia (BA) is a chronic neonatal cholangiopathy characterized by fibroinflammatory bile duct damage. Reliable biomarkers for predicting native liver survival (NLS) following portoenterostomy (PE) surgery are lacking. Herein we explore the utility of 22 preidentified profibrotic molecules closely connected to ductular reaction (DR) and prevailing after successful PE (SPE), in predicting PE outcomes and liver injury. We used qPCR and immunohistochemistry in a BA cohort including liver samples obtained at PE (n = 53) and during postoperative follow-up after SPE (n = 25). Of the 13 genes over-expressed in relation to cholestatic age-matched controls at PE, only secretin receptor (SCTR) expression predicted cumulative 5-year NLS and clearance of jaundice. Patients in the highest SCTR expression tertile showed 34–55% lower NLS than other groups at 1–5 years after PE (P = 0.006–0.04 for each year). SCTR expression was also significantly lower [42 (24–63) vs 75 (39–107) fold, P = 0.015] among those who normalized their serum bilirubin after PE. Liver SCTR expression localized in cholangiocytes and correlated positively with liver fibrosis, DR, and transcriptional markers of fibrosis (ACTA2) and cholangiocytes (KRT7, KRT19) both at PE and after SPE. SCTR is a promising prognostic marker for PE outcomes and associates with liver injury in BA.
In-vitro NET-osis induced by COVID-19 sera is associated to severe clinical course in not vaccinated patients and immune-dysregulation in breakthrough infection
Authors: Romano Alessandra , Parrinello Nunziatina Laura , Barchitta Martina , Manuele Rosy , Puglisi Fabrizio , Maugeri Andrea , Barbato Alessandro , Triolo Anna Maria , Giallongo Cesarina , Tibullo Daniele , La Ferla Lucia , Botta Ciro , Siragusa Sergio , Iacobello Carmelo , Montineri Arturo , Volti Giovanni Li , Agodi Antonella , Palumbo Giuseppe Alberto , Di Raimondo Francesco
Published: May 2022

Since neutrophil extracellular traps formation (NET-osis) can be assessed indirectly by treating healthy neutrophils with blood-derived fluids from patients and then measuring the NETs response, we designed a pilot study to convey high-dimensional cytometry of peripheral blood immune cells and cytokines, combined with clinical features, to understand if NET-osis assessment could be included in the immune risk profiling to early prediction of clinical patterns, disease severity, and viral clearance at 28 days in COVID-19 patients. Immune cells composition of peripheral blood, cytokines concentration and in-vitro NETosis were detected in peripheral blood of 41 consecutive COVID-19 inpatients, including 21 mild breakthrough infections compared to 20 healthy donors, matched for sex and age. Major immune dysregulation in peripheral blood in not-vaccinated COVID-19 patients compared to healthy subjects included: a significant reduction of percentage of unswitched memory B-cells and transitional B-cells; loss of naïve CD3+CD4+CD45RA+ and CD3+CD8+CD45RA+ cells, increase of IL-1β, IL-17A and IFN-γ. Myeloid compartment was affected as well, due to the increase of classical (CD14++CD16−) and intermediate (CD14++CD16+) monocytes, overexpressing the activation marker CD64, negatively associated to the absolute counts of CD8+ CD45R0+ cells, IFN-γ and IL-6, and expansion of monocytic-like myeloid derived suppressor cells. In not-vaccinated patients who achieved viral clearance by 28 days we found at hospital admission lower absolute counts of effector cells, namely CD8+T cells, CD4+ T-cells and CD4+CD45RO+ T cells. Percentage of in-vitro NET-osis induced by patients’ sera and NET-osis density were progressively higher in moderate and severe COVID-19 patients than in mild disease and controls. The percentage of in-vitro induced NET-osis was positively associated to circulating cytokines IL-1β, IFN-γ and IL-6. In breakthrough COVID-19 infections, characterized by mild clinical course, we observed increased percentage of in-vitro NET-osis, higher CD4+ CD45RO+ and CD8+ CD45RO+ T cells healthy or mild-COVID-19 not-vaccinated patients, reduced by 24 h of treatment with ACE inhibitor ramipril. Taken together our data highlight the role of NETs in orchestrating the complex immune response to SARS-COV-2, that should be considered in a multi-target approach for COVID-19 treatment.
Artificial neural network-boosted Cardiac Arrest Survival Post-Resuscitation In-hospital (CASPRI) score accurately predicts outcome in cardiac arrest patients treated with targeted temperature management
Authors: Chou Szu-Yi , Bamodu Oluwaseun Adebayo , Chiu Wei-Ting , Hong Chien-Tai , Chan Lung , Chung Chen-Chih
Published: May 2022

Existing prognostic models to predict the neurological recovery in patients with cardiac arrest receiving targeted temperature management (TTM) either exhibit moderate accuracy or are too complicated for clinical application. This necessitates the development of a simple and generalizable prediction model to inform clinical decision-making for patients receiving TTM. The present study explores the predictive validity of the Cardiac Arrest Survival Post-resuscitation In-hospital (CASPRI) score in cardiac arrest patients receiving TTM, regardless of cardiac event location, and uses artificial neural network (ANN) algorithms to boost the prediction performance. This retrospective observational study evaluated the prognostic relevance of the CASPRI score and applied ANN to develop outcome prediction models in a cohort of 570 patients with cardiac arrest and treated with TTM between 2014 and 2019 in a nationwide multicenter registry in Taiwan. In univariate logistic regression analysis, the CASPRI score was significantly associated with neurological outcome, with the area under the receiver operating characteristics curve (AUC) of 0.811. The generated ANN model, based on 10 items of the CASPRI score, achieved a training AUC of 0.976 and validation AUC of 0.921, with the accuracy, precision, sensitivity, and specificity of 89.2%, 91.6%, 87.6%, and 91.2%, respectively, for the validation set. CASPRI score has prognostic relevance in patients who received TTM after cardiac arrest. The generated ANN-boosted, CASPRI-based model exhibited good performance for predicting TTM neurological outcome, thus, we propose its clinical application to improve outcome prediction, facilitate decision-making, and formulate individualized therapeutic plans for patients receiving TTM.
Maximizing coverage, reducing time: a usability evaluation method for web-based library systems
Authors: Iqbal Shumaila , Ikram Naveed , Imtiaz Salma , Imtiaz Saima
Published: May 2022

The usability of a Web Based Library System (WBLS) is an important quality attribute that must be met in order for the intended users to be satisfied. These usability quality attributes are available in two forms: general to web systems and domain-specific. It must be evaluated through some evaluation method such as checklist. Many evaluation checklists have been proposed, although they mostly facilitate the evaluation of WBLS’s general usability aspects, but they lack in covering domain-specific usability aspects of WBLS. There is a need to define domain specific usability aspects to maximize the usability for such systems. The purpose of this research is to develop and validates a usability evaluation checklist that supports the evaluation of general as well as specific usability aspects of WBLS. To accomplish this, a control experiment was conducted in the first phase with undergraduate students to develop a usability evaluation checklist that includes both general and specific usability aspects. Another controlled experiment will be used in the second phase to evaluate the effectiveness and efficiency of the proposed checklist with the existing checklist as "Academic Library Website Evaluation Checklist". The manual and statistical result shows that, the proposed usability evaluation checklist is effective with maximum coverage of general and specific usability aspects. Furthermore, the proposed checklist is equally efficient while identifying the usability errors in WBLS. The proposed checklist is beneficial for the academia as well as industry to evaluate the usability of WBLS to an optimal level.
Molecular confirmation of the hybrid origin of Sparganium longifolium (Typhaceae)
Authors: Yu Yinjiao , Li Fengxia , Belyakov Eugeny A. , Yang Weidong , Lapirov Alexander G. , Xu Xinwei
Published: May 2022

Sparganium longifolium was reported as a hybrid between S. emersum and S. gramineum based on its intermediate type or the common characteristics of its parent species. Its hybrid origin needs to be confirmed using molecular technology. We investigated the origin of S. longifolium based on 10 populations of S. emersum, S. gramineum and S. longifolium from five lakes in European Russia, using sequences of six nuclear loci and one chloroplast DNA fragment. Haplotype network, principal coordinate analysis and genetic clustering based on data of nuclear loci confirmed that S. longifolium is the hybrid between S. emersum and S. gramineum. We found that the natural hybridization between S. emersum and S. gramineum is bidirectional but asymmetrical, and the latter mainly acts as maternal species. We also found that all samples of S. longifolium were F1 generations, and thus hypothesized that S. emersum and S. gramineum could likely maintain their species boundary through the post-zygote reproductive isolation mechanism of F1 generation sterility.
Vertical semiconductor deep ultraviolet light emitting diodes on a nanowire-assisted aluminum nitride buffer layer
Authors: Zhang Qihua , Parimoo Heemal , Martel Eli , Zhao Songrui
Published: May 2022

Vertical light-emitting diodes (LEDs) have many advantages such as uniform current injection, excellent scalability of the chip size, and simple packaging process. Hitherto, however, technologically important semiconductor aluminum gallium nitride (AlGaN) deep ultraviolet (UV) LEDs are mainly through lateral injection. Herein, we demonstrate a new and practical path for vertical AlGaN deep UV LEDs, which exploits a thin AlN buffer layer formed on a nanowire-based template on silicon (Si). Such a buffer layer enables in situ formation of vertical AlGaN deep UV LEDs on Si. Near Lambertian emission pattern is measured from the top surface. The decent reflectivity of Si in the deep UV range makes such a configuration a viable low-cost solution for vertical AlGaN deep UV LEDs. More importantly, the use of such a thin AlN buffer layer can allow an easy transfer of device structures to other carrier wafers for vertical AlGaN deep UV LEDs with ultimately high electrical and optical performance.
The development of Friedländer heteroannulation through a single electron transfer and energy transfer pathway using methylene blue (MB+)
Authors: Mohamadpour Farzaneh
Published: May 2022

The radical Friedländer hetero-annulation of 2-aminoaryl ketone and -methylene carbonyl compound was used to develop a green tandem approach for the metal-free synthesis of polysubstitutedquinolines. At room temperature in an ethanol solvent, photo-excited state functions generated from MB+ were used as single-electron transfer (SET) and energy transfer (EnT) catalysts, utilizing visible light as a renewable energy source in the air atmosphere. The purpose of this research is to increase the use of a nonmetal cationic dye that is both inexpensive and widely available. High yields, energy-effectiveness, high atom economy, time-saving features of the reaction, and operational simplicity, and the least amount of a catalyst are the benefits of this study. As a result, a wide range of ecological and long-term chemical properties are obtained. Polysubstitutedquinolines' turnover number (TON) and turnover frequency (TOF) have been calculated. Surprisingly, such cyclization can be accomplished on a gram scale, indicating that the process has industrial potential.
Shorter pruritus period and milder disease stage are associated with response to nalfurafine hydrochloride in patients with chronic liver disease
Authors: Kawano Tadamichi , Atsukawa Masanori , Tsubota Akihito , Shimada Noritomo , Toyoda Hidenori , Takaguchi Koichi , Tani Joji , Morishita Asahiro , Hiraoka Atsushi , Mikami Shigeru , Ishikawa Toru , Okubo Hironao , Watanabe Tsunamasa , Okubo Tomomi , Arai Taeang , Hayama Korenobu , Itokawa Norio , Kondo Chisa , Iwakiri Katsuhiko
Published: May 2022

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima’s pruritus score. Nalfurafine hydrochloride 2.5 μg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima’s pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.
Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance
Authors: Ge Rongbin , Wang Zongwei , Cheng Liang
Published: May 2022

Prostate cancer is characterized by a high degree of heterogeneity, which poses a major challenge to precision therapy and drug development. In this review, we discuss how nongenetic factors contribute to heterogeneity of prostate cancer. We also discuss tumor heterogeneity and phenotypic switching related to anticancer therapies. Lastly, we summarize the challenges targeting the tumor environments, and emphasize that continued exploration of tumor heterogeneity is needed in order to offer a personalized therapy for advanced prostate cancer patients.
Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction
Authors: Nayar Saba , Pontarini Elena , Campos Joana , Berardicurti Onorina , Smith Charlotte G. , Asam Saba , Gardner David H. , Colafrancesco Serena , Lucchesi Davide , Coleby Rachel , Chung Ming-May , Iannizzotto Valentina , Hunter Kelly , Bowman Simon J. , Carlesso Gianluca , Herbst Ronald , McGettrick Helen M. , Browning Jeff , Buckley Christopher D. , Fisher Benjamin A. , Bombardieri Michele , Barone Francesca
Published: May 2022

Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.
Social synchronization of brain activity increases during eye-contact
Authors: Luft Caroline Di Bernardi , Zioga Ioanna , Giannopoulos Anastasios , Di Bona Gabriele , Binetti Nicola , Civilini Andrea , Latora Vito , Mareschal Isabelle
Published: May 2022

Humans make eye-contact to extract information about other people’s mental states, recruiting dedicated brain networks that process information about the self and others. Recent studies show that eye-contact increases the synchronization between two brains but do not consider its effects on activity within single brains. Here we investigate how eye-contact affects the frequency and direction of the synchronization within and between two brains and the corresponding network characteristics. We also evaluate the functional relevance of eye-contact networks by comparing inter- and intra-brain networks of friends vs. strangers and the direction of synchronization between leaders and followers. We show that eye-contact increases higher inter- and intra-brain synchronization in the gamma frequency band. Network analysis reveals that some brain areas serve as hubs linking within- and between-brain networks. During eye-contact, friends show higher inter-brain synchronization than strangers. Dyads with clear leader/follower roles demonstrate higher synchronization from leader to follower in the alpha frequency band. Importantly, eye-contact affects synchronization between brains more than within brains, demonstrating that eye-contact is an inherently social signal. Future work should elucidate the causal mechanisms behind eye-contact induced synchronization.
GATA6 is predicted to regulate DNA methylation in an in vitro model of human hepatocyte differentiation
Authors: Suzuki Takahiro , Furuhata Erina , Maeda Shiori , Kishima Mami , Miyajima Yurina , Tanaka Yuki , Lim Joanne , Nishimura Hajime , Nakanishi Yuri , Shojima Aiko , Suzuki Harukazu
Published: May 2022

Hepatocytes are the dominant cell type in the human liver, with functions in metabolism, detoxification, and producing secreted proteins. Although gene regulation and master transcription factors involved in the hepatocyte differentiation have been extensively investigated, little is known about how the epigenome is regulated, particularly the dynamics of DNA methylation and the critical upstream factors. Here, by examining changes in the transcriptome and the methylome using an in vitro hepatocyte differentiation model, we show putative DNA methylation-regulating transcription factors, which are likely involved in DNA demethylation and maintenance of hypo-methylation in a differentiation stage-specific manner. Of these factors, we further reveal that GATA6 induces DNA demethylation together with chromatin activation in a binding-site-specific manner during endoderm differentiation. These results provide an insight into the spatiotemporal regulatory mechanisms exerted on the DNA methylation landscape by transcription factors and uncover an epigenetic role for transcription factors in early liver development.
PGC1 alpha coactivates ERG fusion to drive antioxidant target genes under metabolic stress
Authors: Dhara Aiindrila , Aier Imlimaong , Paladhi Ankush , Varadwaj Pritish Kumar , Hira Sumit Kumar , Sen Nirmalya
Published: May 2022

The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis1–3. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.
Urbanized knowledge syndrome—erosion of diversity and systems thinking in urbanites’ mental models
Authors: Aminpour Payam , Gray Steven A. , Beck Michael W. , Furman Kelsi L. , Tsakiri Ismini , Gittman Rachel K. , Grabowski Jonathan H. , Helgeson Jennifer , Josephs Lauren , Ruth Matthias , Scyphers Steven B.
Published: May 2022

Coastal ecosystems nearby human societies collectively shape complex social-ecological systems (SESs). These ecosystems support high levels of ecological biodiversity while providing resources and services to humans. However, shoreline armoring, land transformation, and urban homogenization across urbanized coastal areas may degrade natural ecosystems and alter how humans and nature are connected. We hypothesize that these alterations extend to residents’ knowledge of SESs. We explore evidence of such cognitive outcomes in graphical mental models of more than 1350 coastal residents across eight states in the Northeast United States. Our results revealed that, in more urbanized areas, residents’ mental models underrepresented complex interdependence between humans and natural components, indicating limited systems thinking. Additionally, urbanization and shoreline armoring were associated with homogenization of mental models. We refer to these results as Urbanized Knowledge Syndrome (UKS). Importantly, respondents with more symptoms of UKS were less likely to self-report adoption of pro-environmental behaviors. These results indicate a potential societal-level erosion of ecological knowledge associated with urbanization in the same way more urbanized areas are associated with diminishing ecological function. Thus, diagnosing and treating UKS is an essential component of urban sustainability.
Unique Nature of Phosphate and Borate Bioactive Glasses
Authors: Kasuga Toshihiro
Published: May 2022

In recent years, as new fields in biomedical applications have emerged, considerable attention has been devoted to glass materials for their ability to promote bone formation and their application for the treatment and repair of soft tissue. So far, silicate-based glasses have been widely applied as biomedical glasses. In some cases, however, silicate-based glasses are not suitable for all applications. Phosphate-based and borate-based glasses are proposed as attractive alternatives. They are prospective biomaterials, because their structures are controllable and their characteristic ion-releasing behaviour can be tuned.
Structure and Thermal Properties of Phosphate Glasses
Authors: Brauer Delia S.
Published: May 2022

For several decades, phosphate glasses have been studied as biomaterials, particularly because of their solubility in water, which predestines them for use as controlled release materials. The present chapter looks at the atomic structure and the basic building units of these glasses. Both phosphate network polymerisation and the type of modifier present determine the properties of phosphate glass. Increasing modifier contents disrupt the phosphate structure, making it change from a network to entangled chains of decreasing length. By varying the type of modifier cation present, we can adjust glass properties even when we keep the network polymerisation constant. An understanding of how composition, structure and properties are connected helps us to interpret experimental findings or design new glass compositions with specific properties.
Dissolution Behaviour of Phosphate Glasses
Authors: Brauer Delia S.
Published: May 2022

The key property of biomedical phosphate glasses is their solubility in aqueous solutions. Depending on the composition, they may dissolve completely, and the dissolution rate can be adjusted to suit the application. Although the importance of phosphate glasses compared to bioactive silicate glasses has been small so far, their solubility, which ranges over several orders of magnitude, makes them a promising class of materials for biomedical applications. As phosphate glasses degrade and dissolve, they release ions, such as modifier ions present in the glass, which allows phosphate glasses to be used as controlled-release vehicles for the delivery of therapeutic ions. This chapter looks at the mechanism of phosphate glass dissolution and at ways of adjusting and controlling their solubility.
The Role of Phosphate Glasses in Bone Regeneration Remedies
Authors: Obata Akiko
Published: May 2022

Phosphate ions are thought to influence osteogenic cells and enhance new bone formation. There is a long history of investigating osteoblast responses in vitro using various types of ions, such as orthophosphates and polyphosphates. This chapter focuses on cell responses to these ions, the mechanisms of the responses, and their relation to calcium phosphate deposits, which are induced by ions in culture medium. The influence of phosphate ions on osteoblast-like cells is also discussed by comparing it with the influence of silicate ions, which are reported to stimulate mineralization of osteogenic cells.
Amorphous Calcium Phosphate Coatings
Authors: Ueda Kyosuke , Narushima Takayuki
Published: May 2022

Amorphous calcium phosphate (ACP) is unique among calcium phosphates because it lacks the long-range, periodic atomic-scale order observed in crystalline calcium phosphates. In addition, ACP exhibits a high dissolution rate in vitro and in vivo. In this chapter, the fabrication processes of ACP coating films, based on wet and dry processes, are reviewed. Particularly, radiofrequency (RF) magnetron sputtering is elucidated in detail, and the features of sputtered coatings, such as bonding strength, Ca/P atomic ratio, in vitro and in vivo dissolution, and bone formation, are discussed. Further, Ag-added ACP coating films are discussed as one of the applications of highly bioresorbable ACP coating films.
Phosphate Glasses for Biophotonic Applications
Authors: Petit Laeticia , Massera Jonathan
Published: May 2022

With this chapter, our goal is to highlight important research topics in which biophotonics will play a crucial role in the near future. Biophotonics offers tremendous opportunities for applied and fundamental research and has been successfully used for early disease detection and for light-guided/activated therapies. However, there is still an urgent need for the development of a material platform for biophotonic applications, especially biocompatible and biodegradable materials with optimized biological, chemical, optical and mechanical properties. Phosphate glasses are clearly promising biophotonic materials and their use opens the path to the development of clinically relevant biophotonic devices for in vitro optical techniques to be used in situ and in vivo. These new phosphate glasses could be used not only for early detection of diseases but also for effective targeted therapies. They could also re-establish impaired biological functions. We expect these new materials to have a significant influence on the development of new technologies, offering huge commercial rewards worldwide.
Sol–Gel Borate Glasses
Authors: Lepry William C. , Nazhat Showan N.
Published: May 2022

This chapter examines the history, chemistry, and applications of sol–gel-derived borate glasses. Despite a significant lack of literature compared to silicate sol–gel glasses, sol–gel borate glasses offer interesting properties for a wide range of applications. In particular, these glasses show great promise for specialty optical coatings and tissue-engineering applications.
Recent Advances in the Development and Applications of Phosphate and Borate Glass Microspheres
Authors: Islam MD TOWHIDUL , Ahmed Ifty
Published: May 2022

An overview of recent findings and advancements concerning development of phosphate and borate glass microspheres, their manufacturing processes and potential use in biomedical applications are presented in this chapter. Phosphate and Borate glasses of varying compositions in the form of solid (non-porous) and highly porous microspheres are discussed. This chapter also highlights the methodologies used for the manufacture of these microspheres, including a very recent breakthrough development of a single-stage manufacturing process to produce highly porous microspheres from these glasses. The advantages of using microspheres in terms of their injectability/delivery to target site, dissolution, in vitro bioactivity and in vivo biocompatibility properties for bone repair applications are also presented.
Ophthalmic Formulation
Authors: Wilson Clive G.
Published: May 2022

The eye receives only a small proportion of the cardiac output as, although highly vascular, the retinal tissue is weighed in milligrammes and the eye surface area is small. Direct delivery to the eye is the preferred method of medication, particularly via topical systems such as eyedroppers which are well established. It is, however, very inefficient as the eye cannot hold a large reservoir and the refractive and sensory changes caused by instillation further stimulate clearance. For some applications, the transfer to deeper tissue is inefficient, and a more invasive administration is needed. Although necessary and effective in preserving sight, injection into the eye carries a risk of infection and is painful or uncomfortable with a fine gauge needle. The range of substances that can used to treat the eye is wide and includes diverse chemical motifs ranging from small molecules to macromolecular biologics. The delivery requires innovation, especially to sustain the effect, and a wide range of delivery devices will be encountered. Dosing the eye and sustaining the reservoir is not a simple task, especially compared with oral dosing. The formulator must have a good awareness of anatomical and physiological factors in addition to the understanding of control of solubility, sterility, stability and material properties in cocktails of compositions. This chapter attempts to consider some of the constraints on design and should provide a wider appreciation of the factors to be considered in ophthalmic formulation.
Dermal Formulations for Local Treatment
Authors: Lane Majella E. , Parisi Nicola
Published: May 2022

This chapter reviews the major classes of topical formulations currently available for delivery of actives locally to the skin. An overview of the physiology of the outermost layers of the skin is presented. The principles of drug penetration through the stratum corneum from topical formulations are outlined. Rational selection of candidates for topical delivery is explained. Dermal products are classified based on formulation type and examples of marketed preparations are provided. Finally, research and development in the field and likely future impact are briefly considered.