bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of Organized Porcine Testicular Organoids in Solubilized Hydrogels from Decellularized Extracellular Matrix
Authors: Vermeulen Maxime , Del Vento Federico , Kanbar Marc , Pyr dit Ruys Sébastien , Vertommen Didier , Poels Jonathan , Wyns Christine
Published: November 2019

Cryopreservation of immature testicular tissue (ITT) prior to chemo/radiotherapy is now ethically accepted and is currently the only way to preserve fertility of prepubertal boys about to undergo cancer therapies. So far, three-dimensional culture of testicular cells isolated from prepubertal human testicular tissue was neither efficient nor reproducible to obtain mature spermatozoa, and ITT transplantation is not a safe option when there is a risk of cancer cell contamination of the testis. Hence, generation of testicular organoids (TOs) after cell selection is a novel strategy aimed at restoring fertility in these patients. Here, we created TOs using hydrogels developed from decellularized porcine ITT and compared cell numbers, organization and function to TOs generated in collagen only hydrogel. Organotypic culture of porcine ITT was used as a control. Rheological and mass spectrometry analyses of both hydrogels highlighted differences in terms of extracellular matrix stiffness and composition, respectively. Sertoli cells (SCs) and germ cells (GCs) assembled into seminiferous tubule-like structures delimited by a basement membrane while Leydig cells (LCs) and peritubular cells localized outside. TOs were maintained for 45 days in culture and secreted stem cell factor and testosterone demonstrating functionality of SCs and LCs, respectively. In both TOs GC numbers decreased and SC numbers increased. However, LC numbers decreased significantly in the collagen hydrogel TOs (p < 0.05) suggesting a better preservation of growth factors within TOs developed from decellularized ITT and thus a better potential to restore the reproductive capacity.
Exploring the Regulatory Role of Circular RNAs in Neurodegenerative Disorders
Authors: D’Ambra Eleonora , Capauto Davide , Morlando Mariangela
Published: November 2019

Circular RNAs (circRNAs) are a distinctive class of regulatory non-coding RNAs characterised by the presence of covalently closed ends. They are evolutionary conserved molecules, and although detected in different tissues, circRNAs resulted specifically enriched in the nervous system. Recent studies have shown that circRNAs are dynamically modulated during neuronal development and aging, that circRNAs are enriched at synaptic levels and resulted modulated after synaptic plasticity induction. This has suggested that circRNAs might play an important role in neuronal specification and activity. Despite the exact function of circRNAs is still poorly understood, emerging evidence indicates that circRNAs have important regulatory functions that might extensively contribute to the dynamic modulation of gene expression that supports neuronal pathways. More interestingly, deregulation of circRNAs expression has been linked with various pathological conditions. In this review, we describe current advances in the field of circRNA biogenesis and function in the nervous system both in physiological and in pathological conditions, and we specifically lay out their association with neurodegenerative diseases. Furthermore, we discuss the opportunity to exploit circRNAs for innovative therapeutic approaches and, due to their high stability, to use circRNAs as suitable biomarkers for diagnosis and disease progression.
Emerging Highly Virulent Porcine Epidemic Diarrhea Virus: Molecular Mechanisms of Attenuation and Rational Design of Live Attenuated Vaccines
Authors: Hou Yixuan , Wang Qiuhong
Published: November 2019

The highly virulent porcine epidemic diarrhea virus (PEDV) emerged in China in 2010. It infects pigs of all ages, and causes severe diarrhea and high mortality rates in newborn pigs, leading to devastating economic losses in the pork industry worldwide. Effective and safe vaccines against highly virulent PEDV strains are still unavailable, hampering the further prevention, control and eradication of the disease in herds. Vaccination of pregnant sows with live attenuated vaccines (LAVs) is the most effective strategy to induce lactogenic immunity in the sows, which provides A passive protection of suckling piglets against PEDV via the colostrum (beestings, or first milk) and milk. Several LAV candidates have been developed via serially passaging the highly virulent PEDV isolates in non-porcine Vero cells. However, their efficacies in the induction of sufficient protection against virulent PEDV challenge vary in vivo. In this review, we summarize the current knowledge of the virulence-related mutations of PEDV and their potential roles in PEDV attenuation in vivo. With the successful development of reverse genetics systems for PEDV, we also discuss how to use them to generate promising LAV candidates that are safe, effective and genetically stable. This article provides timely insight into the rational design of effective and safe PEDV LAV candidates.
Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease
Authors: Ham Sangwoo , Kim Heejeong , Yoon Jin-Ha , Kim Hyojung , Song Bo Reum , Choi Jeong-Yun , Lee Yun-Song , Paek Seung-Mann , Maeng Han-Joo , Lee Yunjong
Published: November 2019

The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII’s neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.
Genetics and Extracellular Vesicles of Pediatrics Sleep Disordered Breathing and Epilepsy
Authors: Khalyfa Abdelnaby , Sanz-Rubio David
Published: November 2019

Sleep remains one of the least understood phenomena in biology, and sleep disturbances are one of the most common behavioral problems in childhood. The etiology of sleep disorders is complex and involves both genetic and environmental factors. Epilepsy is the most popular childhood neurological condition and is characterized by an enduring predisposition to generate epileptic seizures, and the neurobiological, cognitive, psychological, and social consequences of this condition. Sleep and epilepsy are interrelated, and the importance of sleep in epilepsy is less known. The state of sleep also influences whether a seizure will occur at a given time, and this differs considerably for various epilepsy syndromes. The development of epilepsy has been associated with single or multiple gene variants. The genetics of epilepsy is complex and disorders exhibit significant genetic heterogeneity and variability in the expressivity of seizures. Phenobarbital (PhB) is the most widely used antiepileptic drug. With its principal mechanism of action to prolong the opening time of the γ-aminobutyric acid (GABA)-A receptor-associated chloride channel, it enhances chloride anion influx into neurons, with subsequent hyperpolarization, thereby reducing excitability. Enzymes that metabolize pharmaceuticals including PhB are well known for having genetic polymorphisms that contribute to adverse drug–drug interactions. PhB metabolism is highly dependent upon the cytochrome P450 (CYP450) and genetic polymorphisms can lead to variability in active drug levels. The highly polymorphic CYP2C19 isozymes are responsible for metabolizing a large portion of routinely prescribed drugs and variants contribute significantly to adverse drug reactions and therapeutic failures. A limited number of CYP2C19 single nucleotide polymorphisms (SNPs) are involved in drug metabolism. Extracellular vesicles (EVs) are circular membrane fragments released from the endosomal compartment as exosomes are shed from the surfaces of the membranes of most cell types. Increasing evidence indicated that EVs play a pivotal role in cell-to-cell communication. Theses EVs may play an important role between sleep, epilepsy, and treatments. The discovery of exosomes provides potential strategies for the diagnosis and treatment of many diseases including neurocognitive deficit. The aim of this study is to better understand and provide further knowledge about the metabolism and interactions between phenobarbital and CYP2C19 polymorphisms in children with epilepsy, interplay between sleep, and EVs. Understanding this interplay between epilepsy and sleep is helpful in the optimal treatment of all patients with epileptic seizures. The use of genetics and extracellular vesicles as precision medicine for the diagnosis and treatment of children with sleep disorder will improve the prognosis and the quality of life in patients with epilepsy.
Whole-Genome and Transposed Duplication Contributes to the Expansion and Diversification of TLC Genes in Maize
Authors: Si Weina , Hang Tianlu , Guo Mingyue , Chen Zhen , Liang Qizhi , Gu Longjiang , Ding Ting
Published: November 2019

TLC (TRAM/LAG/CRN8) proteins play important roles in ceramide metabolism and mycotoxin resistance. Herein a comparative genomics analysis of TLCs was performed in 31 plant and 3 species from other kingdoms, with an emphasis mainly on maize. TLCs were conserved across kingdoms and expanded in angiosperms, largely due to whole-genome/segmental duplication (WGD/SD) under purifying selection. Phylogeny reconstruction by maximum-likelihood method uncovered five TLC clades, subsequently named as TRAM/LAG, CLN8, PS-TLC, TM136 and TLCD clades. Each clade of TLCs shared specific transmembrane regions and motif composition. Divisions of conserved motifs to subunits may have occurred in TM136-type TLCs. Focusing on maize, five WGD and two DNA-mediated transposed duplication (TD) pairs were discovered, accounting for 61.11% ZmTLCs. Combined with further expression analysis, significant divergence was found in expression patterns between most maize WGD pairs, indicating subfunctionalization or/and neofunctionalization. Moreover, ZmTLC5, a deduced parental copy in a TD pair, was highly induced under FB1 and fungus pathogen injection and exhibited potential capacity to respond to environmental stimuli. Additionally, population genetics analysis showed that ZmTLC10 in the CLN8-clade may have experienced significant positive selection and differentiated between wild and inbred maize populations. Overall, our results help to decipher the evolutionary history of TLCs in maize and plants, facilitating further functional analysis of them.
Transcription of the Sox30 Gene Is Positively Regulated by Dmrt1 in Nile Tilapia
Authors: Tang Yaohao , Li Xiaoyan , Xiao Hesheng , Li Minghui , Li Yueqin , Wang Deshou , Wei Ling
Published: November 2019

The Sox family member Sox30 is highly expressed in the testis of several vertebrate species and has been shown to play key roles in spermiogenesis. However, its transcription regulation remains unclear. Here, we analyzed the Sox30 promoter from the teleost fish Nile tilapia (Oreochromis niloticus) and predicted a putative cis-regulatory element (CRE) for doublesex and mab-3 related transcription factor 1 (Dmrt1), a male-specific transcription factor involved in male sex differentiation. Transcriptional profiling revealed that Sox30 and Dmrt1 similarly exhibited a high expression in tilapia testes from 90 days after hatching (dah) to 300 dah, and the transcription of the Sox30 gene was reduced about one-fold in the testes of male tilapia with Dmrt1 knockdown. Further dual-luciferase reporter assay confirmed that Dmrt1 overexpression significantly promoted transcriptional activity of the Sox30 promoter and this promotion was decreased following the mutation of putative CRE for Dmrt1 within the Sox30 promoter. Chromatin immunoprecipitation-based PCR (ChIP-PCR) and electrophoretic mobility shift assay (EMSA) demonstrated that Dmrt1 directly binds to putative CRE within the Sox30 promoter. These results together indicate that Dmrt1 positively regulates the transcription of the tilapia Sox30 gene by directly binding to specific CRE within the Sox30 promoter.
Composition of the Reconstituted Cell Wall in Protoplast-Derived Cells of Daucus Is Affected by Phytosulfokine (PSK)
Authors: Godel-Jędrychowska Kamila , Maćkowska Katarzyna , Kurczyńska Ewa , Grzebelus Ewa
Published: November 2019

Phytosulfokine-α (PSK), a peptidyl plant growth factor, has been recognized as a promising intercellular signaling molecule involved in cellular proliferation and dedifferentiation. It was shown that PSK stimulated and enhanced cell divisions in protoplast cultures of several species leading to callus and proembryogenic mass formation. Since PSK had been shown to cause an increase in efficiency of somatic embryogenesis, it was reasonable to check the distribution of selected chemical components of the cell walls during the protoplast regeneration process. So far, especially for the carrot, a model species for in vitro cultures, it has not been specified what pectic, arabinogalactan protein (AGP) and extensin epitopes are involved in the reconstruction of the wall in protoplast-derived cells. Even less is known about the correlation between wall regeneration and the presence of PSK during the protoplast culture. Three Daucus taxa, including the cultivated carrot, were analyzed during protoplast regeneration. Several antibodies directed against wall components (anti-pectin: LM19, LM20, anti-AGP: JIM4, JIM8, JIM13 and anti-extensin: JIM12) were used. The obtained results indicate a diverse response of the used Daucus taxa to PSK in terms of protoplast-derived cell development, and diversity in the chemical composition of the cell walls in the control and the PSK-treated cultures.
The Development of Functional Non-Viral Vectors for Gene Delivery
Authors: Patil Suryaji , Gao Yong-Guang , Lin Xiao , Li Yu , Dang Kai , Tian Ye , Zhang Wen-Juan , Jiang Shan-Feng , Qadir Abdul , Qian Ai-Rong
Published: November 2019

Gene therapy is manipulation in/of gene expression in specific cells/tissue to treat diseases. This manipulation is carried out by introducing exogenous nucleic acids, such as DNA or RNA, into the cell. Because of their negative charge and considerable larger size, the delivery of these molecules, in general, should be mediated by gene vectors. Non-viral vectors, as promising delivery systems, have received considerable attention due to their low cytotoxicity and non-immunogenicity. As research continued, more and more functional non-viral vectors have emerged. They not only have the ability to deliver a gene into the cells but also have other functions, such as the performance of fluorescence imaging, which aids in monitoring their progress, targeted delivery, and biodegradation. Recently, many reviews related to non-viral vectors, such as polymers and cationic lipids, have been reported. However, there are few reviews regarding functional non-viral vectors. This review summarizes the common functional non-viral vectors developed in the last ten years and their potential applications in the future. The transfection efficiency and the transport mechanism of these materials were also discussed in detail. We hope that this review can help researchers design more new high-efficiency and low-toxicity multifunctional non-viral vectors, and further accelerate the progress of gene therapy.
Fuzzy Reinforcement Learning and Curriculum Transfer Learning for Micromanagement in Multi-Robot Confrontation
Authors: Hu Chunyang , Xu Meng
Published: November 2019

Multi-Robot Confrontation on physics-based simulators is a complex and time-consuming task, but simulators are required to evaluate the performance of the advanced algorithms. Recently, a few advanced algorithms have been able to produce considerably complex levels in the context of the robot confrontation system when the agents are facing multiple opponents. Meanwhile, the current confrontation decision-making system suffers from difficulties in optimization and generalization. In this paper, a fuzzy reinforcement learning (RL) and the curriculum transfer learning are applied to the micromanagement for robot confrontation system. Firstly, an improved Q-learning in the semi-Markov decision-making process is designed to train the agent and an efficient RL model is defined to avoid the curse of dimensionality. Secondly, a multi-agent RL algorithm with parameter sharing is proposed to train the agents. We use a neural network with adaptive momentum acceleration as a function approximator to estimate the state-action function. Then, a method of fuzzy logic is used to regulate the learning rate of RL. Thirdly, a curriculum transfer learning method is used to extend the RL model to more difficult scenarios, which ensures the generalization of the decision-making system. The experimental results show that the proposed method is effective.
Current Knowledge of the Entomopathogenic Fungal Species Metarhizium flavoviride Sensu Lato and Its Potential in Sustainable Pest Control
Authors: Tóthné Bogdányi Franciska , Petrikovszki Renáta , Balog Adalbert , Putnoky-Csicsó Barna , Gódor Anita , Bálint János , Tóth Ferenc
Published: November 2019

Fungal entomopathogens are gaining increasing attention as alternatives to chemical control of arthropod pests, and the literature on their use under different conditions and against different species keeps expanding. Our review compiles information regarding the entomopathogenic fungal species Metarhizium flavoviride (Gams and Rozsypal 1956) (Hypocreales: Clavicipitaceae) and gives account of the natural occurrences and target arthropods that can be controlled using M. flavoviride. Taxonomic problems around M. flavoviride species sensu lato are explained. Bioassays, laboratory and field studies examining the effect of fermentation, culture regimes and formulation are compiled along with studies on the effect of the fungus on target and non-target organisms and presenting the effect of management practices on the use of the fungus. Altogether, we provide information to help conducting basic studies, and by pointing out relatively uncharted territories, help to set new research areas.
Effect of Diets and Low Temperature Storage on Adult Performance and Immature Development of Phyllonorycter ringoniella in Laboratory
Authors: Geng Shubao , Hou Heli , Jung Chuleui
Published: November 2019

The Asiatic apple leaf miner, Phyllonorycter ringoniella (Matsumura), is an important insect pest to apples. We developed a rearing method for P. ringoniella in the laboratory. Overwintering pupae were collected from our apple orchard, and crabapple seedlings were selected as oviposition substrate and food source for the larval development. The mean developmental period was 25.9 ± 0.49 days from egg to adult and the survival rate was 0.387 under 25 ± 1 °C, 65 ± 5% RH and a photoperiod of 14:10 (L:D) h. Mean egg length and egg width were 0.336 ± 0.0043 and 0.259 ± 0.0046 mm, respectively. Mean body length and head width increased from 1.070 ± 0.0245 and 0.180 ± 0.0021 mm in first instar larvae to 5.027 ± 0.0718 and 0.321 ± 0.0021 mm in fifth instar larvae, respectively. The mean weight of the pupae was 0.946 ± 0.0132 mg. The wingspan of male adult (6.280 ± 0.0639 mm) was significantly larger than female (6.040 ± 0.0753 mm). The mean fecundity (56.9 ± 8.58 eggs per female) and longevity (8.2 ± 0.55 days) of females was highest when they were provided with 10% honey solution, followed by 10% sugar, water, and control. The females preferred to lay eggs (56.5 ± 3.84%) near the secondary leaf vein in a leaf. The larval mortality increased linearly (R2 = 0.94) with the number of larvae per leaf. The mortality of pupae increased from 5.6 ± 4.01 to 51.1 ± 9.88% as storage periods at 4 °C increased from 0 to 105 days. The rearing method and its biological characteristics presented in this study will contribute to further studies on this pest insect.
Transgenic Winter Wheat Expressing the Sucrose Transporter HvSUT1 from Barley does not Affect Aphid Performance
Authors: Yang Yan , Kloos Stefanie , Mora-Ramírez Isabel , Romeis Jörg , Brunner Susanne , Li Yunhe , Meissle Michael
Published: November 2019

Winter wheat expressing the sucrose transporter HvSUT1 from barley (HOSUT) has an increased yield potential. Genetic engineering should improve cultivars without increasing susceptibility to biotic stresses or causing negative impacts on ecosystem services. We studied the effects of HOSUT wheat on cereal aphids that feed on the sugar-rich phloem sap. Three HOSUT winter wheat lines, their conventional parental cultivar Certo, and three conventional cultivars were used. Clip cage experiments in the greenhouse showed no differences in life-table parameters of Rhopalosiphum padi and Sitobion avenae (Hemiptera: Aphididae) on transgenic lines compared to Certo, except higher fecundity of S. avenae on one HOSUT line. Population development of both aphid species over three weeks on caged flowering tillers did not reveal differences between the HOSUT lines and Certo. When aphids were monitored in a Swiss field study over two years, no differences between HOSUT lines and Certo were observed. We conclude that HOSUT wheat did not have consistent effects on aphids compared to the parental cultivar and measured parameters were generally in the range observed for the conventional winter wheat cultivars. Thus, HOSUT wheat is unlikely to suffer from increased aphid damage.
Symbolic Recurrence Analysis of RR Interval to Detect Atrial Fibrillation
Authors: Pérez-Valero Jesús , Caballero Pintado M. Victoria , Melgarejo Francisco , García-Sánchez Antonio-Javier , Garcia-Haro Joan , García Córdoba Francisco , García Córdoba José A. , Pinar Eduardo , García Alberola Arcadio , Matilla-García Mariano , Curtin Paul , Arora Manish , Ruiz Marín Manuel
Published: November 2019

Atrial fibrillation (AF) is a sustained cardiac arrhythmia associated with stroke, heart failure, and related health conditions. Though easily diagnosed upon presentation in a clinical setting, the transient and/or intermittent emergence of AF episodes present diagnostic and clinical monitoring challenges that would ideally be met with automated ambulatory monitoring and detection. Current approaches to address these needs, commonly available both in smartphone applications and dedicated technologies, combine electrocardiogram (ECG) sensors with predictive algorithms to detect AF. These methods typically require extensive preprocessing, preliminary signal analysis, and the integration of a wide and complex array of features for the detection of AF events, and are consequently vulnerable to over-fitting. In this paper, we introduce the application of symbolic recurrence quantification analysis (SRQA) for the study of ECG signals and detection of AF events, which requires minimal pre-processing and allows the construction of highly accurate predictive algorithms from relatively few features. In addition, this approach is robust against commonly-encountered signal processing challenges that are expected in ambulatory monitoring contexts, including noisy and non-stationary data. We demonstrate the application of this method to yield a highly accurate predictive algorithm, which at optimal threshold values is 97.9% sensitive, 97.6% specific, and 97.7% accurate in classifying AF signals. To confirm the robust generalizability of this approach, we further evaluated its performance in the implementation of a 10-fold cross-validation paradigm, yielding 97.4% accuracy. In sum, these findings emphasize the robust utility of SRQA for the analysis of ECG signals and detection of AF. To the best of our knowledge, the proposed model is the first to incorporate symbolic analysis for AF beat detection.
Usefulness of Liquid Biopsy Biomarkers from Aqueous Humor in Predicting Anti-VEGF Response in Diabetic Macular Edema: Results of a Pilot Study
Authors: Udaondo Patricia , Hernández Cristina , Briansó-Llort Laura , García-Delpech Salvador , Simó-Servat Olga , Simó Rafael
Published: November 2019

The objective was to investigate the usefulness of the “liquid biopsy” of aqueous humor (AH) to predict the clinical response after intravitreal injections (IVT) of anti-VEGF agents for treating diabetic macular edema (DME). For this purpose, AH samples obtained during the first anti-VEGF IVT from 31 type two diabetic patients were analyzed. Patients were classified into three groups according to their anti-VEGF response: rapid responders (n = 11), slow responders (n = 11), and non-responders (n = 9). In addition, patients (n = 7) who showed good response to corticosteroids but a delayed or no response to anti-VEGF therapy were analyzed. Levels of 17 different cytokines, chemokines, and growth factors in AH were measured using a multiplex immunoassay. We found higher concentrations of VEGF in rapid responders to anti-VEGF therapy compared to non-responders. In addition, slow responders to anti-VEGF treatment showed higher levels of inflammatory markers than rapid responders, but did not reach statistical significance. Finally, those patients who responded to corticosteroids but not to anti-VEGF therapy showed significantly lower levels of VEGF than patients with rapid response (p = 0.01). In conclusion, “liquid biopsy” of AH could be useful to determine whether the predominant pathogenic event is primarily angiogenic or inflammatory in nature. This approach would allow physicians to select a more rational and cost-effective treatment. Further studies to validate these preliminary results are warranted.
Gastrointestinal Microbiota and Type 1 Diabetes Mellitus: The State of Art
Authors: Durazzo Marilena , Ferro Arianna , Gruden Gabriella
Published: November 2019

The incidence of autoimmune type 1 diabetes (T1DM) is increasing worldwide and disease onset tends to occur at a younger age. Unfortunately, clinical trials aiming to detect predictive factors of disease, in individuals with a high risk of T1DM, reported negative results. Hence, actually there are no tools or strategies to prevent T1DM onset. The importance of the gut microbiome in autoimmune diseases is increasingly recognized and recent data suggest that intestinal dysbiosis has a pathogenic role in T1DM by affecting both intestinal immunostasis and the permeability of the gut barrier. An improved understanding of the mechanisms whereby dysbiosis in the gut favors T1DM development may help develop new intervention strategies to reduce both the incidence and burden of T1DM. This review summarizes available data on the associations between gut microbiota and T1DM in both experimental animals and humans and discusses future perspectives in this novel and exciting area of research.
Effectiveness of Chronic Wound Debridement with the Use of Larvae of Lucilia Sericata
Authors: Bazaliński Dariusz , Kózka Maria , Karnas Magdalena , Więch Paweł
Published: November 2019

The process of successful wound healing depends on effective debridement and infection control. One method of wound debridement, known since antiquity, is based on the use of fly larvae. Solid scientific evidence proves that maggot debridement therapy (MDT), like surgical intervention, can be effectively and safely used to remove necrotic tissue. Based on a review of the related literature, this study was designed to assess the effectiveness of chronic wound cleansing with the use of larvae of Lucilia sericata (Phaenicia sericata). Maggot therapy, applied in wound debridement and treatment, is a safe and effective method. Its benefits are associated with debridement, disinfection and faster tissue growth. MDT may reduce the duration of antibiotic therapy and the need for hospitalization, or it may decrease the number of outpatient visits required. It is a relatively cost-effective method, and, in addition to financial gains, it may reduce the frequency of inpatient treatment. In the literature, an increasing amount of scientific evidence confirms that such treatment can effectively reduce the biofilm and bacterial load in a wound.
Targeting Endotypic Traits with Medications for the Pharmacological Treatment of Obstructive Sleep Apnea. A Review of the Current Literature
Authors: Taranto-Montemurro Luigi , Messineo Ludovico , Wellman Andrew
Published: November 2019

Obstructive sleep apnea (OSA) is a highly prevalent condition with few therapeutic options. To date there is no approved pharmacotherapy for this disorder, but several attempts have been made in the past and are currently ongoing to find one. The recent identification of multiple endotypes underlying this disorder has oriented the pharmacological research towards tailored therapies targeting specific pathophysiological traits that contribute differently to cause OSA in each patient. In this review we retrospectively analyze the literature on OSA pharmacotherapy dividing the medications tested on the basis of the four main endotypes: anatomy, upper airway muscle activity, arousal threshold and ventilatory instability (loop gain). We show how recently introduced drugs for weight loss that modify upper airway anatomy may play an important role in the management of OSA in the near future, and promising results have been obtained with drugs that increase upper airway muscle activity during sleep and reduce loop gain. The lack of a medication that can effectively increase the arousal threshold makes this strategy less encouraging, although recent studies have shown that the use of certain sedatives do not worsen OSA severity and could actually improve patients’ sleep quality.
Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy
Authors: Kim Byung-Hak , Lee Haeri , Song Yeonghun , Park Joon-Suk , Gadhe Changdev G. , Choi Jiwon , Lee Chung-Gi , Pae Ae Nim , Kim Sanghee , Ye Sang-Kyu
Published: November 2019

Persistently activated STAT3 is a promising target for a new class of anticancer drug development and cancer therapy, as it is associated with tumor initiation, progression, malignancy, drug resistance, cancer stem cell properties, and recurrence. Here, we discovered 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117) as a small-molecule inhibitor of STAT3 to be used in STAT3-targeted cancer therapy. ODZ10117 targeted the SH2 domain of STAT3 regardless of other STAT family proteins and upstream regulators of STAT3, leading to inhibition of the tyrosine phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3. The inhibitory effect of ODZ10117 on STAT3 was stronger than the known STAT3 inhibitors such as S3I-201, STA-21, and nifuroxazide. ODZ10117 suppressed the migration and invasion, induced apoptosis, reduced tumor growth and lung metastasis, and extended the survival rate in both in vitro and in vivo models of breast cancer. Overall, we demonstrated that ODZ10117 is a novel STAT3 inhibitor and may be a promising agent for the development of anticancer drugs.
Evaluation of Concomitant Orbital Floor Fractures in Patients with Head Trauma Using Conventional Head CT Scan: A Retrospective Study at a Level II Trauma Center
Authors: Huang Li-Kuo , Tu Hsi-Feng , Jiang Liang-De , Chen Ying-Yuan , Fu Chih-Yuan
Published: November 2019

Background: Patients with head trauma may have concomitant orbital floor fractures (OFFs). The objective of our study was to determine the specific CT findings and investigate the diagnostic performance of head CT in detecting OFFs. Methods: We analyzed 3534 head trauma patients undergoing simultaneous head and facial CT over a 3-year period. The clinical data and specific head CT findings between patients with and without OFFs were compared. Results: In our cohort, 198 patients (5.6%) had OFFs visible on CT. On head CT, orbital floor discontinuity, gas bubbles entrapped between floor fragments, inferior extraconal emphysema, and maxillary hemosinus (MHS) were more commonly observed among patients with OFFs (p < 0.001). The absence of MHS had a high negative predictive value (99.7%) for excluding OFFs. Among the different types of MHS, the pattern showing high-attenuation opacity mixed with mottled gas had the highest positive predictive value (69.5%) for OFFs and was the only independent predictor of OFFs after adjusting for the other CT variables in all patients with MHS. Conclusion: Head CT may serve as a first-line screening tool to detect OFFs in head trauma patients. Hence, unnecessary facial CT and additional radiation exposure may be reduced.
Early Lyme Borreliosis in Patients Treated with Tumour Necrosis Factor-Alfa Inhibitors
Authors: Maraspin Vera , Bogovič Petra , Rojko Tereza , Ogrinc Katarina , Ružić-Sabljić Eva , Strle Franc
Published: November 2019

The study evaluated the course and outcome of erythema migrans in patients receiving tumour necrosis factor-alpha (TNF-α) inhibitors. Among 4157 adults diagnosed with erythema migrans in the period 2009–2018, 16 (2.6%) patients were receiving TNF-α inhibitors (adalimumab, infliximab, etarnecept, golimumab), often in combination with other immunosuppressants, for rheumatic (13 patients) or inflammatory bowel (three patients) disease. Findings in this group were compared with those in 32 sex- and age-matched immunocompetent patients diagnosed with erythema migrans in the same years. In comparison with the control group, the immunocompromised patients had a shorter incubation period (7 vs. 14 days; p = 0.0153), smaller diameter of erythema migrans (10.5 vs. 15.5 cm; p = 0.0014), and more frequent comorbidities other than immune-mediated diseases (62.5% vs. 25%, p = 0.0269), symptoms/signs of disseminated Lyme borreliosis (18.8% vs. 0%, p = 0.0324), and treatment failure (25% vs. 0%, p = 0.0094). After retreatment with an antibiotic, the clinical course of Lyme borreliosis resolved. Continuing TNF inhibitor treatment during concomitant borrelial infection while using identical approaches for antibiotic treatment as in immunocompetent patients resulted in more frequent failure of erythema migrans treatment in patients receiving TNF inhibitors. However, the majority of treatment failures were mild, and the course and outcome of Lyme borreliosis after retreatment with antibiotics was favourable.
Methotrexate Restores CD73 Expression on Th1.17 in Rheumatoid Arthritis and Psoriatic Arthritis Patients and May Contribute to Its Anti-Inflammatory Effect through Ado Production
Authors: Bossennec Marion , Rodriguez Céline , Hubert Margaux , Di-Roio Anthony , Machon Christelle , Guitton Jérôme , Battiston-Montagne Priscilla , Couturier Mathilde , Marotte Hubert , Caux Christophe , Coury Fabienne , Ménétrier-Caux Christine
Published: November 2019

Objectives: Th1.17 are highly polyfunctional, potentially harmful CD4+ effector T cells (Teff) through IFN-γ and IL-17A coproduction. Th1.17 take part in the pathophysiology of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in which their hyper activation results in part from defects in negative regulation mechanisms. We recently demonstrated that the ecto-nucleotidase CD73 delineates a Th1.17-enriched Teff population and acts as an endogenous regulatory mechanism. Because Methotrexate (MTX), used as first line treatment of RA and PsA, increases extracellular concentrations of AMP and immunosuppressive adenosine, we investigated the modulation of CD73 by MTX treatment on Teff in RA/PsA patients. Methods: In a prospective cohort of 26 RA and 15 PsA patients before or under MTX treatment, we evaluated CD73 expression on blood Teff subsets, their cytokine production and AMPase functions. Results: We showed a decreased CD73 expression on Th1.17 and Th1 in untreated patients compared to healthy donors that was partly restored under MTX. This decrease in untreated patients leads to a halved Ado production by Th1.17 cells. CD73+ Teff remained functional under MTX treatment, but their CD73 re-expression may contribute to control their activation. Conclusion: Our study unveils uncovered mode of action of MTX on Teff subsets modulation and in the adenosine-dependent termination of inflammation in RA and PsA.
Lipid Profile Rather Than the LCAT Mutation Explains Renal Disease in Familial LCAT Deficiency
Authors: Lamiquiz-Moneo Itziar , Civeira Fernando , Gómez-Coronado Diego , Blanco-Vaca Francisco , Villafuerte-Ledesma Hilda Mercedes , Gil Miriam , Amigó Nuria , Mateo-Gallego Rocío , Cenarro Ana
Published: November 2019

Renal complications are the major cause of morbidity and mortality in patients with familial lecithin–cholesterol acyltransferase (LCAT) deficiency (FLD). We report three FLD patients, two of them siblings—only one of whom developed renal disease—and the third case being a young man with early renal disease. The aim of this study was to analyze the clinical characteristics and possible mechanisms associated with renal disease in these patients. Plasma lipid levels, LCAT activity, lipoprotein particle profile by NMR and FPLC, free and esterified cholesterol, presence of lipoprotein X (LpX) and DNA sequencing in the three FLD patients have been determined. The three cases presented clinical characteristics of FLD, although only one of the siblings developed renal disease, at 45 years of age, while the other patient developed the disease in his youth. Genetic analysis revealed new missense homozygous mutations, p.(Ile202Thr) in both siblings and p.(Arg171Glu) in the other patient. Lipoprotein particle analysis showed that the two patients with renal disease presented higher numbers of small very low-density lipoprotein (VLDL) and a higher concentration of triglycerides in VLDL. This study reports three new cases of LCAT deficiency, not previously described. Renal disease is not only dependent on LCAT deficiency, and could be due to the presence of VLDL particles, which are rich in triglycerides, free cholesterol and LpX.
Hypovitaminosis D Influences the Clinical Presentation of Immune Thrombocytopenia in Children with Newly Diagnosed Disease
Authors: Petrovic Davor , Benzon Benjamin , Batinic Marijan , Culic Srđana , Roganovic Jelena , Markic Josko
Published: November 2019

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by isolated thrombocytopenia defined as platelet count in peripheral blood <100 × 109/L. Hypovitaminosis D is very common in children with autoimmune diseases. To analyze whether hypovitaminosis D is associated with the clinical presentation of ITP in children, medical records of 45 pediatric patients with newly diagnosed immune thrombocytopenia in the coastal region of Croatia were evaluated. The severity of bleeding was assessed using two bleeding scores. Children with lower 25-hydroxyvitamin D (25(OH)D) values had higher values of the skin-mucosa-organ-gradation (SMOG) bleeding score and respectively more severe bleeding on diagnosis of ITP. With further analysis of the main domains of that score, we found that patients with a lower 25(OH)D value had more severe bleeding in the skin and organs. When 25(OH)D and ITP Bleeding Scale (IBLS) score were analyzed, a negative correlation was found, but it was not significant. Our findings suggest that hypovitaminosis D influences the severity of the clinical presentation of ITP in children on initial diagnosis of the disease. Therefore, therapy with 25(OH)D could be a new potential option for treatment of ITP. To investigate the connection between 25(OH)D and the incidence and severity of ITP, further studies, especially randomized controlled studies, are needed.
Associations of Anti-Aquaporin 5 Autoantibodies with Serologic and Histopathological Features of Sjögren’s Syndrome
Authors: Jeon Sumin , Lee Jennifer , Park Sung-Hwan , Kim Hyun-Duck , Choi Youngnim
Published: November 2019

Biomarkers to stratify the complex and heterogeneous phenotypes of Sjogren’s syndrome (SS) are needed. We aimed to validate the prevalence of anti-aquaporin 5 (AQP5) IgG in a non-Korean cohort and to optimize the method to screen the anti-AQP5 IgG. The study cohort included 111 primary SS and 43 non-SS Sjögren’s International Collaborative Clinical Alliance (SICCA) controls that were obtained from the Sjögren’s International Collaborative Clinical Alliance registry, in addition to 35 systemic lupus erythematosus (SLE) and 35 rheumatoid arthritis (RA) phenotypes. Anti-AQP5 IgG was screened by cell-based immunofluorescence cytochemistry (CB-IFC) assay in the absence or presence of epitope peptides, as well as by ELISA using the epitope peptides as coated antigens. Anti-AQP5 IgG specific to an E1 epitope was best at discriminating between SS and non-SS, and the two different methods (CB-IFC and ELISA) presented comparable performance in diagnostic accuracy (0.690 vs. 0.707). Notably, the SLE and RA groups had substantially lower levels of anti-AQP5 IgG than the SS group. In addition, the presence of anti-AQP5_E1 IgG was associated with serologic and histopathological features of SS. In conclusion, a similar prevalence of anti-AQP5 IgG was confirmed in a non-Korean cohort. Screening anti-AQP5 autoantibodies may help to form subgroups of SS for targeted therapy.
Correction: Fast Tac Metabolizers at Risk—It is Time for a C/D Ratio Calculation. J. Clin. Med. 2019, 8, 587
Authors: Schütte-Nütgen Katharina , Thölking Gerold , Steinke Julia , Pavenstädt Hermann , Schmidt René , Suwelack Barbara , Reuter Stefan
Published: November 2019

The authors wish to make the following corrections to this paper [...]
Emerging Constructions in the L2 Italian Spoken by Low Literate Migrants
Authors: Mocciaro Egle
Published: November 2019

The emergence of autonomous interlanguage constructions is widely recognised in the literature on L2 Italian. These constructions involve the overgeneralisation of functional forms learners are in the process of acquiring, e.g., siamo in siamo mangiare ‘be:1PL eat:INF’ (target Italian: mangiamo ‘eat:1PL’); facciamo in facciamo cucinare ‘do:1PL cook:INF’ (target Italian: cuciniamo ‘cook:1PL’); per in piaciare per uscire fuori ‘like:INF for go:INF out’ (target Italian: mi piace uscire fuori ‘to.me like:3SG go:INF out’. ‘Be’/‘do’ forms are assigned a morphosyntactic function to convey temporal/aspectual/person information instead of inflecting the verb, while per ‘for’ is a generic subordinating marker. Based on new corpus data, I claim that such constructions may correlate with a learners’ degree of first language (L1) literacy. In detail, and consistent with, both literate and non-literate learners overgeneralise functional forms while working on the newly acquired morphosyntax; this shows that the non-literates are perfectly able to subconsciously identify functional forms in the input. Non-literates, however, show a stronger tendency than literates to select lexical-syntactic sub-patterns.
Study of Break-In Process and its Effects on Piston Skirt Lubrication in Internal Combustion Engines
Authors: Meng Zhen , Zhang Linfeng , Tian Tian
Published: November 2019

The piston skirt is one of the main contributors to the total mechanical loss in internal combustion engines. Usually, the skirt friction experiences a rapid change during the break-in period largely due to the wear of the machine marks or roughness against soft coatings. It is thus important to consider the effect of the change of the roughness for a realistic prediction of the piston skirt friction and system optimization. In this work, an existing model of piston skirt lubrication was improved with the consideration of a breaking in process for the most commonly used triangle machine marks. A new set of flow factors in the averaged Reynolds equation were analytically derived for the trapezoid shape formed after wear of the original triangle shape. A new asperity contact model was developed for the trapezoid shape. The calculation results reflect the trend of friction mean effective pressure (FMEP) during break-in in an engine test and showed quantitative agreement under the same amount of wear.
Ultrasound-Mediated Atom Transfer Radical Polymerization (ATRP)
Authors: Zaborniak Izabela , Chmielarz Paweł
Published: November 2019

Ultrasonic agitation is an external stimulus, rapidly developed in recent years in the atom transfer radical polymerization (ATRP) approach. This review presents the current state-of-the-art in the application of ultrasound in ATRP, including an initially-developed, mechanically-initiated solution with the use of piezoelectric nanoparticles, that next goes to the ultrasonication-mediated method utilizing ultrasound as a factor for producing radicals through the homolytic cleavage of polymer chains, or the sonolysis of solvent or other small molecules. Future perspectives in the field of ultrasound in ATRP are presented, focusing on the preparation of more complex architectures with highly predictable molecular weights and versatile properties. The challenges also include biohybrid materials. Recent advances in the ultrasound-mediated ATRP point out this approach as an excellent tool for the synthesis of advanced materials with a wide range of potential industrial applications.
Effects of Aggregate Mesostructure on Permanent Deformation of Asphalt Mixture Using Three-Dimensional Discrete Element Modeling
Authors: Zhang Deyu , Gu Linhao , Zhu Junqing
Published: November 2019

This paper investigated the effects of aggregate mesostructures on permanent deformation behavior of an asphalt mixture using the three-dimensional (3D) discrete element method (DEM). A 3D discrete element (DE) model of an asphalt mixture composed of coarse aggregates, asphalt mastic, and air voids was developed. Mesomechanical models representing the interactions among the components of asphalt mixture were assigned. Based on the mesomechanical modeling, the uniaxial static load creep tests were simulated using the prepared models, and effects of aggregate angularity, orientation, surface texture, and distribution on the permanent deformation behavior of the asphalt mixtures were analyzed. It was proven that good aggregate angularity had a positive effect on the permanent deformation performance of the asphalt mixtures, especially when approximate cubic aggregates were used. Aggregate packing was more stable when the aggregate orientations tended to be horizontal, which improved the permanent deformation performance of the asphalt mixture. The influence of orientations of 4.75 mm size aggregates on the permanent deformation behavior of the asphalt mixture was significant. Use of aggregates with good surface texture benefitted the permanent deformation performance of the asphalt mixture. Additionally, the non-uniform distribution of aggregates had a negative impact on the permanent deformation performance of the asphalt mixtures, especially when aggregates were distributed non-uniformly in the vertical direction.