bluuebunny/crossref_metadata_2025 huggingface dataset:
Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features
Authors: Pozsonyi Zoltán , Peskó Gergely , Takács Hedvig , Csuka Dorottya , Nagy Viktória , Szilágyi Ágnes , Hategan Lidia , Muk Balázs , Csányi Beáta , Nyolczas Noémi , Dézsi Lívia , Molnár Judit Mária , Csillik Anita , Révész Katalin , Iványi Béla , Szabó Fruzsina , Birtalan Krisztián , Masszi Tamás , Arányi Zsuzsanna , Sepp Róbert
Published: July 2021

Background: Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited disease, where the mutation of the transthyretin gene (TTR) results in the deposition of pathogenic protein fibrils in various tissues. The mutation type influences the clinical course. Until now, no data were available on the genotype, phenotype, and prevalence of Hungarian ATTRv patients. The aim of our study was to assess the prevalence, regional distribution, genotypes, and phenotypes of Hungarian patients with ATTRv. Methods: With the collaboration of Hungarian regional and university centers, we identified patients diagnosed with ATTRv. We also searched prior publications for case studies of Hungarian ATTRv patients. Results: 40 individuals in 23 families with ATTRv were identified within the borders of Hungary. At the time of the diagnosis, 24 of them were symptomatic. The two most common mutations were ATTRHis88Arg (nine families) and ATTRIle107Val (8 families). ATTRVal30Met was demonstrated in 2 families, and ATTRVal122del, ATTRPhe33Leu, ATTRIle84Ser, and ATTRAsp18Gly in one family each. The median age of the symptomatic patients at the time of clinical diagnosis was 65 years. The most common clinically significant organ involvement was restrictive cardiomyopathy, found in 24 patients. Polyneuropathy was diagnosed in 20 patients. A total of 19 patients showed a mixed phenotype. The leading symptom was heart failure in 8 cases (3 of them had only cardiac symptoms), polyneuropathy in 11 cases (all of them also had cardiac symptoms), and equally severe cardiac and neuropathy symptoms were present in 3 cases. Out of 24 symptomatic patients, 10 received targeted pharmacological therapy. The follow-up period ranged from 1 to 195 months. At the time of the retrospective analysis, 12 patients had already died, and 1 patient underwent heart transplantation. Conclusions: As TTR genotype influences the phenotype and clinical course of ATTRv, it is important to know the regional data. In Hungary, ATTRHis88Arg and ATTRIle107Val are the most common mutations in ATTRv, both presenting with mixed phenotype, but the median age at the time of the diagnosis is 9 years lower in patients with ATTRHis88Arg than in patients with ATTRIle107Val.
Ethically Researching Local Impacts of Environmental Change without Travel
Authors: Kelman Ilan
Published: July 2021

Responses to the COVID-19 pandemic, which began in 2020, included local and international travel restrictions alongside limits on face-to-face gatherings. These measures impinged on participatory research examining local impacts of environmental change. In response, many researchers adopted techniques that could be implemented without travel. This article explores some of the consequent research ethics issues.
Machine Learning to Predict the Progression of Bone Mass Loss Associated with Personal Characteristics and a Metabolic Syndrome Scoring Index
Authors: Cheng Chao-Hsin , Lin Ching-Yuan , Cho Tsung-Hsun , Lin Chih-Ming
Published: July 2021

A relationship exists between metabolic syndrome (MetS) and human bone health; however, whether the combination of demographic, lifestyle, and socioeconomic factors that are associated with MetS development also simultaneously affects bone density remains unclear. Using a machine learning approach, the current study aimed to estimate the usefulness of predicting bone mass loss using these potentially related factors. The present study included a sample of 23,497 adults who routinely visited a health screening center at a large health center at least once during each of three 3-year stages (i.e., 2006–2008, 2009–2011, and 2012–2014). The demographic, socioeconomic, lifestyle characteristics, body mass index (BMI), and MetS scoring index recorded during the first 3-year stage were used to predict the subsequent occurrence of osteopenia using a non-concurrence design. A concurrent prediction was also performed using the features recorded from the same 3-year stage as the predicted outcome. Machine learning algorithms, including logistic regression (LR), support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost), were applied to build predictive models using a unique feature set. The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, precision, and F1 score were used to evaluate the predictive performances of the models. The XGBoost model presented the best predictive performance among the non-concurrence models. This study suggests that the ensemble learning model with a MetS severity score can be used to predict the progression of osteopenia. The inclusion of an individual’s features into a predictive model over time is suggested for future studies.
The Key Techno-Economic and Manufacturing Drivers for Reducing the Cost of Power-to-Gas and a Hydrogen-Enabled Energy System
Authors: Bristowe George , Smallbone Andrew
Published: July 2021

Water electrolysis is a process which converts electricity into hydrogen and is seen as a key technology in enabling a net-zero compatible energy system. It will enable the scale-up of renewable electricity as a primary energy source for heating, transport, and industry. However, displacing the role currently met by fossil fuels might require a price of hydrogen as low as 1 $/kg, whereas renewable hydrogen produced using electrolysis is currently 10 $/kg. This article explores how mass manufacturing of proton exchange membrane (PEM) electrolysers can reduce the capital cost and, thus, make the production of renewable power to hydrogen gas (PtG) more economically viable. A bottom up direct manufacturing model was developed to determine how economies of scale can reduce the capital cost of electrolysis. The results demonstrated that (assuming an annual production rate of 5000 units of 200 kW PEM electrolysis systems) the capital cost of a PEM electrolysis system can reduce from 1990 $/kW to 590 $/kW based on current technology and then on to 431 $/kW and 300 $/kW based on the an installed capacity scale-up of ten- and one-hundred-fold, respectively. A life-cycle costing analysis was then completed to determine the importance of the capital cost of an electrolysis system to the price of hydrogen. It was observed that, based on current technology, mass manufacturing has a large impact on the price of hydrogen, reducing it from 6.40 $/kg (at 10 units units per year) to 4.16 $/kg (at 5000 units per year). Further analysis was undertaken to determine the cost at different installed capacities and found that the cost could reduce further to 2.63 $/kg and 1.37 $/kg, based on technology scale-up by ten- and one hundred-fold, respectively. Based on the 2030 (and beyond) baseline assumptions, it is expected that hydrogen production from PEM electrolysis could be used as an industrial process feed stock, provide power and heat to buildings and as a fuel for heavy good vehicles (HGVs). In the cases of retrofitted gas networks for residential or industrial heating solutions, or for long distance transport, it represents a more economically attractive and mass-scale compatible solution when compared to electrified heating or transport solutions.
Beautiful China Construction Evaluation Method Based on POIs: Case Study of the Inner Mongolia Autonomous Region
Authors: Liang Yuting , Hu Yunfeng
Published: July 2021

Point of interest (POI) data can provide a clear spatial location and accurate attributes for geoscience research. The traditional assessment of Beautiful China construction (BCC) has relied on statistical materials, which have shortcomings in terms of timeliness, authenticity, efficiency, and accuracy. Referring to the theoretical framework of the Zhongke Beauty Index, we built an evaluation index system and technical process based on POI data. In terms of the Inner Mongolia Autonomous Region (IMAR), 5.09 million POIs were collected using the web crawler technique, and the Beautiful Inner Mongolia construction evaluation and analysis were performed. The results show the following: (1) POI data can be used to establish an evaluation index system for the construction of Beautiful Inner Mongolia on the county scale; in the dimensions of industrial development, social harmony, and institutional improvement, it shows especially good application prospects. (2) The Beautiful Inner Mongolia index in 2020 was 0.22. Among the five dimensions, the industrial development index was the highest, while the cultural heritage index was the lowest. We found significant spatial differences in the dimensions of cultural heritage as well as social harmony. (3) The areas in the IMAR with a low-level construction were mostly industrial and mining areas, agricultural counties, and other economically developing areas, among which the Baiyunebo mining area and Xianghuangqi and Shiguai areas had the lowest comprehensive beauty index values. (4) We also found large numerical disparities in the level of Beautiful Inner Mongolia construction between municipal districts and banners/counties, and the ranking of each region was affected by the population and coverage areas of administrative units. After verification, we found an overall good consistency between the evaluation indexes proposed in this paper and a previous study. Therefore, this paper provides a new perspective and an effective method for the application of Internet big data in economic and social evaluation work.
The Role of Gut Microbiota in Overcoming Resistance to Checkpoint Inhibitors in Cancer Patients: Mechanisms and Challenges
Authors: Bouferraa Youssef , Chedid Andrea , Amhaz Ghid , El Lakkiss Ahmed , Mukherji Deborah , Temraz Sally , Shamseddine Ali
Published: July 2021

The introduction of immune checkpoint inhibitors has constituted a major revolution in the treatment of patients with cancer. In contrast with the traditional cytotoxic therapies that directly kill tumor cells, this treatment modality enhances the ability of the host’s immune system to recognize and target cancerous cells. While immune checkpoint inhibitors have been effective across multiple cancer types, overcoming resistance remains a key area of ongoing research. The gut microbiota and its role in cancer immunosurveillance have recently become a major field of study. Gut microbiota has been shown to have direct and systemic effects on cancer pathogenesis and hosts anti-tumor immune response. Many studies have also shown that the host microbiota profile plays an essential role in the response to immunotherapy, especially immune checkpoint inhibitors. As such, modulating this microbial environment has offered a potential path to overcome the resistance to immune checkpoint inhibitors. In this review, we will talk about the role of microbiota in cancer pathogenesis and immune-system activity. We will also discuss preclinical and clinical studies that have increased our understanding about the roles and the mechanisms through which microbiota influences the response to treatment with immune checkpoint inhibitors.
Design and Encapsulation of Immunomodulators onto Gold Nanoparticles in Cancer Immunotherapy
Authors: Chauhan Akshita , Khan Tabassum , Omri Abdelwahab
Published: July 2021

The aim of cancer immunotherapy is to reactivate autoimmune responses to combat cancer cells. To stimulate the immune system, immunomodulators, such as adjuvants, cytokines, vaccines, and checkpoint inhibitors, are extensively designed and studied. Immunomodulators have several drawbacks, such as drug instability, limited half-life, rapid drug clearance, and uncontrolled immune responses when used directly in cancer immunotherapy. Several strategies have been used to overcome these limitations. A simple and effective approach is the loading of immunomodulators onto gold-based nanoparticles (GNPs). As gold is highly biocompatible, GNPs can be administered intravenously, which aids in increasing cancer cell permeability and retention time. Various gold nanoplatforms, including nanospheres, nanoshells, nanorods, nanocages, and nanostars have been effectively used in cancer immunotherapy. Gold nanostars (GNS) are one of the most promising GNP platforms because of their unusual star-shaped geometry, which significantly increases light absorption and provides high photon-to-heat conversion efficiency due to the plasmonic effect. As a result, GNPs are a useful vehicle for delivering antigens and adjuvants that support the immune system in killing tumor cells by facilitating or activating cytotoxic T lymphocytes. This review represents recent progress in encapsulating immunomodulators into GNPs for utility in a cancer immunotherapeutic regimen.
Investigating the Intermediate Water Feature of Hydrated Titanium Containing Bioactive Glass
Authors: Mabrouk Mostafa , Beherei Hanan H. , Tanaka Yukiko , Tanaka Masaru
Published: July 2021

Intermediate water (IW) in hydrated bioactive glasses remains uninvestigated. We obtained titanium (Ti)-containing bioactive glasses (BGTs) (Ti at 5%, 7.5% and 10% of the glass system) using the sol–gel technique. Their thermal, physicochemical, and morphological properties, before and after Ti-doping, were analysed using DTA, XRD, FTIR, TEM, and SEM accessorised with EDAX, and size distribution and zeta potential surface charges were determined using a NanoZetasizer. The IW in hydrated BGTs was investigated by cooling and heating runs of DSC measurements. Moreover, the mode of death in an osteosarcoma cell line (MG63) was evaluated at different times of exposure to BGT discs. Ti doping had no remarkable effect on the thermal, physicochemical, and morphological properties of BGTs. However, the morphology, size, and charges of BGT nano-powders were slightly changed after inclusion of Ti compared with those of BGT0; for example, the particle size increased with increasing Ti content (from 4–5 to 7–28 nm). The IW content was enhanced in the presence of Ti. The mode of cell death revealed the effect of IW content on the proliferation of cells exposed to BGTs. These findings should help improve the biocompatibility of inorganic biomaterials.
A Review of the Neutrophil Extracellular Traps (NETs) from Cow, Sheep and Goat Models
Authors: Worku Mulumebet , Rehrah Djaafar , Ismail Hamid D. , Asiamah Emmanuel , Adjei-Fremah Sarah
Published: July 2021

This review provides insight into the importance of understanding NETosis in cows, sheep, and goats in light of the importance to their health, welfare and use as animal models. Neutrophils are essential to innate immunity, pathogen infection, and inflammatory diseases. The relevance of NETosis as a conserved innate immune response mechanism and the translational implications for public health are presented. Increased understanding of NETosis in ruminants will contribute to the prediction of pathologies and design of strategic interventions targeting NETs. This will help to control pathogens such as coronaviruses and inflammatory diseases such as mastitis that impact all mammals, including humans. Definition of unique attributes of NETosis in ruminants, in comparison to what has been observed in humans, has significant translational implications for one health and global food security, and thus warrants further study.
Development of MRI-Detectable Boron-Containing Gold Nanoparticle-Encapsulated Biodegradable Polymeric Matrix for Boron Neutron Capture Therapy (BNCT)
Authors: Wu Chun-Yi , Hsieh Hsin-Hua , Chang Ting-Yu , Lin Jia-Jia , Wu Chin-Ching , Hsu Ming-Hua , Lin Ming-Chia , Peng Shin-Lei
Published: July 2021

This study aimed to develop a novel magnetic resonance imaging (MRI)-detectable boron (B)-containing nanoassemblies and evaluate their potential for boron neutron capture therapy (BNCT). Starting from the citrate-coated gold nanoparticles (AuNPs) (23.9 ± 10.2 nm), the diameter of poly (D, L-lactide-co-glycolide) AuNPs (PLGA-AuNPs) increased approximately 110 nm after the encapsulation of the PLGA polymer. Among various B drugs, the self-produced B cages had the highest loading efficiency. The average diameter of gadolinium (Gd)- and B-loaded NPs (PLGA-Gd/B-AuNPs) was 160.6 ± 50.6 nm with a B encapsulation efficiency of 28.7 ± 2.3%. In vitro MR images showed that the signal intensity of PLGA-Gd/B-AuNPs in T1-weighted images was proportional to its Gd concentration, and there exists a significantly positive relationship between Gd and B concentrations (R2 = 0.74, p < 0.005). The hyperintensity of either 250 ± 50 mm3 (larger) or 100 ± 50 mm3 (smaller) N87 xenograft was clearly visualized at 1 h after intravenous injection of PLGA-Gd/B-AuNPs. However, PLGA-Gd/B-AuNPs stayed at the periphery of the larger xenograft while located near the center of the smaller one. The tumor-to-muscle ratios of B content, determined by inductively coupled plasma mass spectrometry, in smaller- and larger-sized tumors were 4.17 ± 1.42 and 1.99 ± 0.55, respectively. In summary, we successfully developed theranostic B- and Gd-containing AuNPs for BNCT in this study.
SLIDE—Novel Approach to Apocrine Sweat Sampling for Lipid Profiling in Healthy Individuals
Authors: Kvasnička Aleš , Friedecký David , Tichá Alena , Hyšpler Radomír , Janečková Hana , Brumarová Radana , Najdekr Lukáš , Zadák Zdeněk
Published: July 2021

We designed a concept of 3D-printed attachment with porous glass filter disks—SLIDE (Sweat sampLIng DevicE) for easy sampling of apocrine sweat. By applying advanced mass spectrometry coupled with the liquid chromatography technique, the complex lipid profiles were measured to evaluate the reproducibility and robustness of this novel approach. Moreover, our in-depth statistical evaluation of the data provided an insight into the potential use of apocrine sweat as a novel and diagnostically relevant biofluid for clinical analyses. Data transformation using probabilistic quotient normalization (PQN) significantly improved the analytical characteristics and overcame the ‘sample dilution issue’ of the sampling. The lipidomic content of apocrine sweat from healthy subjects was described in terms of identification and quantitation. A total of 240 lipids across 15 classes were identified. The lipid concentrations varied from 10−10 to 10−4 mol/L. The most numerous class of lipids were ceramides (n = 61), while the free fatty acids were the most abundant ones (average concentrations of 10−5 mol/L). The main advantages of apocrine sweat microsampling include: (a) the non-invasiveness of the procedure and (b) the unique feature of apocrine sweat, reflecting metabolome and lipidome of the intracellular space and plasmatic membranes. The SLIDE application as a sampling technique of apocrine sweat brings a promising alternative, including various possibilities in modern clinical practice.
K-mer Content Changes with Node Degree in Promoter–Enhancer Network of Mouse ES Cells
Authors: Szyman Kinga , Wilczyński Bartek , Dąbrowski Michał
Published: July 2021

Maps of Hi-C contacts between promoters and enhancers can be analyzed as networks, with cis-regulatory regions as nodes and their interactions as edges. We checked if in the published promoter–enhancer network of mouse embryonic stem (ES) cells the differences in the node type (promoter or enhancer) and the node degree (number of regions interacting with a given promoter or enhancer) are reflected by sequence composition or sequence similarity of the interacting nodes. We used counts of all k-mers (k = 4) to analyze the sequence composition and the Euclidean distance between the k-mer count vectors (k-mer distance) as the measure of sequence (dis)similarity. The results we obtained with 4-mers are interpretable in terms of dinucleotides. Promoters are GC-rich as compared to enhancers, which is known. Enhancers are enriched in scaffold/matrix attachment regions (S/MARs) patterns and depleted of CpGs. Furthermore, we show that promoters are more similar to their interacting enhancers than vice-versa. Most notably, in both promoters and enhancers, the GC content and the CpG count increase with the node degree. As a consequence, enhancers of higher node degree become more similar to promoters, whereas higher degree promoters become less similar to enhancers. We confirmed the key results also for human keratinocytes.
The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis
Authors: Vourakis Margaret , Mayer Gaétan , Rousseau Guy
Published: July 2021

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one of the main risk factors for cardiovascular disease (CVD), the leading cause of death worldwide especially in developed countries. Current data show that the role of microbiota extends beyond digestion by being implicated in several metabolic and inflammatory processes linked to several diseases including CVD. Studies have reported associations between bacterial metabolites and hypercholesterolemia. However, such associations remain poorly investigated and characterized. In this review, the mechanisms of microbial derived metabolites such as primary and secondary bile acids (BAs), trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) will be explored in the context of cholesterol metabolism. These metabolites play critical roles in maintaining cardiovascular health and if dysregulated can potentially contribute to CVD. They can be modulated via nutritional and pharmacological interventions such as statins, prebiotics, and probiotics. However, the mechanisms behind these interactions also remain unclear, and mechanistic insights into their impact will be provided. Therefore, the objectives of this paper are to present current knowledge on potential mechanisms whereby microbial metabolites regulate cholesterol homeostasis and to discuss the feasibility of modulating intestinal microbes and metabolites as a novel therapeutic for hypercholesterolemia.
Mast Cell Cytokines IL-1, IL-33, and IL-36 Mediate Skin Inflammation in Psoriasis: A Novel Therapeutic Approach with the Anti-Inflammatory Cytokines IL-37, IL-38, and IL-1Ra
Authors: Conti Pio , Pregliasco Fabrizio E. , Bellomo Rosa G. , Gallenga Carla E. , Caraffa Alessandro , Kritas Spyros K. , Lauritano Dorina , Ronconi Gianpaolo
Published: July 2021

Psoriasis (PS) is a skin disease with autoimmune features mediated by immune cells, which typically presents inflammatory erythematous plaques, and is associated with many comorbidities. PS exhibits excessive keratinocyte proliferation, and a high number of immune cells, including macrophages, neutrophils, Th1 and Th17 lymphocytes, and mast cells (MCs). MCs are of hematopoietic origin, derived from bone marrow cells, which migrate, mature, and reside in vascularized tissues. They can be activated by antigen-provoking overexpression of proinflammatory cytokines, and release a number of mediators including interleukin (IL)-1 and IL-33. IL-1, released by activated keratinocytes and MCs, stimulates skin macrophages to release IL-36—a powerful proinflammatory IL-1 family member. IL-36 mediates both innate and adaptive immunity, including chronic proinflammatory diseases such as psoriasis. Suppression of IL-36 could result in a dramatic improvement in the treatment of psoriasis. IL-36 is inhibited by IL-36Ra, which binds to IL-36 receptor ligands, but suppression can also occur by binding IL-38 to the IL-36 receptor (IL-36R). IL-38 specifically binds only to IL-36R, and inhibits human mononuclear cells stimulated with IL-36 in vitro, sharing the effect with IL-36Ra. Here, we report that inflammation in psoriasis is mediated by IL-1 generated by MCs—a process that activates macrophages to secrete proinflammatory IL-36 inhibited by IL-38. IL-37 belongs to the IL-1 family, and broadly suppresses innate inflammation via IL-1 inhibition. IL-37, in murine models of inflammatory arthritis, causes the suppression of joint inflammation through the inhibition of IL-1. Therefore, it is pertinent to think that IL-37 can play an inhibitory role in inflammatory psoriasis. In this article, we confirm that IL-38 and IL-37 cytokines emerge as inhibitors of inflammation in psoriasis, and hold promise as an innovative therapeutic tool.
Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes
Authors: Nandi Purbasha , Li Shan , Columbres Rod Carlo A. , Wang Feng , Williams Dewight R. , Poh Yu-Ping , Chou Tsui-Fen , Chiu Po-Lin
Published: July 2021

IBMPFD/ALS is a genetic disorder caused by a single amino acid mutation on the p97 ATPase, promoting ATPase activity and cofactor dysregulation. The disease mechanism underlying p97 ATPase malfunction remains unclear. To understand how the mutation alters the ATPase regulation, we assembled a full-length p97R155H with its p47 cofactor and first visualized their structures using single-particle cryo-EM. More than one-third of the population was the dodecameric form. Nucleotide presence dissociates the dodecamer into two hexamers for its highly elevated function. The N-domains of the p97R155H mutant all show up configurations in ADP- or ATPγS-bound states. Our functional and structural analyses showed that the p47 binding is likely to impact the p97R155H ATPase activities via changing the conformations of arginine fingers. These functional and structural analyses underline the ATPase dysregulation with the miscommunication between the functional modules of the p97R155H.
Enhanced Autophagic Activity Improved the Root Growth and Nitrogen Utilization Ability of Apple Plants under Nitrogen Starvation
Authors: Huo Liuqing , Guo Zijian , Wang Qi , Cheng Li , Jia Xin , Wang Ping , Gong Xiaoqing , Li Cuiying , Ma Fengwang
Published: July 2021

Autophagy is a conserved degradation pathway for recycling damaged organelles and aberrant proteins, and its important roles in plant adaptation to nutrient starvation have been generally reported. Previous studies found that overexpression of autophagy-related (ATG) gene MdATG10 enhanced the autophagic activity in apple roots and promoted their salt tolerance. The MdATG10 expression was induced by nitrogen depletion condition in both leaves and roots of apple plants. This study aimed to investigate the differences in the growth and physiological status between wild type and MdATG10-overexpressing apple plants in response to nitrogen starvation. A hydroponic system containing different nitrogen levels was used. The study found that the reduction in growth and nitrogen concentrations in different tissues caused by nitrogen starvation was relieved by MdATG10 overexpression. Further studies demonstrated the increased root growth and the higher nitrogen absorption and assimilation ability of transgenic plants. These characteristics contributed to the increased uptake of limited nitrogen nutrients by transgenic plants, which also reduced the starvation damage to the chloroplasts. Therefore, the MdATG10-overexpressing apple plants could maintain higher photosynthetic ability and possess better growth under nitrogen starvation stress.
Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability
Authors: Jang Grace , MacIver M. Bruce
Published: July 2021

Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine’s actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.
Effect of Different Bone Grafting Materials and Mesenchymal Stem Cells on Bone Regeneration: A Micro-Computed Tomography and Histomorphometric Study in a Rabbit Calvarial Defect Model
Authors: Shiu Shiau-Ting , Lee Wei-Fang , Chen Sheng-Min , Hao Liu-Ting , Hung Yuan-Ting , Lai Pin-Chuang , Feng Sheng-Wei
Published: July 2021

This study evaluated the new bone formation potential of micro–macro biphasic calcium phosphate (MBCP) and Bio-Oss grafting materials with and without dental pulp-derived mesenchymal stem cells (DPSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) in a rabbit calvarial bone defect model. The surface structure of the grafting materials was evaluated using a scanning electron microscope (SEM). The multipotent differentiation characteristics of the DPSCs and BMSCs were assessed. Four circular bone defects were created in the calvarium of 24 rabbits and randomly allocated to eight experimental groups: empty control, MBCP, MBCP+DPSCs, MBCP+BMSCs, Bio-Oss+DPSCs, Bio-Oss+BMSCs, and autogenous bone. A three-dimensional analysis of the new bone formation was performed using micro-computed tomography (micro-CT) and a histological study after 2, 4, and 8 weeks of healing. Homogenously porous structures were observed in both grafting materials. The BMSCs revealed higher osteogenic differentiation capacities, whereas the DPSCs exhibited higher colony-forming units. The micro-CT and histological analysis findings for the new bone formation were consistent. In general, the empty control showed the lowest bone regeneration capacity throughout the experimental period. By contrast, the percentage of new bone formation was the highest in the autogenous bone group after 2 (39.4% ± 4.7%) and 4 weeks (49.7% ± 1.5%) of healing (p < 0.05). MBCP and Bio-Oss could provide osteoconductive support and prevent the collapse of the defect space for new bone formation. In addition, more osteoblastic cells lining the surface of the newly formed bone and bone grafting materials were observed after incorporating the DPSCs and BMSCs. After 8 weeks of healing, the autogenous bone group (54.9% ± 6.1%) showed a higher percentage of new bone formation than the empty control (35.3% ± 0.5%), MBCP (38.3% ± 6.0%), MBCP+DPSC (39.8% ± 5.7%), Bio-Oss (41.3% ± 3.5%), and Bio-Oss+DPSC (42.1% ± 2.7%) groups. Nevertheless, the percentage of new bone formation did not significantly differ between the MBCP+BMSC (47.2% ± 8.3%) and Bio-Oss+BMSC (51.2% ± 9.9%) groups and the autogenous bone group. Our study results demonstrated that autogenous bone is the gold standard. Both the DPSCs and BMSCs enhanced the osteoconductive capacities of MBCP and Bio-Oss. In addition, the efficiency of the BMSCs combined with MBCP and Bio-Oss was comparable to that of the autogenous bone after 8 weeks of healing. These findings provide effective strategies for the improvement of biomaterials and MSC-based bone tissue regeneration.
Inflammation, Extracellular Matrix Remodeling, and Proteostasis in Tumor Microenvironment
Authors: Marozzi Marina , Parnigoni Arianna , Negri Aide , Viola Manuela , Vigetti Davide , Passi Alberto , Karousou Evgenia , Rizzi Federica
Published: July 2021

Cancer is a multifaceted and complex pathology characterized by uncontrolled cell proliferation and decreased apoptosis. Most cancers are recognized by an inflammatory environment rich in a myriad of factors produced by immune infiltrate cells that induce host cells to differentiate and to produce a matrix that is more favorable to tumor cells’ survival and metastasis. As a result, the extracellular matrix (ECM) is changed in terms of macromolecules content, degrading enzymes, and proteins. Altered ECM components, derived from remodeling processes, interact with a variety of surface receptors triggering intracellular signaling that, in turn, cancer cells exploit to their own benefit. This review aims to present the role of different aspects of ECM components in the tumor microenvironment. Particularly, we highlight the effect of pro- and inflammatory factors on ECM degrading enzymes, such as metalloproteases, and in a more detailed manner on hyaluronan metabolism and the signaling pathways triggered by the binding of hyaluronan with its receptors. In addition, we sought to explore the role of extracellular chaperones, especially of clusterin which is one of the most prominent in the extracellular space, in proteostasis and signaling transduction in the tumor microenvironment. Although the described tumor microenvironment components have different biological roles, they may engage common signaling pathways that favor tumor growth and metastasis.
Characterization of the Intramolecular Interactions and Regulatory Mechanisms of the Scaffold Protein Tks4
Authors: Merő Balázs , Koprivanacz Kitti , Cserkaszky Anna , Radnai László , Vas Virag , Kudlik Gyöngyi , Gógl Gergő , Sok Péter , Póti Ádám L. , Szeder Bálint , Nyitray László , Reményi Attila , Geiszt Miklós , Buday László
Published: July 2021

The scaffold protein Tks4 is a member of the p47phox-related organizer superfamily. It plays a key role in cell motility by being essential for the formation of podosomes and invadopodia. In addition, Tks4 is involved in the epidermal growth factor (EGF) signaling pathway, in which EGF induces the translocation of Tks4 from the cytoplasm to the plasma membrane. The evolutionarily-related protein p47phox and Tks4 share many similarities in their N-terminal region: a phosphoinositide-binding PX domain is followed by two SH3 domains (so called “tandem SH3”) and a proline-rich region (PRR). In p47phox, the PRR is followed by a relatively short, disordered C-terminal tail region containing multiple phosphorylation sites. These play a key role in the regulation of the protein. In Tks4, the PRR is followed by a third and a fourth SH3 domain connected by a long (~420 residues) unstructured region. In p47phox, the tandem SH3 domain binds the PRR while the first SH3 domain interacts with the PX domain, thereby preventing its binding to the membrane. Based on the conserved structural features of p47phox and Tks4 and the fact that an intramolecular interaction between the third SH3 and the PX domains of Tks4 has already been reported, we hypothesized that Tks4 is similarly regulated by autoinhibition. In this study, we showed, via fluorescence-based titrations, MST, ITC, and SAXS measurements, that the tandem SH3 domain of Tks4 binds the PRR and that the PX domain interacts with the third SH3 domain. We also investigated a phosphomimicking Thr-to-Glu point mutation in the PRR as a possible regulator of intramolecular interactions. Phosphatidylinositol-3-phosphate (PtdIns(3)P) was identified as the main binding partner of the PX domain via lipid-binding assays. In truncated Tks4 fragments, the presence of the tandem SH3, together with the PRR, reduced PtdIns(3)P binding, while the presence of the third SH3 domain led to complete inhibition.
Evolution of Adaptive Variation in the Mosquito Culex pipiens: Multiple Independent Origins of Insecticide Resistance Mutations
Authors: Mastrantonio Valentina , Porretta Daniele , Lucchesi Valentina , Güz Nurper , Çağatay Naciye Sena , Bellini Romeo , Vontas John , Urbanelli Sandra
Published: July 2021

Insecticide resistance is an informative model for studying the appearance of adaptive traits. Simultaneously, understanding how many times resistance mutations originate is essential to design effective resistance management. In the mosquito Culex pipiens, target–site resistance to the insecticide diflubenzuron (DFB) has been recently found in Italian and Turkish populations. Three point mutations confer it at the codon 1043 of the chitin synthase 1 gene (chs-1): I1043L, I1043M, and I1043F. Whether the resistant mutations originated independently from different susceptible alleles or sequentially from resistant alleles and whether resistant alleles from Italy and Turkey have originated once or multiple times remain unresolved. Here, we sequenced a fragment of the chs-1 gene carrying the resistant mutations and inferred the phylogenetic relationships among susceptible and resistant alleles. Confirming previous findings, we found the three mutations in Italy and the I1043M in Turkey. Notably, the I1043F was also found for the first time in Turkish samples, highlighting the need for extensive monitoring activities. Phylogenetic analyses are consistent with an independent origin of the I1043F, I1043M, and I1043L mutations from different susceptible alleles and with multiple independent origins of the Italian and Turkish I1043M and I1043F alleles.
Reply to Schausberger, P. Not Seeing the Mites for the Hairs. Comment on “Möth et al. Unexpected Effects of Local Management and Landscape Composition on Predatory Mites and Their Food Resources in Vineyards. Insects 2021, 12, 180”
Authors: Möth Stefan , Walzer Andreas , Redl Markus , Petrović Božana , Hoffmann Christoph , Winter Silvia
Published: July 2021

This is a reply to the comment from Schausberger [...]
Pupal Cues Increase Sperm Production but Not Testis Size in an Insect
Authors: Liu Junyan , He Xiong Z. , Zheng Xia-Lin , Zhang Yujing , Wang Qiao
Published: July 2021

Theoretic and empirical studies show that social surroundings experienced by male insects during their larval or adult stage can influence their testicular investment in diverse ways. Although insect pupae do not feed and crawl, they can communicate using sex-specific and/or non-sex specific cues. Yet, it is unknown, in any insect, whether and how male pupae can fine-tune their resource allocation to sperm production and testis size in response to socio-sexual environments. We investigated this question using a moth, Ephestia kuehniella, which produces fertile eupyrene sperm and unfertile apyrene sperm. We held male pupae individually or in groups with different sex ratios, and dissected adults upon eclosion, measured their testis size, and counted both types of sperm. We demonstrated that after exposure to conspecific pupal cues regardless of sex, male pupae increased production of eupyrenes and apyrenes at the same rate but kept testis size unchanged. We suggest that testis size is fixed after pupation because most morphological traits are formed during the larval stage, allowing little room for pupae to adjust testis size. Like adults, male pupae with fully grown testes have sufficient resources to produce more sperm of both types according to the perceived increase in sperm competition risk.
Towards a Hybrid Deep Learning Model for Anomalous Activities Detection in Internet of Things Networks
Authors: Ullah Imtiaz , Ullah Ayaz , Sajjad Mazhar
Published: July 2021

The tremendous number of Internet of Things (IoT) applications, with their ubiquity, has provided us with unprecedented productivity and simplified our daily life. At the same time, the insecurity of these technologies ensures that our daily lives are surrounded by vulnerable computers, allowing for the launch of multiple attacks via large-scale botnets through the IoT. These attacks have been successful in achieving their heinous objectives. A strong identification strategy is essential to keep devices secured. This paper proposes and implements a model for anomaly-based intrusion detection in IoT networks that uses a convolutional neural network (CNN) and gated recurrent unit (GRU) to detect and classify binary and multiclass IoT network data. The proposed model is validated using the BoT-IoT, IoT Network Intrusion, MQTT-IoT-IDS2020, and IoT-23 intrusion detection datasets. Our proposed binary and multiclass classification model achieved an exceptionally high level of accuracy, precision, recall, and F1 score.
Evaluation of the Efficacy of Dexamethasone-Eluting Electrode Array on the Post-Implant Cochlear Fibrotic Reaction by Three-Dimensional Immunofluorescence Analysis in Mongolian Gerbil Cochlea
Authors: Toulemonde Philippine , Risoud Michaël , Lemesre Pierre Emmanuel , Beck Cyril , Wattelet Jean , Tardivel Meryem , Siepmann Juergen , Vincent Christophe
Published: July 2021

Cochlear implant is the method of choice for the rehabilitation of severe to profound sensorineural hearing loss. The study of the tissue response to cochlear implantation and the prevention of post-cochlear-implant damages are areas of interest in hearing protection research. The objective was to assess the efficacy of dexamethasone-eluting electrode array on endo canal fibrosis formation by three-dimensional immunofluorescence analysis in implanted Mongolian gerbil cochlea. Two trials were conducted after surgery using Mongolian gerbil implanted with dexamethasone-eluting or non-eluting intracochlear electrode arrays. The animals were then euthanised 10 weeks after implantation. The cochleae were prepared (electrode array in place) according to a 29-day protocol with immunofluorescent labelling and tissue clearing. The acquisition was carried out using light-sheet microscopy. Imaris software was then used for three-dimensional analysis of the cochleae and quantification of the fibrotic volume. The analysis of 12 cochleae showed a significantly different mean volume of fibrosis (2.16 × 108 μm3 ± 0.15 in the dexamethasone eluting group versus 3.17 × 108 μm3 ± 0.54 in the non-eluting group) (p = 0.004). The cochlear implant used as a corticosteroid delivery system appears to be an encouraging device for the protection of the inner ear against fibrosis induced by implantation. Three-dimensional analysis of the cochlea by light-sheet microscopy was suitable for studying post-implantation tissue damage.
Prognostic Significance of Tumor Location in T2 Gallbladder Cancer: A Systematic Review and Meta-Analysis
Authors: Kang Hyun , Choi Yoo Shin , Suh Suk-Won , Choi Geunjoo , Do Jae Hyuk , Oh Hyoung-Chul , Kim Hong Jin , Lee Seung Eun
Published: July 2021

(1) Background: The AJCC Cancer Staging Manual, Eighth Edition, subdivided T2 GBC into T2a and T2b. However, there still exist a lack of evidence on the prognostic significance of tumor location. The aim of the present study was to examine the existing evidence to determine the prognostic significance of tumor location of T2 gallbladder cancer (GBC) and to evaluate the optimal surgical extent according to tumor location. (2) Methods: We searched for relevant literature published in the electronic databases PubMed, MEDLINE, Web of Science, Cochrane Library, and Embase before September 2020 using search terms related to gallbladder, cancer, and stage. Data were weighted and pooled using random-effects modeling. (3) Results: Seven studies were deemed eligible for inclusion, representing a cohort of 1789 cases of resected T2 GBC. The overall survival for T2b tumor was significantly worse than that for T2a tumor (HR, 2.141; 95% confidence interval (CI), 1.140 to 4.023; I2 = 71.4%; Pchi2 = 0.007). The rate of lymph node metastasis was lower in the T2a group (26.6%) than in the T2b group (36.6%) (OR, 2.164; 95% CI, 1.309 to 3.575). There was no evidence of a survival difference between the patients who underwent extended cholecystectomy and simple cholecystectomy in T2a GBC (OR, 0.802; 95% CI, 0.618 to 1.042) and T2b GBC (OR, 0.820; 95% CI, 0.620 to 1.083). (4) Conclusions: Hepatic side tumor was a significant poor prognostic factor in T2 GBC. Extended cholecystectomy and simple cholecystectomy showed comparable survival outcomes in T2 GBC, and additional large-scale prospective studies are warranted to establish evidence-based treatment guidelines for T2 GBC.
Validation and Classification of the 9-Item Voice Handicap Index (VHI-9i)
Authors: Caffier Felix , Nawka Tadeus , Neumann Konrad , Seipelt Matthias , Caffier Philipp P.
Published: July 2021

The international nine-item Voice Handicap Index (VHI-9i) is a clinically established short-scale version of the original VHI, quantifying the patients’ self-assessed vocal handicap. However, the current vocal impairment classification is based on percentiles. The main goals of this study were to establish test–retest reliability and a sound statistical basis for VHI-9i severity levels. Between 2009 and 2021, 17,660 consecutive cases were documented. A total of 416 test–retest pairs and 3661 unique cases with complete multidimensional voice diagnostics were statistically analyzed. Classification candidates were the overall self-assessed vocal impairment (VHIs) on a four-point Likert scale, the dysphonia severity index (DSI), the vocal extent measure (VEM), and the auditory–perceptual evaluation (GRB scale). The test–retest correlation of VHI-9i total scores was very high (r = 0.919, p < 0.01). Reliability was excellent regardless of gender or professional voice use, with negligible dependency on age. The VHIs correlated best with the VHI-9i, whereas statistical calculations proved that DSI, VEM, and GRB are unsuitable classification criteria. Based on ROC analysis, we suggest modifying the former VHI-9i severity categories as follows: 0 (healthy): 0 ≤ 7; 1 (mild): 8 ≤ 16; 2 (moderate): 17 ≤ 26; and 3 (severe): 27 ≤ 36.
Effects of Preoperative Intraocular Pressure Level on Surgical Results of Microhook Ab Interno Trabeculotomy
Authors: Tanito Masaki , Sugihara Kazunobu , Tsutsui Aika , Hara Katsunori , Manabe Kaoru , Matsuoka Yotaro
Published: July 2021

To assess the roles of preoperative intraocular pressure (IOP) level on the IOP reducing efficacy of microhook ab interno trabeculotomy (µLOT), 126 consecutive open-angle glaucomatous eyes (90 primary open angle glaucoma, 36 exfoliation glaucoma) of 126 Japanese subjects (60 men, 66 women; mean age ± standard deviation, 70.5 ± 11.4 years) who underwent µLOT alone (25 eyes, 20%) or combined µLOT and cataract surgery (101 eyes, 80%) were retrospectively included, and subdivided into four groups based on the quartile of preoperative IOP: Q1, ≤15 mmHg; Q2, 15–18 mmHg, Q3, 18–21 mmHg, and Q4, >21 mmHg. Preoperative and 12 months postoperative IOPs and numbers of antiglaucoma medications were compared among IOP groups. Factors associated with postoperative IOP were assessed using multivariate analysis, and the success of IOP control was assessed with various definitions. Postoperatively, IOP was significantly higher in Q3 (p < 0.0146) and Q4 (p = 0.0320) groups than Q1 group, while the number of medications was not significantly different among four IOP groups (p = 0.1966). Older age was associated with lower postoperative IOP, and higher preoperative IOP was associated with higher postoperative IOP, while sex, glaucoma type, surgical procedure, lens status, extent of trabeculotomy incision, and preoperative number of medications were not associated with postoperative IOP. The success rates for IOP ≤ 18 and ≤15 mmHg were higher in lower preoperative IOP groups (i.e., Q1 and Q2) than higher preoperative IOP groups (Q3 and Q4), while the success rate for ≥20% IOP reduction was higher in higher preoperative IOP groups than in lower preoperative IOP groups; the success rate for ≥0% IOP reduction was equivalent among groups. By reviewing the previous studies in ab interno trabeculotomy/goniotomy procedures, positive correlation between preoperative and postoperative IOPs was preserved throughout the studies and surgical procedures. After the µLOT, larger %IOP reduction was achieved in higher preoperative IOP groups than in lower preoperative IOP groups, while postoperative IOP was still lower than in lower preoperative IOP groups.