bluuebunny/crossref_metadata_2025 huggingface dataset:
Holistic Approach for Artificial Intelligence Implementation in Pharmaceutical Products Lifecycle: A Meta-Analysis
Authors: Koshechkin Konstantin A. , Lebedev Georgiy S. , Fartushnyi Eduard N. , Orlov Yuriy L.
Published: August 2022

Recent developments in Digital Medicine approaches concern pharmaceutical product optimization. Artificial Intelligence (AI) has multiple applications for pharmaceutical products’ lifecycle, increasing development speed, quality of the products, and efficiency of the therapy. Here, we systematically review the overall approach for AI implementation in pharmaceutical products’ lifecycle. The published studies in PubMed and IEEE Xplore were searched from inception to March 2022. The papers were screened for relevant outcomes, publication types, and data sufficiency, and a total of 73 (1.2%) out of 6131 studies were retrieved after the selection. We extracted the data according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. All Artificial Intelligence systems could be divided into multiple overlapping categories by implementation. For the 177 projects found, the most popular areas of AI implementation are clinical trials and pre-clinical tests (34%). In second place are novel small molecule design systems, with 33% of the total. The third most popular scope for AI implementation is target identification for novel medicines. More than 25% of the systems provide this functionality. It is interesting that most of the systems specialize in only one area (102 systems—57%). None of the systems provide functionality for full coverage of the lifecycle and function in all categories of the tasks. This meta-analysis demonstrated that Artificial Intelligence solutions in pharmaceutical products’ lifecycle could find numerous implementations, and none of the available market solutions covers them all.
QoS/QoE in Flying Ad Hoc Networks Applied in Natural Disasters
Authors: Monedero Jesús Hamilton Ortiz , Arciniegas Herrera José Luis , Cuellar Quiñones Juan Carlos , Tavera Romero Carlos Andrés , Ahmed Bazil Taha
Published: August 2022

In this work, a group of mechanisms are exposed to provide quality of experience in flying ad hoc networks using a swarm of drones in a natural disaster service. End-to-end video traffic was analyzed. The metrics used to experimentally measure QoE/QoS are: delay, jitter and packet loss. The experience quality was evaluated before the disaster (C00), at the moment (B00) and after the disaster (I00). The methodology used to perform the design was experimental, and the NS simulator was used to evaluate the behavior of the swarm of drones connected through a flying ad hoc network. To perform data analysis, treatment and repetitions related to video traffic, the response surface methodology (MSR) was used, which is a set of mathematical techniques in order to optimize the obtained responses. The composite core design (DCC) was also used as it was the best fit to our experiment due to its flexibility. Since the quality of the experience was evaluated at three moments, the quality of services was also analyzed with three metrics. The main contributions of the research are a mathematical model of the quality of the experience based on the quality of the service; an experiment design using the end-to-end NS simulator; a methodology for the mathematical and statistical analysis of the data obtained; an algorithm that allows, from service quality metrics, to obtain the quality of the experience for end-to-end video traffic; and a proposal for future work for data analysis in a physical environment and applied to the environmental sector.
The Liminal Space of Medieval Dance Practices: The Case of St. Eluned’s Feast Day
Authors: Hellsten Laura
Published: August 2022

This article scrutinizes the use of liminality as a term to understand medieval dance practices. With the case of the feast day of St. Eluned described in Gerald of Wales Itinerarium Cambriae, I first present common ways that historians and theologians have used the term liminality in order to describe historical depictions of feasts of saints where more unruly forms of movement and dancing have happened. I then analyze this specific depiction by Gerald of Wales through a combination of a kinesic approach and a hermeneutics of suspicion and charity. This approach shows that earlier understandings of dancing always being a problematic element in traditions of Christianity in the west needs to be nuanced. After this, I turn to the critique that Caroline Bynum Walker has brought up, concerning the use of the term liminality in the medieval context. Taking her critique seriously, I return to the story of St. Eluned by focusing on the lived religion from the perspective of the female characters in the setting. Finally, I also bring in Vincent Lloyd’s distinction between rituals and liturgy, to further strengthen how theological discussions can bring in more nuanced and important additions in how we may understand chaotic forms of medieval dance in new ways.
Assessment and Characterization of Alkylated PAHs in Selected Sites across Canada
Authors: Wnorowski Andrzej , Harnish David , Jiang Ying , Celo Valbona , Dabek-Zlotorzynska Ewa , Charland Jean-Pierre
Published: August 2022

Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs), dibenzothiophenes (DBTs), and unsubstituted polycyclic aromatic hydrocarbons (PAHs) are naturally present in fossil fuels. Thus, they can be considered as candidates for markers of pollution from petrogenic emissions such as those from traffic. Consequently, ambient air concentrations of alkyl-PAHs, DBTs, and PAHs at selected ambient air monitoring sites of various types (residential, near-road, urban-industrial, agricultural) in Montréal, Toronto, Hamilton, Edmonton, and Simcoe, were evaluated from 2015 to 2016 to study their profiles, trends, and assess potential primary emission source types. Alkyl-PAHs were the prevailing species at all sites and were most elevated at the high-traffic impacted near-road site in Toronto which was also accompanied by the highest unsubstituted PAH concentrations. Comparison of relative abundance ratios of alkyl-PAH and PAH groupings suggests that the profile differences amongst sites were small. Source attribution with cluster grouping suggested similar emission sources of alkyl-PAH and PAH at all sites, with the exception of Hamilton which was particularly impacted by additional emission sources of PAHs. The Principal Component Analysis further indicated distinct PAC profiles at HWY401 and HMT that have the same variability of “heavy PACs” but differ in “medium mass PAHs” sources. Seasonality affected the bulk species trends (alkylated naphthalenes, fluorenes, and phenanthrenes/anthracenes), especially at sites with lower concentrations of these species. This study findings confirm a notable contribution of traffic emissions to alkyl-PAH levels in urban ambient air at the studied Canadian sites, and show that enhanced speciation of alkyl-PAHs provides more data on ambient air quality and additional health risks, and can also help distinguish petrogenic-influenced sources from other sources.
A Coverage Sampling Path Planning Method Suitable for UAV 3D Space Atmospheric Environment Detection
Authors: Yang Lunke , Fan Shurui , Yu Binggang , Jia Yingmiao
Published: August 2022

Air pollution affects people’s life and health, and controlling air pollution requires the collection of polluting gas information. Unmanned aerial vehicles (UAVs) have been used for environmental detection due to their characteristics. However, the limitation of onboard energy sources of UAVs will limit the coverage of the detection area and the number of gas samples collected, which will affect the assessment of pollution levels. In addition, to truly and completely reflect the distribution of atmospheric pollutants, it is necessary to sample the entire three-dimensional space. This paper proposes a three-dimensional space path planning method suitable for UAV atmospheric environment detection, which can generate a full-coverage path with optimal coverage density under energy constraints. Simulation results show that the proposed method can effectively improve the coverage density compared with other path generation methods. Field experiments show that the proposed method is reliable and accurate in the application of UAV atmospheric environment space detection.
Spatio-Temporal Variation of Precipitation and Evaporation on the Tibetan Plateau and Their Influence on Regional Drought
Authors: Tang Yuanzhi , Huo Junjun , Zhu Dejun , Gao Tailai , Jiang Xiaoxuan
Published: August 2022

The Tibetan Plateau (TP) is an important water source in Asia, and precipitation and evaporation patterns at different geographical and temporal scales play a significant role in managing water resource distribution. Based on quality control data from 87 meteorological stations, this study analyzed the spatial and temporal evolution patterns of precipitation and pan evaporation (Epan) on the TP in 1966–2016 using the Mann–Kendall test, the moving t-test, wavelet analysis, Sen’s slope method, and correlation analysis. The results revealed that the average mean temperature in the TP area increased by about 2.1 °C during the study period, and precipitation steadily increased at an average rate of 8.2 mm/10a, with summer and autumn precipitation making up about 80% of the year. In contrast, Epan showed an overall decreasing trend at a decline rate of 20.8 mm/10a, with spring and summer Epan values making up about 67% of the year. The time series of the precipitation and Epan within the TP region clearly exhibit nonstationary features. Precipitation is more concentrated in the southeast than in the northwest, while Epan is mostly concentrated in the southwest and northeast of the plateau around the Qaidam Basin. The “evaporation paradox” phenomenon was common in the TP region for about 40 years (1960s–1990s) and gradually faded in the 21st century. In addition, we introduced a standardized precipitation evaporation index (SPEI) to investigate the differences and relationships between precipitation and Epan time series over the past 50 years. The findings indicate that the southern Qinghai was dominated by an arid trend, while the central and southeast TP remained wet. Droughts and floods coexist in the eastern Qinghai and southern Tibet areas with high population concentrations, and the risk of both is rising as the inhomogeneity of precipitation distribution in the TP region will increase in the future. This study can be used as a reference for managing water resources and predicting regional drought and flood risk.
Microphysical and Kinematic Characteristics of Anomalous Charge Structure Thunderstorms in Cordoba, Argentina
Authors: Medina Bruno , Carey Lawrence , Deierling Wiebke , Lang Timothy
Published: August 2022

Some thunderstorms in Cordoba, Argentina, present a charge structure with an enhanced low-level positive charge layer, and practically nonexistent upper-level positive charge. Storms with these characteristics are uncommon in the United States, even when considering regions with a high frequency of anomalous charge structure storms such as Colorado. In this study, we explored the microphysical and kinematic conditions inferred by radar that led to storms with this unique low-level anomalous charge structure in Argentina, and compared them to conditions conducive for anomalous and normal charge structures. As high liquid water contents in the mixed-phase layer lead to positive charging of graupel and anomalous storms through the non-inductive charging mechanism, we explored radar parameters hypothesized to be associated with large cloud supercooled liquid water contents in the mixed-phase layer and anomalous storms, such as mass and volume of hail and high-density graupel, large reflectivity associated with the growth of rimed precipitation to hail size, and parameters that are proxies for strong updrafts such as echo-top and Zdr column heights. We found that anomalous storms had higher values of mass and volume of hail in multiple sub-layers of the mixed-phase zone and higher frequency of high reflectivity values. Low-level anomalous events had higher hail mass in the lower portion of the mixed-phase zone when compared to normal events. Weaker updraft proxies were found for low-level anomalous events due to the shallow nature of these events while there was no distinction between the updraft proxies of normal and anomalous storms.
Statistical Associations between Geomagnetic Activity, Solar Wind, Cosmic Ray Intensity, and Heart Rate Variability in Patients after Open-Heart Surgery
Authors: Vencloviene Jone , Beresnevaite Margarita , Cerkauskaite Sonata , Ragaisyte Nijole , Pilviniene Rugile , Benetis Rimantas
Published: August 2022

The aim of this study was to identify associations of the parameters of heart rate variability (HRV) with the variations in geomagnetic activity (GMA), solar wind, and cosmic ray intensity (CRI) in patients after coronary artery bypass grafting or valve surgery in Kaunas, Lithuania, during 2008–2012. The data from 5-minute electrocardiograms (ECGs) in 220 patients were used. ECGs were carried out at 1.5 months, 1 year, and 2 years after the surgery (N = 495). A lower (higher) very-low-frequency-band (VLF) and a higher (lower) high-frequency band (HF) in normalised units (n.u.) were associated with a low maximal daily 3-hourly ap (the DST index > 1). A lower mean standard deviation of beat-to-beat intervals (SDNN) and VLF, LF, and HF powers were lower in patients when Ap < 8 occurred two days after the surgery, and a low solar wind speed (SWS) occurred two days before the ECG. The effect of CRI was non-significant if the linear trend was included in the model. Low GMA and a low SWS may effect some HRV variables in patients after open-heart surgery. The GMA during the surgery may affect the SDNN in short-term ECG during the longer period.
Rehabilitation of Severe-to-Profound Hearing Loss in Adults in Sweden
Authors: Löfvenberg Christian , Turunen-Taheri Satu , Carlsson Per-Inge , Skagerstrand Åsa
Published: August 2022

Severe-to-profound hearing loss (STPHL) can affect a person negatively in many ways. Audiological rehabilitation is important for these patients. Patients receiving cochlear implants make up less than 10% of this group but have been studied extensively. In 2005, a national registry for adult patients with STPHL was introduced in Sweden. Its purpose was to evaluate and improve rehabilitation for all patients with STPHL. Data from the Swedish registry for adult patients with STPHL were used to evaluate variables affecting the audiological rehabilitation. Previous published data from the registry were reviewed, and new data from the follow-up questionnaire were presented. More than 90% of patients rehabilitated with hearing aids experienced a good or very good benefit of audiological rehabilitation. Tinnitus and vertigo affected quality of life negatively and were reported by many patients with STPHL (41% and 31%) at follow-up. To maintain the high number of patients who find audiological rehabilitation beneficial, individualized treatment plans and timely re-evaluations are crucial. Tinnitus and vertigo need to be addressed repeatedly in the rehabilitation process.
Modulation Transfer between Microwave Beams: A Hypothesized Case of a Classically-Forbidden Stochastic Process
Authors: Ranfagni Anedio , Cacciari Ilaria
Published: August 2022

Measurements of delay time in the transfer of modulation between a modulated to an unmodulated one, both of them derived by the same microwave source, are reported and interpreted. In the light of these results, the transfer of modulation can be hypothesized as due to a stochastic, classically-forbidden process, assisted by a photon–photon scattering mechanism.
The Independence Number Conditions for 2-Factors of a Claw-Free Graph
Authors: Lei Wanpeng , Xiong Liming , Yin Jun
Published: August 2022

In 2014, some scholars showed that every 2-connected claw-free graph G with independence number α(G)≤3 is Hamiltonian with one exception of family of graphs. If a nontrivial path contains only internal vertices of degree two and end vertices of degree not two, then we call it a branch. A set S of branches of a graph G is called a branch cut if we delete all edges and internal vertices of branches of S leading to more components than G. We use a branch bond to denote a minimal branch cut. If a branch-bond has an odd number of branches, then it is called odd. In this paper, we shall characterize all 2-connected claw-free graphs G such that every odd branch-bond of G has an edge branch and such that α(G)≤5 but has no 2-factor. We also consider the same problem for those 2-edge-connected claw-free graphs with α(G)≤4.
Binder-Free Ge-Co-P Anode Material for Lithium-Ion and Sodium-Ion Batteries
Authors: Kulova Tatiana , Skundin Alexander , Gavrilin Il’ya , Kudryashova Yulia , Martynova Irina , Novikova Svetlana
Published: August 2022

Nanostructure composites Ge-Co-P with brutto-composition CoGe2P0.1, or CoGe2@GeP were manufactured via electrolysis of aqueous electrolyte. Such composites are able to reversible insertion of lithium and sodium with specific capacities up to 855 and 425 mAh/g, respectively. The main advantage of the composites consists in their excellent cycleability.
Polycyclic Aromatic Hydrocarbon-Enabled Wet Chemical Prelithiation and Presodiation for Batteries
Authors: Su Yu-Sheng , Chang Jeng-Kuei
Published: August 2022

The current mainstream energy storage systems are in urgent need of performance improvements to meet novel application requirements. In pursuit of a higher energy density in Li-ion and Na-ion batteries, the conventional electrode materials have reached the upper limit of their theoretical specific capacities. Hence, facile methods of reducing irreversible lithium-ion/sodium-ion loss are developed to further boost the battery energy density. Herein, we review studies that use polycyclic aromatic hydrocarbons for wet chemical prelithiation and presodiation. The molecular structures of arenes and solvents used for solution-based prelithiation/presodiation have a substantial impact on the prelithiation/presodiation power and effectiveness. Multiple reports have already shown excellent initial Coulombic efficiency and streamlined processes by using this type of wet chemical prelithiation/presodiation strategy. This review article will cover how to select appropriate polycyclic aromatic hydrocarbon prelithiation/presodiation reagents for various materials/electrodes and provide possible directions and guidelines for future works.
Nickel-Doped Ceria Bifunctional Electrocatalysts for Oxygen Reduction and Evolution in Alkaline Media
Authors: Milikić Jadranka , Fuentes Rodolfo O. , Tasca Julia E. , Santos Diogo M. F. , Šljukić Biljana , Figueiredo Filipe M. L.
Published: August 2022

Nickel-doped ceria (Ce1−xNixO2−δ) nanopowders (7 to 5 nm in size) synthesized by the cation complexation method with 5, 10, 15, and 20 Ni at.% are studied with respect to their electrochemical activity for the oxygen reduction (ORR) and oxygen evolution (OER) reactions in alkaline medium. One finds good bifunctional electrocatalytic activity of the four Ce1−xNixO2−δ electrocatalysts. The Tafel analysis of the ORR in the 0.57–0.78 V vs. RHE potential window leads to slopes in the 70–108 mV dec−1 range. The number of electrons exchanged during ORR is between 2 and 2.7. The OER Tafel slopes are determined to be in the range 192 –281 mV dec−1. OER activation energies are found to range between 28 and 43 kJ mol−1. The specific capacitance of Ce1−xNixO2−δ electrocatalysts measured at a scan rate of 100 mV s−1 varies between 0.7 and 1.4 Fg−1. The results demonstrate that Ce1−xNixO2−δ nanopowders can act as bifunctional electrocatalysts for ORR/OER for potential application in the oxygen electrode of devices such as rechargeable metal–air batteries.
Topical and Non-Topical Approaches to Measure Similarity between Arabic Questions
Authors: Daoud Mohammad
Published: August 2022

Questions are crucial expressions in any language. Many Natural Language Processing (NLP) or Natural Language Understanding (NLU) applications, such as question-answering computer systems, automatic chatting apps (chatbots), digital virtual assistants, and opinion mining, can benefit from accurately identifying similar questions in an effective manner. We detail methods for identifying similarities between Arabic questions that have been posted online by Internet users and organizations. Our novel approach uses a non-topical rule-based methodology and topical information (textual similarity, lexical similarity, and semantic similarity) to determine if a pair of Arabic questions are similarly paraphrased. Our method counts the lexical and linguistic distances between each question. Additionally, it identifies questions in accordance with their format and scope using expert hypotheses (rules) that have been experimentally shown to be useful and practical. Even if there is a high degree of lexical similarity between a When question (Timex Factoid—inquiring about time) and a Who inquiry (Enamex Factoid—asking about a named entity), they will not be similar. In an experiment using 2200 question pairs, our method attained an accuracy of 0.85, which is remarkable given the simplicity of the solution and the fact that we did not employ any language models or word embedding. In order to cover common Arabic queries presented by Arabic Internet users, we gathered the questions from various online forums and resources. In this study, we describe a unique method for detecting question similarity that does not require intensive processing, a sizable linguistic corpus, or a costly semantic repository. Because there are not many rich Arabic textual resources, this is especially important for informal Arabic text processing on the Internet.
Molecular and Morphological Characterization of Exserohilum turcicum (Passerini) Leonard and Suggs Causing Northern Corn Leaf Blight of Maize in Bihar
Authors: Anwer Md Arshad , Niwas Ram , Ranjan Tushar , Mandal Shyam Sundar , Ansar Mohammad , Srivastava Jitendra Nath , Kumar Jitesh , Jain Khushbu , Kumari Neha , Bharti Aditya
Published: August 2022

Maize is considered the third most important cereal crop in Asia after rice and wheat. Many diseases affect this crop due to the cultivation of various hybrids. This research aimed to characterize the causative agent of northern corn leaf blight disease in Bihar, India, caused by Exserohilum turcicum (Passerini) Leonard and Suggs. Leaf samples were collected from infected fields in five maize growing districts of Bihar in 2020–2022. A total of 45 fungal isolates from 135 samples were examined for cultural, morphological, and molecular characteristics and were identified as E. turcicum. The isolates were grouped into four groups based on colony color, i.e., olivaceous brown, blackish brown, whitish black, and grayish, and into two groups based on regular and irregular margins. The conidial shapes were observed to be elongated and spindle-shaped with protruding hilum, with conidial septa ranging from 2–12. Similarly, conidial length varied from 52.94 μm to 144.12 μm. β-tubulin gene sequences analysis made it possible to verify the identities of fungal strains and the phylogenetic relationships of all isolates, which were clustered in the same clade. The β-tubulin gene sequences of all the isolates showed a high level of similarity (100%) with reference isolates from GenBank accession numbers KU670342.1, KU670344.1, KU670343.1, KU670341.1, and KU670340.1. The findings of this study will serve as a baseline for future studies and will help to minimize yield losses.
Ventral Morphology of the Non-Trilobite Artiopod Retifacies abnormalis Hou, Chen & Lu, 1989, from the Early Cambrian Chengjiang Biota, China
Authors: Zhang Maoyin , Liu Yu , Hou Xianguang , Ortega-Hernández Javier , Mai Huijuan , Schmidt Michel , Melzer Roland R. , Guo Jin
Published: August 2022

The artiopodans represent a diverse group of euarthropods with a typically flattened dorsal exoskeleton that covers numerous pairs of biramous ventral appendages, and which are ubiquitous faunal components of the 518-million-year-old Chengjiang Lagerstätte in South China. Despite their abundance, several Chengjiang artiopodans remain poorly known, such as the large euarthropoda Retifacies abnormalis, Hou, Chen & Lu, 1989, which is distinguished by the presence of mesh-like ornamentation on its dorsal exoskeleton. Although only a few ventral details were described in a single study in 25 years, it has been frequently featured in phylogenetic analyses that explore the relationships between Cambrian euarthropods. Here, we employ micro-CT and fluorescent microphotography to investigate the exceptionally preserved ventral morphology of R. abnormalis and explore its phylogenetic implications through maximum parsimony and Bayesian inference. Detailed morphology revealed here better supports R. abnormalis as a sister group to the diminutive artiopod Pygmaclypeatus daziensis, also known from Chengjiang, and strengthens the close relationship of these taxa that have been suggested by previous studies as early-branching representatives of Trilobitomorpha. Cephalic appendages suggest this animal might be a scavenger, possibly feeding on soft-bodied organisms. Different pairs of pygidial appendages suggest an anamorphic post-embryonic ontogeny, which adds to the understanding of the developmental mode of Cambrian artiopods, and further supports the statement that post-hatching segment addition occurred in the ancestor of Euarthropoda.
Potential of Whole-Body Vibration in Parkinson’s Disease: A Systematic Review and Meta-Analysis of Human and Animal Studies
Authors: Arenales Arauz Y. Laurisa , Ahuja Gargi , Kamsma Ype P. T. , Kortholt Arjan , van der Zee Eddy A. , van Heuvelen Marieke J. G.
Published: August 2022

(1) Background: When the severity of Parkinson’s Disease (PD) increases, patients often have difficulties in performing exercises. Whole-Body Vibration (WBV) may be a suitable alternative. This systematic review aims to clarify if WBV shows potential as rehabilitative therapy for PD patients. (2) Methods: We searched several databases for controlled trials investigating the effects of WBV (1) on PD populations and (2) PD neuropathological mechanisms. We included both human and animal studies and performed meta-analyses. (3) Results: The studies on PD populations (14 studies) show an overall significant, but small, effect in favor of WBV (Hedges’ g = 0.28), for which the effects on stability (Hedges’ g = 0.39) and balance (Hedges’ g = 0.30) are the most prominent. The studies on the neuropathological mechanisms (18 studies) show WBV effects on neuroinflammation (Hedges’ g = –1.12) and several specific WBV effects on neurotransmitter systems, growth factors, neurogenesis, synaptic plasticity and oxidative stress. (4) Conclusions: The effects of WBV on human PD patients remains inconclusive. Nevertheless, WBV protocols with sufficient duration (≥3 weeks), session frequency (≥3 sessions/week) and vibration frequency (≥20 Hz) show potential as a treatment method, especially for motor function. The potential of WBV for PD patients is confirmed by the effects on the neuropathological mechanisms in mostly non-PD populations. We recommend high-quality future studies on both PD patients and PD mouse models to optimize WBV protocols and to examine the neuropathological mechanisms in PD populations.
Plasma Proteomic Profiling Reveals the Regulatory Factors of Milk Protein Synthesis in Holstein Cows
Authors: Wang Xinling , Xu Jie , Han Zhaoyu
Published: August 2022

Milk protein concentrations in dairy cows are considered to be related to some plasma biomolecules. However, the characteristics of plasma biomolecules in dairy cows with different long-term milk protein concentrations are not fully elucidated. This study was conducted to understand the mechanism of plasma proteins in milk protein synthesis by the comparative analysis of the plasma proteomics of cows with different milk protein concentrations. Three groups of Holstein cows (per group = 10) with low (LMP), medium (MMP), and high long-term milk protein concentrations (HMP) were selected for the experiment to determine plasma hormones, biochemical parameters, and proteome. We found that HMP cows had higher concentrations of plasma insulin-like growth factor 1 (IGF-1), glucose, prolactin, insulin, and growth hormone than LMP cows. Additionally, plasma proteomic identified 91 differential proteins, including IGF-1 between the LMP and HMP groups, and the mTOR pathway was enriched. In vitro, IGF-1 treatment increased β-casein expression and simultaneously activated S6K1 and mTOR phosphorylation in bovine mammary epithelial cells. Taken together, these data demonstrate the differences in plasma hormones, biochemical parameters, and proteome of cows with different milk protein concentrations and indicate that IGF-1 enhanced milk protein synthesis, associated with activation of the mTOR signaling pathway.
Changes in Dendritic Spine Morphology and Density of Granule Cells in the Olfactory Bulb of Anguilla anguilla (L., 1758): A Possible Way to Understand Orientation and Migratory Behavior
Authors: Porceddu Riccardo , Podda Cinzia , Mulas Giovanna , Palmas Francesco , Picci Luca , Scano Claudia , Spiga Saturnino , Sabatini Andrea
Published: August 2022

Olfaction could represent a pivotal process involved in fish orientation and migration. The olfactory bulb can manage olfactive signals at the granular cell (GC) and dendritic spine levels for their synaptic plasticity properties and changing their morphology and structural stability after environmental odour cues. The GCs’ dendritic spine density and morphology were analysed across the life stages of the catadromous Anguilla anguilla. According to the head and neck morphology, spines were classified as mushroom (M), long thin (LT), stubby (S), and filopodia (F). Total spines’ density decreased from juvenile migrants to no-migrant stages, to increase again in the adult migrant stage. Mean spines’ density was comparable between glass and silver eels as an adaptation to migration. At non-migrating phases, spines’ density decreased for M and LT, while M, LT, and S density increased in silver eels. A great dendritic spine development was found in the two migratory phases, regressing in trophic phases, but that could be recreated in adults, tracing the migratory memory of the routes travelled in juvenile phases. For its phylogenetic Elopomorph attribution and its complex life cycle, A. anguilla could be recommended as a model species to study the development of dendritic spines in GCs of the olfactory bulb as an index of synaptic plasticity involved in the modulation of olfactory stimuli. If olfaction is involved in the orientation and migration of A. anguilla and if eels possess a memory, these processes could be influenced by the modification of environmental stimuli (ocean alterations and rapid climate change) contributing to threatening this critically endangered species.
New Insights into the Diversity of Branchiomeric Muscle Development: Genetic Programs and Differentiation
Authors: Yahya Imadeldin , Hockman Dorit , Brand-Saberi Beate , Morosan-Puopolo Gabriela
Published: August 2022

Branchiomeric skeletal muscles are a subset of head muscles originating from skeletal muscle progenitor cells in the mesodermal core of pharyngeal arches. These muscles are involved in facial expression, mastication, and function of the larynx and pharynx. Branchiomeric muscles have been the focus of many studies over the years due to their distinct developmental programs and common origin with the heart muscle. A prerequisite for investigating these muscles’ properties and therapeutic potential is understanding their genetic program and differentiation. In contrast to our understanding of how branchiomeric muscles are formed, less is known about their differentiation. This review focuses on the differentiation of branchiomeric muscles in mouse embryos. Furthermore, the relationship between branchiomeric muscle progenitor and neural crest cells in the pharyngeal arches of chicken embryos is also discussed. Additionally, we summarize recent studies into the genetic networks that distinguish between first arch-derived muscles and other pharyngeal arch muscles.
Maternal Chronic Ethanol Exposure Decreases Stress Responses in Zebrafish Offspring
Authors: Kitson Juliet E. , Ord James , Watt Penelope J.
Published: August 2022

In humans, prenatal alcohol exposure can cause serious health issues in children, known collectively as Foetal Alcohol Spectrum Disorders (FASD). Despite the high prevalence of FASD and a lack of effective treatments, the underlying mechanisms causing the teratogenic action of ethanol are still obscure. The limitations of human studies necessitate the use of animal models for identifying the underlying processes, but few studies have investigated the effects of alcohol in the female germline. Here, we used the zebrafish Danio rerio to investigate the effects of chronic (repeated for seven days) exposure to alcohol. Specifically, we tested whether the offspring of females chronically exposed to ethanol during oogenesis exhibited hormonal abnormalities when subjected to a stressor (alarm cue) as larvae, and if they exhibited anxiety-like behaviours as adults. Exposure to alarm cue increased whole-body cortisol in control larvae but not in those of ethanol-treated females. Furthermore, adult offspring of ethanol-treated females showed some reduced anxiety-like behaviours. These findings suggest that the offspring of ethanol-treated females had reduced stress responses. This study is the first to investigate how maternal chronic ethanol exposure prior to fertilisation influences hormonal and behavioural effects in a non-rodent model.
The Catalytic Domain Mediates Homomultimerization of MT1-MMP and the Prodomain Interferes with MT1-MMP Oligomeric Complex Assembly
Authors: Fogarasi Marton , Dima Simona
Published: August 2022

Homomultimerization of MT1-MMP (membrane type 1 matrix metalloproteinase) through the hemopexin, transmembrane, and cytoplasmic domains plays a very important role in the activation of proMMP-2 and the degradation of pericellular collagen. MT1-MMP is overexpressed in many types of cancers, and it is considered to be a key enzyme in facilitating cancer cell migration. Since the oligomerization of MT1-MMP is important for its proteolytic activity in promoting cancer invasion, we have further investigated the multimerization by using heterologously expressed MT1-MMP ectodomains in insect cells to gain additional mechanistic insight into this process. We show that the whole ectodomain of MT1-MMP can form dimers and higher-order oligomeric complexes. The enzyme is secreted in its active form and the multimeric complex assembly is mediated by the catalytic domain. Blocking the prodomain removal determines the enzyme to adopt the monomeric structure, suggesting that the prodomain prevents the MT1-MMP oligomerization process. The binding affinity of MT1-MMP to type I collagen is dependent on the oligomeric state. Thus, the monomers have the weakest affinity, while the binding strength increases proportionally with the complexity of the multimers. Collectively, our experimental results indicate that the catalytic domain of MT1-MMP is necessary and sufficient to mediate the formation of multimeric structures.
Prediction of Potential Commercially Available Inhibitors against SARS-CoV-2 by Multi-Task Deep Learning Model
Authors: Hu Fan , Jiang Jiaxin , Yin Peng
Published: August 2022

The outbreak of COVID-19 caused millions of deaths worldwide, and the number of total infections is still rising. It is necessary to identify some potentially effective drugs that can be used to prevent the development of severe symptoms, or even death for those infected. Fortunately, many efforts have been made and several effective drugs have been identified. The rapidly increasing amount of data is of great help for training an effective and specific deep learning model. In this study, we propose a multi-task deep learning model for the purpose of screening commercially available and effective inhibitors against SARS-CoV-2. First, we pretrained a model on several heterogenous protein–ligand interaction datasets. The model achieved competitive results on some benchmark datasets. Next, a coronavirus-specific dataset was collected and used to fine-tune the model. Then, the fine-tuned model was used to select commercially available drugs against SARS-CoV-2 protein targets. Overall, twenty compounds were listed as potential inhibitors. We further explored the model interpretability and exhibited the predicted important binding sites. Based on this prediction, molecular docking was also performed to visualize the binding modes of the selected inhibitors.
Periostin Augments Vascular Smooth Muscle Cell Calcification via β-Catenin Signaling
Authors: Alesutan Ioana , Henze Laura A. , Boehme Beate , Luong Trang T. D. , Zickler Daniel , Pieske Burkert , Eckardt Kai-Uwe , Pasch Andreas , Voelkl Jakob
Published: August 2022

Medial vascular calcification is common in chronic kidney disease (CKD) and is closely linked to hyperphosphatemia. Vascular smooth muscle cells (VSMCs) can take up pro-calcific properties and actively augment vascular calcification. Various pro-inflammatory mediators are able to promote VSMC calcification. In this study, we investigated the effects and mechanisms of periostin, a matricellular signaling protein, in calcifying human VSMCs and human serum samples. As a result, periostin induced the mRNA expression of pro-calcific markers in VSMCs. Furthermore, periostin augmented the effects of β-glycerophosphate on the expression of pro-calcific markers and aggravated the calcification of VSMCs. A periostin treatment was associated with an increased β-catenin abundance as well as the expression of target genes. The pro-calcific effects of periostin were ameliorated by WNT/β-catenin pathway inhibitors. Moreover, a co-treatment with an integrin αvβ3-blocking antibody blunted the pro-calcific effects of periostin. The silencing of periostin reduced the effects of β-glycerophosphate on the expression of pro-calcific markers and the calcification of VSMCs. Elevated serum periostin levels were observed in hemodialysis patients compared with healthy controls. These observations identified periostin as an augmentative factor in VSMC calcification. The pro-calcific effects of periostin involve integrin αvβ3 and the activation of the WNT/β-catenin pathway. Thus, the inhibition of periostin may be beneficial to reduce the burden of vascular calcification in CKD patients.
Research Progress on the Role of RNA m6A Modification in Glial Cells in the Regulation of Neurological Diseases
Authors: You Siyi , Su Xiaojuan , Ying Junjie , Li Shiping , Qu Yi , Mu Dezhi
Published: August 2022

Glial cells are the most abundant and widely distributed cells that maintain cerebral homeostasis in the central nervous system. They mainly include microglia, astrocytes, and the oligodendrocyte lineage cells. Moreover, glial cells may induce pathological changes, such as inflammatory responses, demyelination, and disruption of the blood–brain barrier, to regulate the occurrence and development of neurological diseases through various molecular mechanisms. Furthermore, RNA m6A modifications are involved in various pathological processes associated with glial cells. In this review, the roles of glial cells in physiological and pathological states, as well as advances in understanding the mechanisms by which glial cells regulate neurological diseases under RNA m6A modification, are summarized, hoping to provide new perspectives on the deeper mechanisms and potential therapeutic targets for neurological diseases.
The Resistome of ESKAPEE Pathogens in Untreated and Treated Wastewater: A Polish Case Study
Authors: Hubeny Jakub , Korzeniewska Ewa , Ciesielski Sławomir , Płaza Grażyna , Harnisz Monika
Published: August 2022

The aim of this study was to quantify ESKAPEE bacteria, genes encoding resistance to antibiotics targeting this group of pathogens, as well as integrase genes in municipal wastewater and river water. Environmental DNA was extracted from the collected samples and used in deep sequencing with the Illumina TruSeq kit. The abundance of bacterial genera and species belonging to the ESKAPEE group, 400 ARGs associated with this microbial group, and three classes of integrase genes were determined. A taxonomic analysis revealed that Acinetobacter was the dominant bacterial genus, whereas Acinetobacter baumannii and Escherichia coli were the dominant bacterial species. The analyzed samples were characterized by the highest concentrations of the following ARGs: blaGES, blaOXA-58, blaTEM, qnrB, and qnrS. Acinetobacter baumannii, E. coli, and genes encoding resistance to β-lactams (blaVEB-1, blaIMP-1, blaGES, blaOXA-58, blaCTX-M, and blaTEM) and fluoroquinolones (qnrS) were detected in samples of river water collected downstream from the wastewater discharge point. The correlation analysis revealed a strong relationship between A. baumannii (bacterial species regarded as an emerging human pathogen) and genes encoding resistance to all tested groups of antimicrobials. The transmission of the studied bacteria (in particular A. baumannii) and ARGs to the aquatic environment poses a public health risk.
Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway
Authors: Pauzaite Tekle , Tollitt James , Sopaci Betul , Caprani Louise , Iwanowytsch Olivia , Thacker Urvi , Hardy John G. , Allinson Sarah L. , Copeland Nikki A.
Published: August 2022

Precise regulation of DNA replication complex assembly requires cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) activities to activate the replicative helicase complex and initiate DNA replication. Chemical probes have been essential in the molecular analysis of DDK-mediated regulation of MCM2-7 activation and the initiation phase of DNA replication. Here, the inhibitory activity of two distinct DDK inhibitor chemotypes, PHA-767491 and XL-413, were assessed in cell-free and cell-based proliferation assays. PHA-767491 and XL-413 show distinct effects at the level of cellular proliferation, initiation of DNA replication and replisome activity. XL-413 and PHA-767491 both reduce DDK-specific phosphorylation of MCM2 but show differential potency in prevention of S-phase entry. DNA combing and DNA replication assays show that PHA-767491 is a potent inhibitor of the initiation phase of DNA replication but XL413 has weak activity. Importantly, PHA-767491 decreased E2F-mediated transcription of the G1/S regulators cyclin A2, cyclin E1 and cyclin E2, and this effect was independent of CDK9 inhibition. Significantly, the enhanced inhibitory profile of PHA-767491 is mediated by potent inhibition of both DDK and the CDK2-Rb-E2F transcriptional network, that provides the molecular basis for its increased anti-proliferative effects in RB+ cancer cell lines.
Suppression of Cardiogenic Edema with Sodium–Glucose Cotransporter-2 Inhibitors in Heart Failure with Reduced Ejection Fraction: Mechanisms and Insights from Pre-Clinical Studies
Authors: Sullivan Ryan D. , McCune Mariana E. , Hernandez Michelle , Reed Guy L. , Gladysheva Inna P.
Published: August 2022

In heart failure with reduced ejection fraction (HFrEF), cardiogenic edema develops from impaired cardiac function, pathological remodeling, chronic inflammation, endothelial dysfunction, neurohormonal activation, and altered nitric oxide-related pathways. Pre-clinical HFrEF studies have shown that treatment with sodium–glucose cotransporter-2 inhibitors (SGLT-2i) stimulates natriuretic and osmotic/diuretic effects, improves overall cardiac function, attenuates maladaptive cardiac remodeling, and reduces chronic inflammation, oxidative stress, and endothelial dysfunction. Here, we review the mechanisms and effects of SGLT-2i therapy on cardiogenic edema in various models of HFrEF. Overall, the data presented suggest a high translational importance of these studies, and pre-clinical studies show that SGLT-2i therapy has a marked effect on suppressing the progression of HFrEF through multiple mechanisms, including those that affect the development of cardiogenic edema.
Targeting Gut Microbiota as a Novel Strategy for Prevention and Treatment of Hypertension, Atrial Fibrillation and Heart Failure: Current Knowledge and Future Perspectives
Authors: Drapkina Oxana M. , Yafarova Adel A. , Kaburova Anastasia N. , Kiselev Anton R.
Published: August 2022

Cardiovascular diseases (CVDs) remain the major public health concern worldwide. Over the last two decades, a considerable amount of literature has been published on gut microbiota (GMB) composition and its metabolites, involved in the pathophysiology of CVDs, including arterial hypertension, atrial fibrillation, and congestive heart failure. Although many types of medicines are available to treat CVD, new therapeutic tools are needed to improve clinical outcomes. A challenge that often arises in the researchers’ community is how to manipulate the GMB to manage cardiovascular risk factors. Therapeutic strategies designed to manipulate GMB composition and/or its metabolites include dietary approaches, prebiotics/probiotics supplementation, and fecal microbiota transplantation (FMT). In this review, we have focused on three main cardiovascular pathologies (arterial hypertension, atrial fibrillation and heart failure) due to their shared common pathophysiological pathways and structural changes in myocardium, such as inflammation, hypertrophy, fibrosis, and myocardial remodeling. The main aims of the review are: (1) to summarize current knowledge on the key pathophysiologic links between GMB and CVDs, and (2) discuss the results of the studies on GMB modulation for the prevention and treatment of selected CVDs.
Combined Immune Defect in B-Cell Lymphoproliferative Disorders Is Associated with Severe Infection and Cancer Progression
Authors: Ochoa-Grullón Juliana , Guevara-Hoyer Kissy , Pérez López Cristina , Pérez de Diego Rebeca , Peña Cortijo Ascensión , Polo Marta , Mateo Morales Marta , Anguita Mandley Eduardo , Jiménez García Carlos , Bolaños Estefanía , Íñigo Belén , Medina Fiorella , Rodríguez de la Peña Antonia , Izquierdo Delgado Carmen , de la Fuente Muñoz Eduardo , Mayol Elsa , Fernández-Arquero Miguel , González-Fernández Ataúlfo , Benavente Cuesta Celina , Sánchez-Ramón Silvia
Published: August 2022

B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan–Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities.