bluuebunny/crossref_metadata_2025 huggingface dataset:
Species distribution and resistance profile of medical importance bacteria isolated from lesions of cats with sporotrichosis
Authors: Salvado Matheus Gomes , Penna Bruno de Araújo , Fereira Eliane de Oliveira , Roier Erica Cristina Rocha , Baêta Bruna de Azevedo , Ferreira Renata Fernandes
Published: May 2021

Sporotrichosis is an infection with zoonotic potential caused by the Sporothrix schenckii complex. It is widely distributed worldwide. The cutaneous form is the most common presentation of the disease. The cat is one of the main animals affected, having numerous fungal cells in its lesions, becoming an important fungi disseminator. Due to the type of skin lesion caused by the fungus, secondary bacterial infections commonly occur. The aim of the present study was to learn about the most common bacterial agents involved in feline lesions with sporotrichosis, as well as their resistance profile to antimicrobial agents. The faster the treatment of bacterial and fungal infections is controlled, the faster the lesions heal. Consequently, the transmission of the disease is controlled. Samples of skin lesions or nasal discharge from 18 domiciled or semi-domiciled cats diagnosed with sporotrichosis were collected. Cats were evaluated for secondary bacterial infections. The samples were processed to isolate aerobic bacteria that were later identified by MALDI TOF. Susceptibility was assessed using the disk diffusion method for a total of 17 antimicrobial agents. The main species identified were Staphylococcus aureus and Staphylococcus felis. Proteus mirabilis has also been identified in some samples. Among these microorganisms, two strains of S. aureus were identified as resistant to methicillin. The TSA's results showed sensitivity to most of the tested antimicrobials. Staphylococcus was the most identified genus in skin lesions and nasal secretions of cats with sporotrichosis. Most microorganisms were sensitive to fluoroquinolones and aminoglycosides. Penicillins and cephalosporins showed less potential for action on these bacteria, which showed greater resistance to these classes.
Process simulation of biodiesel production from vegetable oil deodorization distillate using hydrotalcite-hydroxyapatite as catalyst
Authors: Almeida Laura A. de , Vilas Bôas Renata N. , Mendes Marisa F.
Published: May 2021

In There are few simulation studies in the literature focusing on the production of biodiesel from vegetable oil deodorization distillate (VODD), a waste originating from the vegetable oil processing stage, using hydrotalcite-hydroxyapatite as a heterogeneous catalyst. In this study, the simulation process was performed using open interface software DWSIM® Version 6.3. The motivation relied on the positive performance of the catalyst during the experimental studies. So, in the simulator design, the lipid raw material, ethanol, and the catalyst were fed together in a CSTR-01 conversion reactor. The thermodynamic fluid package used for this process was the Non-Random Two-Liquid (NRTL) activity coefficient model. The process flowchart consisted of the reaction step (oil transesterification), and separation steps of the ethyl esters produced, excess ethanol and purification of biodiesel. As a result, different scenarios were simulated, using commercial soybean oil as a comparative form, different types of catalysts and different molar ratios of alcohol and VODD. Among the main differences between the simulated cases, it was demonstrated that the excess of alcohol (1:45) caused greater quantity of VODD consumption, and consequently the greater formation of ethyl esters (biodiesel), resulting higher conversions (> 95%). In addition, the results obtained confirmed the adequacy of VODD as a potential raw material to produce biodiesel, as it is relatively cheaper than edible oils and contributes to the use of waste. Thus, confirming that the chemical catalyst was able to form the main esters of fatty acids even using a residual raw material.
Assessment of Oral Vancomycin-Induced Alterations in Gut Bacterial Microbiota and Metabolome of Healthy Men
Authors: Kim Andrew HyoungJin , Lee Yujin , Kim Eunwoo , Ji Sang Chun , Chung Jae-Yong , Cho Joo-Youn
Published: May 2021

Several classes of antibiotics have reduced the mortality caused by infectious diseases; however, orally administered antibiotics alter the composition of gut microbiota, leading to dysbiosis-related disease. Therefore, in this study, we used 16S rRNA gene sequencing- and metabolomics-based approaches to investigate the effects of oral vancomycin on gut bacterial microbiota and the metabolome in biospecimens collected from healthy men. Samples collected from 11 healthy men were analyzed using 16S rRNA gene sequencing and metabolomics. 16S rRNA gene sequencing was performed to analyze the gut bacterial microbiota, and GC-TOFMS-based untargeted metabolomics was performed to analyze fecal, urine, and plasma metabolomics. Spearman’s rank correlation was utilized to explore the associations between gut bacterial microbiota and metabolome. Fecal 16S rRNA gene sequencing analysis showed decreased relative abundance of genera belonging to the phyla Bacteroidetes and Firmicutes, and increased relative abundance of genera of the phyla Proteobacteria and Fusobacteria. Fecal metabolomics analysis showed that levels of uracil, L-aspartic acid, lithocholic acid, and deoxycholic acid were significantly higher at baseline, whereas that of dihydrouracil was significantly higher after vancomycin administration. No significant metabolic markers were selected from urine and plasma metabolomics analysis. This study demonstrates that oral vancomycin administration induces alterations in gut bacterial microbiota and metabolome. Correlation analysis between our two datasets shows that alteration of the gut bacterial microbiota, induced by oral vancomycin, potentially affected the systemic activity of dihydropyrimidine dehydrogenase. This correlation should be further examined in future studies to define the effects of gut bacterial microbiota on drug-metabolizing enzymes, thereby contributing to the development of personalized therapy.
Revealing the Immune Infiltration Landscape and Identifying Diagnostic Biomarkers for Lumbar Disc Herniation
Authors: Wang Linbang , He Tao , Liu Jingkun , Tai Jiaojiao , Wang Bing , Zhang Lanyue , Quan Zhengxue
Published: May 2021

Intervertebral disc (IVD) degeneration and its inflammatory microenvironment ultimately led to discogenic pain, which is thought to originate in the nucleus pulposus (NP). In this study, key genes involved in NP tissue immune infiltration in lumbar disc herniation (LDH) were identified by bioinformatic analysis. Gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database. The CIBERSORT algorithm was used to analyze the immune infiltration into NP tissue between the LDH and control groups. Hub genes were identified by the WGCNA R package in Bioconductor and single-cell sequencing data was analyzed using R packages. Gene expression levels were evaluated by quantitative real-time polymerase chain reaction. The immune infiltration profiles varied significantly between the LDH and control groups. Compared with control tissue, LDH tissue contained a higher proportion of regulatory T cells and macrophages, which are associated with the macrophage polarization process. The most significant module contained three hub genes and four subclusters of NP cells. Functional analysis of these genes was performed, the hub gene expression pattern was confirmed by PCR, and clinical features of the patients were investigated. Finally, we identified TGF-β and MAPK signaling pathways as crucial in this process and these pathways may provide diagnostic markers for LDH. We hypothesize that the hub genes expressed in the specific NP subclusters, along with the infiltrating macrophages play important roles in the pathogenesis of IVD degeneration and ultimately, disc herniation.
Case Report: Circulating Myeloid-Derived Suppressive-Like Cells and Exhausted Immune Cells in Non-Small Cell Lung Cancer Patients Treated With Three Immune Checkpoint Inhibitors
Authors: Bronte Giuseppe , Verlicchi Alberto , De Matteis Serena , Rossi Alice , Affatato Alessandra , Sullo Francesco Giulio , Gianni Caterina , Canale Matteo , Burgio Marco Angelo , Delmonte Angelo , Milella Michele , Crinò Lucio
Published: May 2021

Immune checkpoint inhibition induced a great step forward in the treatment of non-small cell lung cancer patients. In cancer immune microenvironment many checkpoints were studied and their involvement could represent a mechanism of resistance to cancer immunotherapy. For this reason, the inhibition of multiple immune checkpoints is under development. However, myeloid-derived suppressor cells (MDSC) and exhausted immune cells could limit the efficacy of cancer immunotherapy. We analyzed the variation of circulating immune suppressive-like cell subsets and exhausted immune cells in three non-small cell lung cancer patients treated with the combination of anti-CTLA-4 plus anti-PD-1 plus anti-LAG-3 at T0 (baseline), T1 (after 2 months) and T2 (after 4 months). We also describe the clinical and radiological course of the disease during this treatment in all three patients. We observed both clinical differences and changes in the composition of immune suppressive-like cell subsets and exhausted immune cells between the patients receiving the same schedule of treatment with immune checkpoint inhibitors. The study on a wider patient population and experimental model design could help to clarify the kinetics of these cell subpopulations with the perspective to find new targets for treatment or new biomarkers for resistance to cancer immunotherapy.
Prognostic and Predictive Value of Immune-Related Gene Pair Signature in Primary Lower-Grade Glioma Patients
Authors: Lei Kunjian , Li Jingying , Tu Zewei , Liu Feng , Ye Minhua , Wu Miaojing , Zhu Yue , Luo Min , Lin Li , Tao Chuming , Huang Kai , Zhu Xingen
Published: May 2021

Immune-related gene pairs (IRGPs) have been associated with prognosis in various cancer types, but few studies have examined their prognostic capabilities in glioma patients. Here, we gathered the gene expression and clinical profile data of primary lower-grade glioma (LGG) patients from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA, containing CGGAseq1 and CGGAseq2), the Gene Expression Omnibus (GEO: GSE16011), and Rembrandt datasets. In the TCGA dataset, univariate Cox regression was performed to detect overall survival (OS)-related IRGs, Lasso regression, and multivariate Cox regression were used to screen robust prognosis-related IRGs, and 19 IRGs were selected for the construction of an IRGP prognostic signature. All patients were allotted to high- and low-risk subgroups based on the TCGA dataset median value risk score. Validation analysis indicated that the IRGP signature returned a stable prognostic value among all datasets. Univariate and multivariate Cox regression analyses indicated that the IRG -signature could efficiently predict the prognosis of primary LGG patients. The IRGP-signature-based nomogram model was built, revealing the reliable ability of the IRGP signature to predict clinical prognosis. The single-sample gene set enrichment analysis (ssGSEA) suggested that high-risk samples contained higher numbers of immune cells but featured lower tumor purity than low-risk samples. Finally, we verified the prognostic ability of the IRGP signature using experiments performed in LGG cells. These results indicated that the IRGP signature could be regarded as a stable prognostic assessment predictor for identifying high-risk primary LGG patients.
Moral Decision Making in Human-Agent Teams: Human Control and the Role of Explanations
Authors: van der Waa Jasper , Verdult Sabine , van den Bosch Karel , van Diggelen Jurriaan , Haije Tjalling , van der Stigchel Birgit , Cocu Ioana
Published: May 2021

With the progress of Artificial Intelligence, intelligent agents are increasingly being deployed in tasks for which ethical guidelines and moral values apply. As artificial agents do not have a legal position, humans should be held accountable if actions do not comply, implying humans need to exercise control. This is often labeled as Meaningful Human Control (MHC). In this paper, achieving MHC is addressed as a design problem, defining the collaboration between humans and agents. We propose three possible team designs (Team Design Patterns), varying in the level of autonomy on the agent’s part. The team designs include explanations given by the agent to clarify its reasoning and decision-making. The designs were implemented in a simulation of a medical triage task, to be executed by a domain expert and an artificial agent. The triage task simulates making decisions under time pressure, with too few resources available to comply with all medical guidelines all the time, hence involving moral choices. Domain experts (i.e., health care professionals) participated in the present study. One goal was to assess the ecological relevance of the simulation. Secondly, to explore the control that the human has over the agent to warrant moral compliant behavior in each proposed team design. Thirdly, to evaluate the role of agent explanations on the human’s understanding in the agent’s reasoning. Results showed that the experts overall found the task a believable simulation of what might occur in reality. Domain experts experienced control over the team’s moral compliance when consequences were quickly noticeable. When instead the consequences emerged much later, the experts experienced less control and felt less responsible. Possibly due to the experienced time pressure implemented in the task or over trust in the agent, the experts did not use explanations much during the task; when asked afterwards they however considered these to be useful. It is concluded that a team design should emphasize and support the human to develop a sense of responsibility for the agent’s behavior and for the team’s decisions. The design should include explanations that fit with the assigned team roles as well as the human cognitive state.
Communication With Older Adults in Times of a Pandemic: Practical Suggestions for the Health Care Professionals
Authors: Pinsonnault-Skvarenina Alexis , Lacerda Adriana Bender Moreira de , Hotton Mathieu , Gagné Jean-Pierre
Published: May 2021

In order to limit the spread of the coronavirus, several protective measures have been put in place in the community, in private and public residences and in health care centers. Some measures have a negative impact on communication. They include physical distancing, the use of face masks and shields as well as the increased use of telephone and videoconferencing for distance communication. The effects of COVID-19 are particularly harsh on older adults. Consequently, older adults, especially those with hearing loss, are particularly at risk of experiencing communication breakdowns and increased social isolation. Health care professionals should learn about and be encouraged to use communication strategies to maintain good interactions with their patients. This article proposes practical suggestions to health professionals who interact with older adults, especially those who have difficulty understanding speech. The goal of this article is to inform on the prevalence of hearing loss, the hearing difficulties experienced by older adults, the manifestations of hearing problems, the effects of pandemic protection measures on communication and the strategies that can be used to optimize professional-patient communication during a pandemic.
Efficient and Scalable Initialization of Partitioned Coupled Simulations with preCICE
Authors: Totounferoush Amin , Simonis Frédéric , Uekermann Benjamin , Schulte Miriam
Published: May 2021

preCICE is an open-source library, that provides comprehensive functionality to couple independent parallelized solver codes to establish a partitioned multi-physics multi-code simulation environment. For data communication between the respective executables at runtime, it implements a peer-to-peer concept, which renders the computational cost of the coupling per time step negligible compared to the typical run time of the coupled codes. To initialize the peer-to-peer coupling, the mesh partitions of the respective solvers need to be compared to determine the point-to-point communication channels between the processes of both codes. This initialization effort can become a limiting factor, if we either reach memory limits or if we have to re-initialize communication relations in every time step. In this contribution, we remove two remaining bottlenecks: (i) We base the neighborhood search between mesh entities of two solvers on a tree data structure to avoid quadratic complexity, and (ii) we replace the sequential gather-scatter comparison of both mesh partitions by a two-level approach that first compares bounding boxes around mesh partitions in a sequential manner, subsequently establishes pairwise communication between processes of the two solvers, and finally compares mesh partitions between connected processes in parallel. We show, that the two-level initialization method is fives times faster than the old one-level scheme on 24,567 CPU-cores using a mesh with 628,898 vertices. In addition, the two-level scheme is able to handle much larger computational meshes, since the central mesh communication of the one-level scheme is replaced with a fully point-to-point mesh communication scheme.
Canadian Melanoma Conference Recommendations on High-Risk Melanoma Surveillance: A Report from the 14th Annual Canadian Melanoma Conference; Banff, Alberta; 20–22 February 2020
Authors: Lee Christina W. , McKinnon J. Gregory , Davis Noelle
Published: May 2021

Introduction: There are a lack of established guidelines for the surveillance of high-risk cutaneous melanoma patients following initial therapy. We describe a novel approach to the development of a national expert recommendation statement on high-risk melanoma surveillance (HRS). Methods: A consensus-based, live, online voting process was undertaken at the 13th and 14th annual Canadian Melanoma Conferences (CMC) to collect expert opinions relating to “who, what, where, and when” HRS should be conducted. Initial opinions were gathered via audience participation software and used as the basis for a second iterative questionnaire distributed online to attendees from the 13th CMC and to identified melanoma specialists from across Canada. A third questionnaire was disseminated in a similar fashion to conduct a final vote on HRS that could be implemented. Results: The majority of respondents from the first two iterative surveys agreed on stages IIB to IV as high risk. Surveillance should be conducted by an appropriate specialist, irrespective of association to a cancer centre. Frequency and modality of surveillance favoured biannual visits and Positron Emission Tomography Computed Tomography (PET/CT) with brain magnetic resonance imaging (MRI) among the systemic imaging modalities available. No consensus was initially reached regarding the frequency of systemic imaging and ultrasound of nodal basins (US). The third iterative survey resolved major areas of disagreement. A 5-year surveillance schedule was voted on with 92% of conference members in agreement. Conclusion: This final recommendation was established following 92% overall agreement among the 2020 CMC attendees.
Study of Molding and Drying Characteristics of Compressed Municipal Sludge-Corn Stalk Fuel Pellets
Authors: Ma Li , Sha Li , Liu Xingxin , Zhang Shuting
Published: May 2021

Sludge incineration is a sludge resource management and disposal method that can greatly decrease the volume of sludge, reduce the degree of harm and realize the recovery of sludge heat energy. Most of the research on sludge incineration focuses on the combustion process and gas emissions, but there are relatively few studies on the sludge fuel molding and drying process before sludge incineration. Besides, independent incineration of sludge has high energy consumption. This paper proposes a pre-incineration treatment method in which sludge and corn stover are mixed to make fuel pellets and then dried. Specifically, the influence of molding pressure, raw material ratio and raw material particle size on the physical properties of the fuel, and the related mechanism, were studied. The density of fuel particles is mainly affected by the forming pressure, and the impermeability is mainly determined by the proportion of sludge in the raw material. The order of the variables based on their effect of improving fuel physical properties was: molding pressure > raw material ratio > raw material particle size. Moreover, the influence of drying temperature (40 °C, 60 °C, 80 °C, 100 °C, 120 °C) has been explored. When the initial water content is similar, the drying rate increases with the increase in temperature. It provides a reference for the sludge fuel molding and drying process, and promotes the practical application of mixing sludge and corn stalks to make fuel.
In-Cylinder Pressure Based Engine Knock Classification Model for High-Compression Ratio, Automotive Spark-Ignition Engines Using Various Signal Decomposition Methods
Authors: Kim Junghwan
Published: May 2021

Engine knock determination has been conducted in various ways for spark timing calibration. In the present study, a knock classification model was developed using a machine learning algorithm. Wavelet packet decomposition (WPD) and ensemble empirical mode decomposition (EEMD) were employed for the characterization of the in-cylinder pressure signals from the experimental engine. The WPD was used to calculate 255 features from seven decomposition levels. EEMD provided total 70 features from their intrinsic mode functions (IMF). The experimental engine was operated at advanced spark timings to induce knocking under various engine speeds and load conditions. Three knock intensity metrics were employed to determine that the dataset included 4158 knock cycles out of a total of 66,000 cycles. The classification model trained with 66,000 cycles achieved an accuracy of 99.26% accuracy in the knock cycle detection. The neighborhood component analysis revealed that seven features contributed significantly to the classification. The classification model retrained with the seven significant features achieved an accuracy of 99.02%. Although the misclassification rate increased in the normal cycle detection, the feature selection decreased the model size from 253 to 8.25 MB. Finally, the compact classification model achieved an accuracy of 99.95% with the second dataset obtained at the knock borderline (KBL) timings, which validates that the model is sufficient for the KBL timing determination.
Physical Simulation and Mathematical Model of the Porous Flow Characteristics of Gas-Bearing Tight Oil Reservoirs
Authors: Rao Yuan , Yang Zhengming , Zhang Yapu , Wu Zhenkai , Luo Yutian , Li Haibo , He Ying
Published: May 2021

The separation of solution gas has great influence on the development of gas-bearing tight oil reservoirs. In this study, physical simulation and high-pressure mercury intrusion were used to establish a method for determining the porous flow resistance gradient of gas-bearing tight oil reservoirs. A mathematical model suitable for injection–production well networks is established based on the streamline integral method. The concept of pseudo-bubble point pressure is proposed. The experimental results show that as the back pressure decreases from above the bubble point pressure to below the bubble point pressure, the solution gas separates out. During this process, the porous flow resistance gradient is initially equal to the threshold pressure gradient of the oil single-phase fluid, then it becomes relatively small and stable, and finally it increases rapidly and exponentially. The lower the permeability, the higher the pseudo-bubble point pressure, and the higher the resistance gradient under the same back pressure. For tight reservoirs, the production pressure should be maintained above the pseudo-bubble point pressure when the permeability is lower than a certain value. When the permeability is higher than a certain value, the pressure can be reduced below the pseudo-bubble point pressure, and there is a reasonable range. The mathematical results show that after degassing, the oil production rate and the effective utilization coefficient of oil wells decline rapidly. These declines occur later and have a flat trend for high permeability formations, and the production well pressure can be reduced to a lower level. Fracturing can effectively increase the oil production rate after degassing. A formation that cannot be utilized before fracturing because of the blocked throats due to the separation of the solution gas can also be utilized after fracturing. When the production well pressure is lower than the bubble point pressure, which is not too large, the fracturing effect is better.
Development of a High-Flux Solar Simulator for Experimental Testing of High-Temperature Applications
Authors: Milanese Marco , Colangelo Gianpiero , de Risi Arturo
Published: May 2021

In the last few years, several studies have been carried out on concentrating solar thermal and thermochemical applications. These studies can be further enhanced by means of high-flux solar simulators (HFSS), since they allow the development of experimental tests under controlled irradiance conditions, regardless of sunshine. In this work, a new high-flux solar simulator, capable of reaching levels of irradiance higher than 100 W/cm2 (1000 suns), has been designed, built and characterized. This simulator is composed of 8 ellipsoidal specular reflectors, arranged face-down on a horizontal plane, in order to irradiate from the upper side any system requiring the simulation of concentrated solar radiation; differently from the HFSSs described in the scientific literature, this configuration allows the avoidance of any distortion of fluid-dynamic or convective phenomena within the system under investigation. As a first step, a numerical analysis of the HFSS has been carried out, simulating each real light source (Xe-arc), having a length of 6.5 mm, as a line of 5 sub-sources. Therefore, the HFSS has been built and characterized, measuring a maximum irradiance of 120 W/cm2 and a maximum temperature of 1007 °C; these values will be enough to develop experimental tests on lab-scale thermal and thermochemical solar applications.
Multiple (TEES)-Criteria-Based Sustainable Planning Approach for Mesh-Configured Distribution Mechanisms across Multiple Load Growth Horizons
Authors: Kazmi Syed Ali Abbas , Ameer Khan Usama , Ahmad Waleed , Hassan Muhammad , Ibupoto Fahim Ahmed , Bukhari Syed Basit Ali , Ali Sajid , Malik M. Mahad , Shin Dong Ryeol
Published: May 2021

Modern distribution mechanisms within the smart grid paradigm are considered both reliable in nature and interconnected in topology. In this paper, a multiple-criteria-based sustainable planning (MCSP) approach is presented that serves as a future planning tool for interconnected distribution mechanisms and aims to find a feasible solution among conflicting criteria of various genres. The proposed methodology is based on three stages. In the stage 1, a weighted voltage stability index (VSI_W) and loss minimization condition (LMC) based approach aims at optimal asset optimization (sitting and sizing). In this stage, an evaluation of alternatives (solutions) is carried out across four dimensions (technical, economic, environmental, and social) of performance metrics. The assets considered in the evaluations include distributed generation (DG), renewable DGs, i.e., photovoltaic (PV), wind, and distributed static compensator (D-STATCOM) units. In the stage 2, various multicriteria decision-making (MCDM) methodologies are applied to ascertain the best trade-off among the available solutions in terms of techno-cost (economic) (TCPE), environment-o-social (ESPE), and techno-economic-environmental-socio (TEES) performance evaluations (OPE). In the stage 3, the alternatives are evaluated across multiple load growth horizons of 5 years each. The proposed MCSP approach is evaluated across a mesh-configured 33-bus active distribution network (ADN) and an actual NUST (which is a university in Islamabad, Pakistan) microgrid (MG), with various variants of load growth. The numerical findings of the proposed MCSP approach are compared with reported works the literature supports its validity and can serve as an important planning tool for interconnected distribution mechanisms for researchers and planning engineers.
A Comprehensive Loss Model and Comparison of AC and DC Boost Converters
Authors: Gerber Daniel L. , Musavi Fariborz , Ghatpande Omkar A. , Frank Stephen M. , Poon Jason , Brown Richard E. , Feng Wei
Published: May 2021

DC microgrids have become a prevalent topic in research in part due to the expected superior efficiency of DC/DC converters compared to their AC/DC counterparts. Although numerous side-by-side analyses have quantified the efficiency benefits of DC power distribution, these studies all modeled converter loss based on product data that varied in component quality and operating voltage. To establish a fair efficiency comparison, this work derives a formulaic loss model of a DC/DC and an AC/DC PFC boost converter. These converters are modeled with identical components and an equivalent input and output voltage. Simulated designs with real components show AC/DC boost converters between 100 W to 500 W having up to 2.5 times more loss than DC/DC boost converters. Although boost converters represent a fraction of electronics in buildings, these loss models can eventually work toward establishing a comprehensive model-based full-building analysis.
Methylation and Noncoding RNAs in Gastric Cancer: Everything Is Connected
Authors: Bure Irina V. , Nemtsova Marina V.
Published: May 2021

Despite recent progress, gastric cancer remains one of the most common cancers and has a high mortality rate worldwide. Aberrant DNA methylation pattern and deregulation of noncoding RNA expression appear in the early stages of gastric cancer. Numerous investigations have confirmed their significant role in gastric cancer tumorigenesis and their high potential as diagnostic and prognostic biomarkers. Currently, it is clear that these epigenetic regulators do not work alone but interact with each other, generating a complex network. The aim of our review was to summarize the current knowledge of this interaction in gastric cancer and estimate its clinical potential for the diagnosis, prognosis, and treatment of the disease.
Propellanes as Rigid Scaffolds for the Stereodefined Attachment of σ-Pharmacophoric Structural Elements to Achieve σ Affinity
Authors: Torres-Gómez Héctor , Daniliuc Constantin , Schepmann Dirk , Laurini Erik , Pricl Sabrina , Wünsch Bernhard
Published: May 2021

Following the concept of conformationally restriction of ligands to achieve high receptor affinity, we exploited the propellane system as rigid scaffold allowing the stereodefined attachment of various substituents. Three types of ligands were designed, synthesized and pharmacologically evaluated as σ1 receptor ligands. Propellanes with (1) a 2-methoxy-5-methylphenylcarbamate group at the “left” five-membered ring and various amino groups on the “right” side; (2) benzylamino or analogous amino moieties on the “right” side and various substituents at the left five-membered ring and (3) various urea derivatives at one five-membered ring were investigated. The benzylamino substituted carbamate syn,syn-4a showed the highest σ1 affinity within the group of four stereoisomers emphasizing the importance of the stereochemistry. The cyclohexylmethylamine 18 without further substituents at the propellane scaffold revealed unexpectedly high σ1 affinity (Ki = 34 nM) confirming the relevance of the bioisosteric replacement of the benzylamino moiety by the cyclohexylmethylamino moiety. Reduction of the distance between the basic amino moiety and the “left” hydrophobic region by incorporation of the amino moiety into the propellane scaffold resulted in azapropellanes with particular high σ1 affinity. As shown for the propellanamine 18, removal of the carbamate moiety increased the σ1 affinity of 9a (Ki = 17 nM) considerably. Replacement of the basic amino moiety by H-bond forming urea did not lead to potent σ ligands. According to molecular dynamics simulations, both azapropellanes anti-5 and 9a as well as propellane 18 adopt binding poses at the σ1 receptor, which result in energetic values correlating well with their different σ1 affinities. The affinity of the ligands is enthalpy driven. The additional interactions of the carbamate moiety of anti-5 with the σ1 receptor protein cannot compensate the suboptimal orientations of the rigid propellane and its N-benzyl moiety within the σ1 receptor-binding pocket, which explains the higher σ1 affinity of the unsubstituted azapropellane 9a.
Mitochondrial Dynamics Markers and Related Signaling Molecules Are Important Regulators of Spermatozoa Number and Functionality
Authors: Starovlah Isidora M. , Radovic Pletikosic Sava M. , Kostic Tatjana S. , Andric Silvana A.
Published: May 2021

Here, we study possible mechanisms of (in/sub)fertility related to the acute or repeated psychological stresses (the most common stresses in human society) by following the transcriptional profile of 22 mitochondrial dynamics/function markers and 22 signaling molecules regulating both mitochondrial dynamics and spermatozoa number/functionality. An in vivo study mimicking acute (once for 3 h) and repeated (3 h for 10 consecutive days) psychophysical stress was performed on adult rats. The analysis of hormones, the number/functionality of spermatozoa, and 44 transcriptional markers were performed on individual samples from up to 12 animals per group. Results showed that both types of stress reduced spermatozoa functionality (acute by 4.4-fold, repeated by 3.3-fold) and ATP production (acute by 2.3-fold, repeated by 14.5-fold), while only repeated stress reduces the number of spermatozoa (1.9-fold). Stress significantly disturbed transcription of 34-out-of-44 markers (77%). Mitochondrial dynamics and functionality markers: 18-out-of-22 =>82% (mitochondrial-biogenesis-markers –>6-out-of-8 =>75%; mitochondrial-fusion-markers –>3-out-of-3 =>100%; mitochondrial-fission-markers –>1-out-of-2 =>50%; mitochondrial-autophagy-markers –>3-out-of-3 =>100%; mitochondrial-functionality-markers –>5-out-of-6 =>83%). Markers of signaling pathways regulating both mitochondrial dynamics/functionality and spermatozoa number/functionality important for male (in/sub)fertility –>16-out-of-22 =>73% (cAMP-signaling-markers –>8-out-of-12 =>67%; MAPK-signaling-markers –>8-out-of-10 =>80%). Accordingly, stress-triggered changes of transcriptional profile of mitochondrial dynamics/functionality markers as well as signaling molecules regulating both mitochondrial dynamics and spermatozoa number and functionality represent adaptive mechanisms.
The Complexities of Organ Crosstalk in Phosphate Homeostasis: Time to Put Phosphate Sensing Back in the Limelight
Authors: Figueres Lucile , Beck-Cormier Sarah , Beck Laurent , Marks Joanne
Published: May 2021

Phosphate homeostasis is essential for health and is achieved via interaction between the bone, kidney, small intestine, and parathyroid glands and via intricate processes involving phosphate transporters, phosphate sensors, and circulating hormones. Numerous genetic and acquired disorders are associated with disruption in these processes and can lead to significant morbidity and mortality. The role of the kidney in phosphate homeostasis is well known, although it is recognized that the cellular mechanisms in murine models and humans are different. Intestinal phosphate transport also appears to differ in humans and rodents, with recent studies demonstrating a dominant role for the paracellular pathway. The existence of phosphate sensing has been acknowledged for decades; however, the underlying molecular mechanisms are poorly understood. At least three phosphate sensors have emerged. PiT2 and FGFR1c both act as phosphate sensors controlling Fibroblast Growth Factor 23 secretion in bone, whereas the calcium-sensing receptor controls parathyroid hormone secretion in response to extracellular phosphate. All three of the proposed sensors are expressed in the kidney and intestine but their exact function in these organs is unknown. Understanding organ interactions and the mechanisms involved in phosphate sensing requires significant research to develop novel approaches for the treatment of phosphate homeostasis disorders.
Design and Evaluation of 223Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy—Part II. Toxicity, Pharmacokinetics and Biodistribution
Authors: Lankoff Anna , Czerwińska Malwina , Walczak Rafał , Karczmarczyk Urszula , Tomczyk Kamil , Brzóska Kamil , Fracasso Giulio , Garnuszek Piotr , Mikołajczak Renata , Kruszewski Marcin
Published: May 2021

Metastatic castration-resistant prostate cancer (mCRPC) is a progressive and incurable disease with poor prognosis for patients. Despite introduction of novel therapies, the mortality rate remains high. An attractive alternative for extension of the life of mCRPC patients is PSMA-based targeted radioimmunotherapy. In this paper, we extended our in vitro study of 223Ra-labeled and PSMA-targeted NaA nanozeolites [223RaA-silane-PEG-D2B] by undertaking comprehensive preclinical in vitro and in vivo research. The toxicity of the new compound was evaluated in LNCaP C4-2, DU-145, RWPE-1 and HPrEC prostate cells and in BALB/c mice. The tissue distribution of 133Ba- and 223Ra-labeled conjugates was studied at different time points after injection in BALB/c and LNCaP C4-2 tumor-bearing BALB/c Nude mice. No obvious symptoms of antibody-free and antibody-functionalized nanocarriers cytotoxicity and immunotoxicity was found, while exposure to 223Ra-labeled conjugates resulted in bone marrow fibrosis, decreased the number of WBC and platelets and elevated serum concentrations of ALT and AST enzymes. Biodistribution studies revealed high accumulation of 223Ra-labeled conjugates in the liver, lungs, spleen and bone tissue. Nontargeted and PSMA-targeted radioconjugates exhibited a similar, marginal uptake in tumour lesions. In conclusion, despite the fact that NaA nanozeolites are safe carriers, the intravenous administration of NaA nanozeolite-based radioconjugates is dubious due to its high accumulation in the lungs, liver, spleen and bones.
Extracellular Matrix Deposition and Remodeling after Corneal Alkali Burn in Mice
Authors: Mutoji Kazadi N. , Sun Mingxia , Elliott Garrett , Moreno Isabel Y. , Hughes Clare , Gesteira Tarsis F. , Coulson-Thomas Vivien J.
Published: May 2021

Corneal transparency relies on the precise arrangement and orientation of collagen fibrils, made of mostly Type I and V collagen fibrils and proteoglycans (PGs). PGs are essential for correct collagen fibrillogenesis and maintaining corneal homeostasis. We investigated the spatial and temporal distribution of glycosaminoglycans (GAGs) and PGs after a chemical injury. The chemical composition of chondroitin sulfate (CS)/dermatan sulfate (DS) and heparan sulfate (HS) were characterized in mouse corneas 5 and 14 days after alkali burn (AB), and compared to uninjured corneas. The expression profile and corneal distribution of CS/DSPGs and keratan sulfate (KS) PGs were also analyzed. We found a significant overall increase in CS after AB, with an increase in sulfated forms of CS and a decrease in lesser sulfated forms of CS. Expression of the CSPGs biglycan and versican was increased after AB, while decorin expression was decreased. We also found an increase in KS expression 14 days after AB, with an increase in lumican and mimecan expression, and a decrease in keratocan expression. No significant changes in HS composition were noted after AB. Taken together, our study reveals significant changes in the composition of the extracellular matrix following a corneal chemical injury.
Importance of Genetic Polymorphisms in MT1 and MT2 Genes in Metals Homeostasis and Their Relationship with the Risk of Acute Pancreatitis Occurrence in Smokers—Preliminary Findings
Authors: Ściskalska Milena , Ołdakowska Monika , Milnerowicz Halina
Published: May 2021

This study was aimed at evaluating the changes in metallothionein (MT) concentration in the blood of patients with acute pancreatitis (AP) and healthy subjects, taking into account the extracellular (plasma) and intracellular (erythrocyte lysate) compartments. The impact of single-nucleotide polymorphisms (SNPs) in the MT1A (rs11640851), MT1B (rs964372) and MT2A (rs10636) genes on MT concentration and their association with the concentration of metals (Cu, Zn, Cd) and ceruloplasmin as Cu-related proteins were analyzed. The concentration of a high-sensitivity C-reactive protein (hs-CRP) and IL-6 as markers of inflammation, and malonyldialdehyde (MDA), superoxide dismutase (SODs) activity and the value of total antioxidant capacity (TAC) as parameters describing the pro/antioxidative balance were also assessed. In the AP patient groups, an increased MT concentration in erythrocyte lysate compared to healthy subjects was shown, especially in individuals with the GG genotype for rs964372 in the MT1B gene. A Zn concentration was especially decreased in the blood of smoking AP patients with the AA genotype for SNP rs11640851 in the MT1A gene and the GC genotype for SNP rs10636 in MT2A, compared to non-smokers with AP, which was accompanied by an increase in the value of the Cu/Zn ratio. The exposure to tobacco smoke xenobiotics increased the risk of AP occurrence in subjects with the CC genotype for SNP rs11640851 in the MT1A gene by more than fourfold. The investigated polymorphisms, rs11640851 in the MT1A gene, rs964372 in the MT1B gene and rs10636 in the MT2A gene, seem to be an important factor in maintaining homeostasis in an organism under oxidative stress conditions.
Novel Methods to Mobilize, Isolate, and Expand Mesenchymal Stem Cells
Authors: Vieira Cristiano P. , McCarrel Taralyn M. , Grant Maria B.
Published: May 2021

Numerous studies demonstrate the essential role of mesenchymal stem cells (MSCs) in the treatment of metabolic and inflammatory diseases, as these cells are known to modulate humoral and cellular immune responses. In this manuscript, we efficiently present two novel approaches to obtain MSCs from equine or human sources. In our first approach, we used electro-acupuncture as previously described by our group to mobilize MSCs into the peripheral blood of horses. For equine MSC collection, culture, and expansion, we used the Miltenyi Biotec CliniMACS Prodigy system of automated cell manufacturing. Using this system, we were able to generate appoximately 100 MSC colonies that exhibit surface marker expression of CD105 (92%), CD90 (85%), and CD73 (88%) within seven days of blood collection. Our second approach utilized the iPSC embryoid bodies from healthy or diabetic subjects where the iPSCs were cultured in standard media (endothelial + mesoderm basal media). After 21 days, the cells were FACS sorted and exhibited surface marker expression of CD105, CD90, and CD73. Both the equine cells and the human iPSC-derived MSCs were able to differentiate into adipogenic, osteogenic, and chondrogenic lineages. Both methods described simple and highly efficient methods to produce cells with surface markers phenotypically considered as MSCs and may, in the future, facilitate rapid production of MSCs with therapeutic potential.
Donor Heart Preservation with Hydrogen Sulfide: A Systematic Review and Meta-Analysis
Authors: Ertugrul Imran A. , van Suylen Vincent , Damman Kevin , de Koning Marie-Sophie L. Y. , van Goor Harry , Erasmus Michiel E.
Published: May 2021

Preclinical studies have shown that postconditioning with hydrogen sulfide (H2S) exerts cardioprotective effects against myocardial ischemia-reperfusion injury (IRI). The aim of this study was to appraise the current evidence of the cardioprotective effects of H2S against IRI in order to explore the future implementation of H2S in clinical cardiac transplantation. The current literature on H2S postconditioning in the setting of global myocardial ischemia was systematically reviewed and analyzed, performing meta-analyses. A literature search of the electronic databases Medline, Embase and Cinahl identified 1835 studies that were subjected to our pre-defined inclusion criteria. Sixteen studies were considered eligible for inclusion. Postconditioning with H2S showed significant robust effects with regard to limiting infarct size (standardized mean difference (SMD) = −4.12, 95% CI [−5.53–−2.71], p < 0.00001). Furthermore, H2S postconditioning consistently resulted in a significantly lower release of cardiac injury markers, lower levels of oxidative stress and improved cardiac function. Postconditioning with slow-releasing H2S donors offers a valuable opportunity for novel therapies within cardiac preservation for transplantation. Before clinical implication, studies evaluating the long-term effects of H2S treatment and effects of H2S treatment in large animal studies are warranted.
Optimization of Process Parameters for Additively Produced Tool Steel 1.2709 with a Layer Thickness of 100 μm
Authors: Andronov Vladislav , Šimota Jan , Beránek Libor , Blažek Jiří , Rušar Filip
Published: May 2021

The purpose of this study was to find and optimize the process parameters of producing tool steel 1.2709 at a layer thickness of 100 μm by DMLS (Direct Metal Laser Sintering). HPDC (High Pressure Die Casting) tools are printed from this material. To date, only layer thicknesses of 20–50 μm are used, and parameters for 100 µm were an undescribed area, according to the state of the art. Increasing the layer thickness could lead to time reduction and higher economic efficiency. The study methodology was divided into several steps. The first step was the research of the single-track 3D printing parameters for the subsequent development of a more accurate description of process parameters. Then, in the second step, volume samples were produced in two campaigns, whose porosity was evaluated by metallographic and CT (computed tomography) analysis. The main requirement for the process parameters was a relative density of the printed material of at least 99.9%, which was achieved and confirmed using the parameters for the production of the samples for the tensile test. Therefore, the results of this article could serve as a methodological procedure for optimizing the parameters to streamline the 3D printing process, and the developed parameters may be used for the productive and quality 3D printing of 1.2709 tool steel.