bluuebunny/crossref_metadata_2025 huggingface dataset:
STATE INTELLECTUAL PROPERTY MANAGEMENT IN THE SPHERE OF NATIONAL SECURITY AND DEFENCE
Authors: Олександр Зайківський  , Олександр Оністрат
Published: June 2021

The state policy on the management of objects of intellectual property right in the sphere of national security and defense is considered.Under the current conditions, national security is unconceivable without solving the problematic issues of intellectual property management and creating the necessary preconditions for the development of intellectual potential and its use for national security.At present, the concept of national security is being expanded to include more and more spheres of public life. New security settings related to the scientific and technological revolution have started to play an important role.Nowadays, issues of the formation of an effective state policy for ensuring national security in all its spheres and manifestations are of great importance. An important component of the mechanism for the formation and implementation of state policy in the field of national security should be the provision of intellectual property management.However, national security legislation does not provide for the development of a strategy or other programmatic document on scientific and technical security, which would envisage measures to ensure the protection of the scientific and intellectual potential of the state, competitive technologies available in the country.The question at issue is the fact that the state has not yet developed a national strategy for the protection of intellectual property, which would provide the protection of interests and rights of all subjects of intellectual property rights, and especially the state. Although the attempts to develop such a strategy were carried out repeatedly. The state system of intellectual property protection and the effectiveness of providingnational interests with its structural elements, in particular in the field of national security and defense, are investigated. Current problems in this area are explored and suggestions are made to resolve them.There exists a necessity for creation of the central executive authority, the main task of which should be the formation and implementation of the state policy on the protection and management of intellectual property, as well as the state body, which, on behalf of the state and in its interests, will execute the ownership rights of the objects of intellectual property rights that are in state property.
Solar System Wave Function and its Achievements
Authors: Soltani Abolfazl
Published: June 2021

Pluto, Ceres and all planets of solar system except Neptune, with a high approximation, follow a rule called Titius-Bode rule or Bode rule, which can by no means be considered as a stochastic event. This rule shows that the distance of the planets from the sun in Solar system is regulated. Here, we prove that the existence of a standing and cosine wave packet in solar system, with the wavelength λ = 0.6 AU (AU represents the distance of earth from the sun), is the reason for Bode rule. And moreover, we prove that this huge wave packet belongs to the sun. In this Article, based on the solar system wave function, we will enter into the atomic field and arrive to a new atomic model that helps us to describe many phenomena such as the normal Zeeman effect.
Wasteful Azo Dyes as a Source of Biologically Active Building Blocks
Authors: Fernandes Ana , Pinto Bruna , Bonardo Lorenzo , Royo Beatriz , Robalo M. Paula , Martins Lígia O.
Published: June 2021

In this work, an environment-friendly enzymatic strategy was developed for the valorisation of dye-containing wastewaters. We set up biocatalytic processes for the conversion of azo dyes representative of the main classes used in the textile industry into valuable aromatic compounds: aromatic amines, phenoxazinones, phenazines, and naphthoquinones. First, purified preparations of PpAzoR azoreductase efficiently reduced mordant, acid, reactive, and direct azo dyes into aromatic amines, and CotA-laccase oxidised these compounds into phenazines, phenoxazinones, and naphthoquinones. Second, whole cells containing the overproduced enzymes were utilised in the two-step enzymatic conversion of the model mordant black 9 dye into sodium 2-amino-3-oxo-3H-phenoxazine-8-sulphonate, allowing to overcome the drawbacks associated with the use of expensive purified enzymes, co-factors, or exquisite reaction conditions. Third, cells immobilised in sodium alginate allowed recycling the biocatalysts and achieving very good to excellent final phenoxazine product yields (up to 80%) in water and with less impurities in the final reaction mixtures. Finally, one-pot systems using recycled immobilised cells co-producing both enzymes resulted in the highest phenoxazinone yields (90%) through the sequential use of static and stirring conditions, controlling the oxygenation of reaction mixtures and the successive activity of azoreductase (anaerobic) and laccase (aerobic).
Non-human Primate Regulatory T Cells and Their Assessment as Cellular Therapeutics in Preclinical Transplantation Models
Authors: Thomson Angus W. , Sasaki Kazuki , Ezzelarab Mohamed B.
Published: June 2021

Non-human primates (NHP) are an important resource for addressing key issues regarding the immunobiology of regulatory T cells (Treg), their in vivo manipulation and the translation of adoptive Treg therapy to clinical application. In addition to their phenotypic and functional characterization, particularly in cynomolgus and rhesus macaques, NHP Treg have been isolated and expanded successfully ex vivo. Their numbers can be enhanced in vivo by administration of IL-2 and other cytokines. Both polyclonal and donor antigen (Ag) alloreactive NHP Treg have been expanded ex vivo and their potential to improve long-term outcomes in organ transplantation assessed following their adoptive transfer in combination with various cytoreductive, immunosuppressive and “Treg permissive” agents. In addition, important insights have been gained into the in vivo fate/biodistribution, functional stability, replicative capacity and longevity of adoptively-transferred Treg in monkeys. We discuss current knowledge of NHP Treg immunobiology, methods for their in vivo expansion and functional validation, and results obtained testing their safety and efficacy in organ and pancreatic islet transplantation models. We compare and contrast results obtained in NHP and mice and also consider prospects for future, clinically relevant studies in NHP aimed at improved understanding of Treg biology, and innovative approaches to promote and evaluate their therapeutic potential.
Protein Motifs for Proton Transfers That Build the Transmembrane Proton Gradient
Authors: Kaur Divya , Khaniya Umesh , Zhang Yingying , Gunner M. R.
Published: June 2021

Biological membranes are barriers to polar molecules, so membrane embedded proteins control the transfers between cellular compartments. Protein controlled transport moves substrates and activates cellular signaling cascades. In addition, the electrochemical gradient across mitochondrial, bacterial and chloroplast membranes, is a key source of stored cellular energy. This is generated by electron, proton and ion transfers through proteins. The gradient is used to fuel ATP synthesis and to drive active transport. Here the mechanisms by which protons move into the buried active sites of Photosystem II (PSII), bacterial RCs (bRCs) and through the proton pumps, Bacteriorhodopsin (bR), Complex I and Cytochrome c oxidase (CcO), are reviewed. These proteins all use water filled proton transfer paths. The proton pumps, that move protons uphill from low to high concentration compartments, also utilize Proton Loading Sites (PLS), that transiently load and unload protons and gates, which block backflow of protons. PLS and gates should be synchronized so PLS proton affinity is high when the gate opens to the side with few protons and low when the path is open to the high concentration side. Proton transfer paths in the proteins we describe have different design features. Linear paths are seen with a unique entry and exit and a relatively straight path between them. Alternatively, paths can be complex with a tangle of possible routes. Likewise, PLS can be a single residue that changes protonation state or a cluster of residues with multiple charge and tautomer states.
GlycanGUI: Automated Glycan Annotation and Quantification Using Glucose Unit Index
Authors: Zhang Rui , Peng Wenjing , Gautam Sakshi , Huang Yifan , Mechref Yehia , Tang Haixu
Published: June 2021

The retention time provides critical information for glycan annotation and quantification from the Liquid Chromatography Mass Spectrometry (LC-MS) data. However, the variation of the precise retention time of glycans is highly dependent on the experimental conditions such as the specific separating columns, MS instruments and/or the buffer used. This variation hampers the exploitation of retention time for the glycan annotation from LC-MS data, especially when inter-laboratory data are compared. To incorporate the retention time of glycan across experiments, Glucose Unit Index (GUI) can be computed using the dextrin ladder as internal standard. The retention time of glycans are then calibrated with respect to glucose units derived from dextrin ladders. Despite the successful application of the GUI approach, the manual calibration process is quite tedious and often error prone. In this work, we present a standalone software tool GlycanGUI, with a graphic user interface to automatically carry out the GUI-based glycan annotation/quantification and subsequent data analysis. When tested on experimental data, GlycanGUI reported accurate GUI values compared with manual calibration, and thus is ready to be used for automated glycan annotation and quantification using GUI.
On the Interaction of Gestural and Linguistic Perspective Taking
Authors: Hinterwimmer Stefan , Patil Umesh , Ebert Cornelia
Published: June 2021

In this paper, we investigate the question of whether and how perspective taking at the linguistic level interacts with perspective taking at the level of co-speech gestures. In an experimental rating study, we compared test items clearly expressing the perspective of an individual participating in the event described by the sentence with test items which clearly express the speaker’s or narrator’s perspective. Each test item was videotaped in two different versions: In one version, the speaker performed a co-speech gesture in which she enacted the event described by the sentence from a participant’s point of view (i.e. with a character viewpoint gesture). In the other version, she performed a co-speech gesture depicting the event described by the sentence as if it was observed from a distance (i.e. with an observer viewpoint gesture). Both versions of each test item were shown to participants who then had to decide which of the two versions they find more natural. Based on the experimental results we argue that there is no general need for perspective taking on the linguistic level to be aligned with perspective taking on the gestural level. Rather, there is clear preference for the more informative gesture.
Halogenases of Qarhan Salt Lake in the Qaidam Basin: Evidence From Halite Fluid Inclusions
Authors: Li Jun , Zhang Xiying , Hu Mingyue , Li Wenxia , Miao Weiliang , Yuan Xiaolong , Li Yongshou , Tang Qiliang , Han Wenxia , Ma Haizhou
Published: June 2021

The fluid inclusion composition of halite can help track chemical composition of ancient fluids and, thus, serves as a reliable index to analyze ancient brine in salt lakes. Qarhan Salt Lake (QSL) is the largest potash brine deposit in China. Although the mixing of modern river water and Ca-Cl deep water is widely accepted as potassium formation, the mixing characteristics in the time domain and driving factors of deep water are still unclear. Here, the chemical composition of fluid inclusions in primary halite samples collected from the ISL1A borehole in QSL was measured by LA-ICP-MS technology. The analysis results show that, during the formation stage of the S4 salt layer in QSL, the main potassium salt layer, the contents of Ca2+ and Sr2+ in brine increased significantly. There is evidence confirming that Ca-Cl deep water is beneficial to the enrichment of potassium and the surrounding rivers generally develop terraces. It suggests that, during the formation stage of the QSL potassium salt layer, more Ca-Cl inflow water of the northern margin supplies the salt lake, inferring that it was driven by tectonic activities. In addition, the chemical composition of halite fluid inclusions shows that there is an anomaly in geochemistry at the early stage of salt formation in QSL. By combining the time of tectonic activities, it is inferred that the anomaly is not caused by tectonic activities but maybe caused by a salt-forming event. This work indicates that deep water and tectonic movement have a huge impact on the evolution of salt lakes. Therefore, it is necessary to consider the influence of deep water and tectonic activities on the salt-forming evolution stage of salt lakes when studying the salt-forming evolution stage of salt lakes and paleoclimate by using salt lake deposition.
Metabolomic Profiling of Pregnancies With Polycystic Ovary Syndrome Identifies a Unique Metabolic Signature and Potential Predictive Biomarkers of Low Birth Weight
Authors: Diboun Ilhame , Ramanjaneya Manjunath , Ahmed Lina , Bashir Mohammed , Butler Alexandra E. , Albagha Omar , Abou-Samra Abdul Badi , Atkin Stephen L. , Mazloum Nayef A. , Elrayess Mohamed A.
Published: June 2021

Background

Polycystic ovary syndrome (PCOS) is a complex syndrome with clinical features of an endocrine/metabolic disorder. Various metabolites show significant association with PCOS; however, studies comparing the metabolic profile of pregnant women with and without PCOS are lacking. In this study, metabolomics analysis of blood samples collected from PCOS women and age and BMI matched controls in the second trimester of pregnancy was performed to identify metabolic differences between the two groups and determine their association with pregnancy outcome.

Methods

Sixteen PCOS and fifty-two healthy women in their second trimester underwent targeted metabolomics of plasma samples using tandem mass spectrometry with the Biocrates MxP® Quant 500 Kit. Linear regression models were used to identify the metabolic alterations associated with PCOS, followed by enrichment and Receiver Operating Characteristic (ROC) analyses to determine the best indicators of pregnancy outcomes.

Results

PCOS women had lower birth weight babies compared to healthy controls. As a group, systolic blood pressure (SBP) at both second trimester and at delivery negatively correlated with birth weight. Regression models indicated significant increases in the triglycerides C20:4_C34:3 and C18:2_C38:6 in the PCOS group [false discovery rate (FDR) <0.05]. Enrichment analysis revealed significant elevations in triglycerides containing arachidonic acid, linoleic acid and palmitic acid in the PCOS group. A number of indicators of baby birth weight were identified including SBP at delivery, hexosylceramide (d18:2/24:0), ceramide (d18.0/24.1) and serine, with an AUC for all predictors combined for low birth weight (≤2500grams) of 0.88 (95%CI: 0.75-1.005, p<0.001).

Conclusions

PCOS pregnancies resulted in babies with a lower birth weight, marked by a unique metabolic signature that was enriched with specific triglycerides and unsaturated fatty acids. The functional significance of these associations needs further investigation.
Circulating PD1+Vδ1+γδ T Cell Predicts Fertility in Endometrial Polyp Patients of Reproductive-Age
Authors: Li Xiao-Hong , Lu Mei-Yin , Li Yi-jia , Liu Zong-hua , Yin Zhi-nan , Liu Bin , Wu Yang-zhe
Published: June 2021

Clinically, immune cell function is correlated with pathogenesis of endometrial polyp (EP) and infertility of women of reproductive-age. However, the underlying immune cell hallmark in EP patients remains unclear. Here, we focused on analyzing circulating immune cells, and attempted to reveal the correlation between peripheral immune cell functional phenotypes and fertility in EP patients. Through comparison of circulating CD4+/CD8+ T cells, NK cells, and γδ T cells between 64 EP patients and 68 healthy females, we found that γδ T cells, but not CD4+/CD8+ T cells and NK cells, were immunologically correlated with conception rate and conception interval time. Specifically, total γδ T cells and the Vδ1+PD1+ γδ T subpopulation decreased whereas the Vδ1/Vδ2 ratio increased in EP patients compared to healthy controls. Moreover, the patients with the higher Vδ1/Vδ2 ratio (median value equals 1.04) had a poorer fertility and longer interval time of conception (210 days versus 158 days for control). Meanwhile, higher Vδ1+PD1+ γδ T cell proportion (median equals 15.7) was positively correlative with both higher conception rate and shortened median conception interval time (130 days for Vδ1+PD1high group versus 194 days for Vδ1+PD1low group). Notably, in healthy controls, both Vδ1/Vδ2 ratio and Vδ1+PD1+ γδ T cell proportion correlated with pregnancy rate oppositely, comparing to EP patients. Together, our results suggested that imbalanced γδ T cell population occurred in EP patients, and that Vδ1/Vδ2 ratio and PD-1 expression of Vδ1+ γδ T cells could be potentially developed into valuable predictors for fertility in EP patients.
Cytoreductive Nephrectomy Promoted Abscopal Effect of Camrelizumab Combined With Radiotherapy for Metastatic Renal Cell Carcinoma: A Case Report and Review of the Literature
Authors: Wu Min , Liu Jie , Seery Samuel , Meng Xue , Yue Jinbo
Published: June 2021

There is little evidence around Camrelizumab combined with cytoreductive nephrectomy (CN) and radiotherapy (RT) as a treatment option for metastatic renal cell carcinoma (mRCC). The influence of CN on immune responses and the abscopal effect are not well understood. In this paper, we report a case of anti-programmed cell death-1 (PD-1) treated with combined RT once CN reduced the primary tumor burden (TB). This patient also encountered an increased response to targeted radiotherapy after immune resistance. We also observed a macrophage-to-lymphocyte ratio (MLR) peak, which may be correlated with subsequent pseudoprogression after thoracic radiotherapy. Consequently, even with the disease, this patient has remained stable. This peculiar instance suggests there is a need to investigate the underlying mechanisms of CN in promoting the abscopal effect during immunotherapy when combined with RT. It also suggests that there is a need for further investigation into the role of RT in overcoming immune resistance, and the value of MLR in predicting pseudoprogression. We hypothesize that a heavy tumor burden might suppress the abscopal effect, thereby ensuring that CN promotes it. However, radiotherapy may overcome immune resistance during oligoprogression.
An IRF1-IRF4 Toggle-Switch Controls Tolerogenic and Immunogenic Transcriptional Programming in Human Langerhans Cells
Authors: Davies James , Vallejo Andres F. , Sirvent Sofia , Porter Gemma , Clayton Kalum , Qumbelo Yamkela , Stumpf Patrick , West Jonathan , Gray Clive M. , Chigorimbo-Murefu Nyaradzo T. L. , MacArthur Ben , Polak Marta E.
Published: June 2021

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF-alpha, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF-alpha enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.
A Novel Orthotopic Implantation Technique for Osteosarcoma Produces Spontaneous Metastases and Illustrates Dose-Dependent Efficacy of B7-H3-CAR T Cells
Authors: Talbot Lindsay Jones , Chabot Ashley , Funk Amy , Nguyen Phuong , Wagner Jessica , Ross Aaron , Tillman Heather , Davidoff Andrew , Gottschalk Stephen , DeRenzo Christopher
Published: June 2021

The outcome for metastatic pediatric osteosarcoma (OS) remains poor. Thus, there is an urgent need to develop novel therapies, and immunotherapy with CAR T cells has the potential to meet this challenge. However, there is a lack of preclinical models that mimic salient features of human disease including reliable development of metastatic disease post orthotopic OS cell injection. To overcome this roadblock, and also enable real-time imaging of metastatic disease, we took advantage of LM7 OS cells expressing firefly luciferase (LM7.ffLuc). LM7.ffLuc were implanted in a collagen mesh into the tibia of mice, and mice reliably developed orthotopic tumors and lung metastases as judged by bioluminescence imaging and histopathological analysis. Intratibial implantation also enabled surgical removal by lower leg amputation and monitoring for metastases development post-surgery. We then used this model to evaluate the antitumor activity of CAR T cells targeting B7-H3, an antigen that is expressed in a broad range of solid tumors including OS. B7-H3-CAR T cells had potent antitumor activity in a dose-dependent manner and inhibited the development of pulmonary metastases resulting in a significant survival advantage. In contrast T cells expressing an inactive B7-H3-CAR had no antitumor activity. Using unmodified LM7 cells also enabled us to demonstrate that B7-H3-CAR T cells traffic to orthotopic tumor sites. Hence, we have developed an orthotopic, spontaneously metastasizing OS model. This model may improve our ability not only to predict the safety and efficacy of current and next generation CAR T cell therapies but also other treatment modalities for metastatic OS.
Cardiovascular Safety of Febuxostat and Allopurinol in Hyperuricemic Patients With or Without Gout: A Network Meta-Analysis
Authors: Zhang Shengzhao , Xu Ting , Shi Qingyang , Li Sheyu , Wang Ling , An Zhenmei , Su Na
Published: June 2021

Background: Hyperuricemia is a common metabolic disease and has become a public health problem because of its increasing prevalence and association with comorbidities. Allopurinol and febuxostat are recommended as the first-line treatments for hyperuricemia and gout. But cardiovascular safety between febuxostat and allopurinol is still controversial. The purpose of this study is to compare the cardiovascular safety of XOIs and placebo in hyperuricemic patients with or without gout.

Methods: PubMed, Embase via OVID, Cochrane Library, CNKI, Wanfang, and VIP were searched from their earliest records to February 8th 2021. ClinicalTrials.gov was also searched for unpublished data. The reference lists of included studies and relevant review articles investigating the cardiovascular safety of XOIs in hyperuricemia patients are screened for potentially eligible studies. Randomized controlled trials (RCTs) evaluating allopurinol (100~900 mg/d), febuxostat (20~120 mg/d), or placebo for hyperuricemia were included. The outcomes were incidence of MACE, non-fatal MI, non-fatal stroke, and cardiovascular death. We conducted a Bayesian random-effects network meta-analysis on the included randomized controlled trials using the Markov Chain Monte Carlo simulation method. The grading of recommendations assessment, development, and evaluation (GRADE) approach was used to assesses the certainty of the evidence.

Results: Ten RCTs with 18,004 participants were included. The network estimates showed that there was no significant difference observed among febuxostat, allopurinol, and placebo regarding outcomes. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and SUCRA showed that compared to placebo, febuxostat, and allopurinol might prevent adverse cardiovascular events.

Conclusion: Febuxostat is not associated with increasing risk of adverse cardiovascular events compared to allopurinol; and compared to placebo, whether febuxostat and allopurinol reduce the risk of adverse cardiovascular events remains uncertain.
Black Soldier Fly Larvae Can Effectively Degrade Oxytetracycline Bacterial Residue by Means of the Gut Bacterial Community
Authors: Liu Cuncheng , Yao Huaiying , Wang Cunwen
Published: June 2021

Antibiotic bacterial residue is a unique hazardous waste, and its safe and effective disposal has always been a concern of pharmaceutical enterprises. This report presents the effective treatment of hazardous waste—antibiotic bacterial residue—by black soldier fly larvae (larvae), oxytetracycline bacterial residue (OBR), and soya meal with mass ratios of 0:1 (soya), 1:20 (OBRlow), and 1:2 (OBRhigh), which were used as substrates for larval bioconversion. Degradation of OBR and oxytetracycline, the bacterial community, the incidence of antibiotic resistance genes (ARGs) and the bacterial function in the gut were examined. When the larvae were harvested, 70.8, 59.3, and 54.5% of the substrates had been consumed for soya, OBRlow and OBRhigh; 65.9 and 63.3% of the oxytetracycline was degraded effectively in OBRlow and OBRhigh, respectively. The larval bacterial communities were affected by OBR, abundant and various ARGs were discovered in the gut, and metabolism was the major predicted function of the gut. These findings show that OBR can be digested and converted by larvae with gut bacteria, and the larvae can be used as a bioremediation tool for the treatment of hazardous waste. Finally, the abundant ARGs in the gut deserve further attention and consideration in environmental health risk assessments.
Enrichment of Autotrophic Denitrifiers From Anaerobic Sludge Using Sulfurous Electron Donors
Authors: Carboni M. F. , Florentino A. P. , Costa R. B. , Zhan X. , Lens P. N. L.
Published: June 2021

Graphical Abstract
Strength Lies in Diversity: How Community Diversity Limits Salmonella Abundance in the Chicken Intestine
Authors: Pedroso Adriana A. , Lee Margie D. , Maurer John J.
Published: June 2021

The transfer of the intestinal microbiota from adult to juvenile animals reducesSalmonellaprevalence and abundance. The mechanism behind this exclusion is unknown, however, certain member species may exclude or promote pathogen colonization andSalmonellaabundance in chickens correlates with intestinal community composition. In this study, newly hatched chicks were colonized withSalmonellaTyphimurium and 16S rRNA libraries were generated from the cecal bacterial community at 21, 28, 35, and 42 days of age.Salmonellawas quantified by real-time PCR. Operational taxonomic units (OTUs) were assigned, and taxonomic assignments were made, using the Ribosomal Database Project. Bacterial diversity was inversely proportional to theSalmonellaabundance in the chicken cecum (p< 0.01). In addition, cecal communities with no detectableSalmonella(exclusive community) displayed an increase in the abundance of OTUs related to specific clostridial families (Ruminococcaceae,Eubacteriaceae, andOscillospiraceae), genera (FaecalibacteriumandTuricibacter) and member species (Ethanoligenens harbinense,Oscillibacter ruminantium, andFaecalibacterium prausnitzii). For cecal communities with highSalmonellaabundance (permissive community), there was a positive correlation with the presence of unclassifiedLachnospiraceae, clostridial generaBlautiaand clostridial speciesRoseburia hominis,Eubacterium biforme, andRobinsoniella peoriensis. These findings strongly support the link between the intestinal bacterial species diversity and the presence of specific member species withSalmonellaabundance in the chicken ceca. Exclusive bacterial species could prove effective as direct-fed microbials for reducingSalmonellain poultry while permissive species could be used to predict which birds will be super-shedders.
Metabolomic Analysis of Hexagenid Mayflies Exposed to Sublethal Concentrations of Naphthenic Acid
Authors: Pomfret Sarah M. , Brua Robert B. , Milani Danielle , Yates Adam G.
Published: June 2021

The oil sands region in northeastern Alberta, Canada contain approximately 165 billion barrels of oil making it the third largest oil reserves in the world. However, processing of extracted bitumen generates vast amounts of toxic byproduct known as oil sands process waters. Naphthenic acids and associated sodium naphthenate salts are considered the primary toxic component of oil sands process waters. Although a significant body of work has been conducted on naphthenic acid toxicity at levels comparable to what is observed in current oil sands process waters, it is also important to understand any impacts of exposure to sublethal concentrations. We conducted a microcosm study using the mayflyHexageniaspp.to identify sublethal impacts of naphthenic acid exposure on the survival, growth, and metabolome across a concentration gradient (0–100 μg L−1) of sodium naphthenate. Nuclear magnetic resonance-based metabolomic analyses were completed on both the polar and lipophilic extracted fractions of whole organism tissue. We observed a positive relationship between sodium naphthenate concentration and mean principal component score of the first axis of the polar metabolome indicating a shift in the metabolome with increasing naphthenic acid exposure. Eleven metabolites correlated with increased naphthenic acid concentration and included those involved in energy metabolism and apoptosis regulation. Survival and growth were both high and did not differ among concentrations, with the exception of a slight increase in mortality observed at the highest concentration. Although lethal concentrations of naphthenic acids in other studies are higher (150–56,200 μg L−1), our findings suggest that physiological changes in aquatic invertebrates may begin at substantially lower concentrations. These results have important implications for the release of naphthenic acids into surface waters in the Alberta oil sands region as an addition of even small volumes of oil sands process waters could initiate chronic effects in aquatic organisms. Results of this research will assist in the determination of appropriate discharge thresholds should oil sands process waters be considered for environmental release.
Alix: A Candidate Serum Biomarker of Alzheimer’s Disease
Authors: Sun Yingni , Hua Jin , Chen Gen , Li Jianjie , Yang Jiateng , Gao Hongwei
Published: June 2021

Alzheimer’s disease (AD) is the most common fatal neurodegenerative disease of the elderly worldwide. The identification of AD biomarkers will allow for earlier diagnosis and thus earlier intervention. The aim of this study was to find such biomarkers. It was observed that the expression of Alix was significantly decreased in brain tissues and serum samples from AD patients compared to the controls. A significant correlation between Alix levels and cognitive decline was observed (r = 0.80; p < 0.001) as well as a significant negative correlation between Alix and Aβ40 in serum levels (r =−0.60, p < 0.001). The receiver operating characteristic curve (ROC) analysis showed the area under the curve (AUC) of Alix was 0.80, and the optimal cut-off point of 199.5 pg/ml was selected with the highest sum of sensitivity and specificity. The diagnostic accuracy for serum Alix was 74%, with 76% sensitivity and 71% specificity respectively, which could differentiate AD from controls. In addition, the expression of Alix was found to be significantly decreased in AD compared to vascular dementia (VaD). ROC analysis between AD and VaD showed that the AUC was 0.777, which could be indicative of the role of serum Alix as a biomarker in the differential diagnosis between AD and VaD. Most surprisingly, the decreased expression of Alix was attenuated after the treatment of Memantine in different AD animal models. In conclusion, our results indicate the possibility of serum Alix as a novel and non-invasive biomarker for AD for the first time.
Microglial Implications in SARS-CoV-2 Infection and COVID-19: Lessons From Viral RNA Neurotropism and Possible Relevance to Parkinson’s Disease
Authors: Awogbindin Ifeoluwa O. , Ben-Azu Benneth , Olusola Babatunde A. , Akinluyi Elizabeth T. , Adeniyi Philip A. , Di Paolo Therese , Tremblay Marie-Ève
Published: June 2021

Since December 2019, humankind has been experiencing a ravaging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, the second coronavirus pandemic in a decade after the Middle East respiratory syndrome coronavirus (MERS-CoV) disease in 2012. Infection with SARS-CoV-2 results in Coronavirus disease 2019 (COVID-19), which is responsible for over 3.1 million deaths worldwide. With the emergence of a second and a third wave of infection across the globe, and the rising record of multiple reinfections and relapses, SARS-CoV-2 infection shows no sign of abating. In addition, it is now evident that SARS-CoV-2 infection presents with neurological symptoms that include early hyposmia, ischemic stroke, meningitis, delirium and falls, even after viral clearance. This may suggest chronic or permanent changes to the neurons, glial cells, and/or brain vasculature in response to SARS-CoV-2 infection or COVID-19. Within the central nervous system (CNS), microglia act as the central housekeepers against altered homeostatic states, including during viral neurotropic infections. In this review, we highlight microglial responses to viral neuroinfections, especially those with a similar genetic composition and route of entry as SARS-CoV-2. As the primary sensor of viral infection in the CNS, we describe the pathogenic and neuroinvasive mechanisms of RNA viruses and SARS-CoV-2 vis-à-vis the microglial means of viral recognition. Responses of microglia which may culminate in viral clearance or immunopathology are also covered. Lastly, we further discuss the implication of SARS-CoV-2 CNS invasion on microglial plasticity and associated long-term neurodegeneration. As such, this review provides insight into some of the mechanisms by which microglia could contribute to the pathophysiology of post-COVID-19 neurological sequelae and disorders, including Parkinson’s disease, which could be pervasive in the coming years given the growing numbers of infected and re-infected individuals globally.
Analysing Intercellular Communication in Astrocytic Networks Using “Astral”
Authors: Dzyubenko Egor , Prazuch Wojciech , Pillath-Eilers Matthias , Polanska Joanna , Hermann Dirk M.
Published: June 2021

Astrocytic networks are critically involved in regulating the activity of neuronal networks. However, a comprehensive and ready-to-use data analysis tool for investigating functional interactions between the astrocytes is missing. We developed the novel software package named “Astral” to analyse intercellular communication in astrocytic networks based on live-cell calcium imaging. Our method for analysing calcium imaging data does not require the assignment of regions of interest. The package contains two applications: the core processing pipeline for detecting and quantifying Ca++ events, and the auxiliary visualization tool for controlling data quality. Our method allows for the network-wide quantification of Ca++ events and the analysis of their intercellular propagation. In a set of proof-of-concept experiments, we examined Ca++ events in flat monolayers of primary astrocytes and confirmed that inter-astrocytic interactions depend on the permeability of gap junctions and connexin hemichannels. The Astral tool is particularly useful for studying astrocyte-neuronal interactions on the network level. We demonstrate that compared with purely astrocytic cultures, spontaneous generation of Ca++ events in astrocytes that were co-cultivated with neurons was significantly increased. Interestingly, the increased astrocytic Ca++ activity after long-term co-cultivation with neurons was driven by the enhanced formation of gap junctions and connexin hemichannels but was not affected by silencing neuronal activity. Our data indicate the necessity for systematic investigation of astrocyte-neuronal interactions at the network level. For this purpose, the Astral software offers a powerful tool for processing and quantifying calcium imaging data.
Exclusion of the Possibility of “False Ripples” From Ripple Band High-Frequency Oscillations Recorded From Scalp Electroencephalogram in Children With Epilepsy
Authors: Kobayashi Katsuhiro , Shibata Takashi , Tsuchiya Hiroki , Akiyama Tomoyuki
Published: June 2021

Aim

Ripple-band epileptic high-frequency oscillations (HFOs) can be recorded by scalp electroencephalography (EEG), and tend to be associated with epileptic spikes. However, there is a concern that the filtration of steep waveforms such as spikes may cause spurious oscillations or “false ripples.” We excluded such possibility from at least some ripples by EEG differentiation, which, in theory, enhances high-frequency signals and does not generate spurious oscillations or ringing.

Methods

The subjects were 50 pediatric patients, and ten consecutive spikes during sleep were selected for each patient. Five hundred spike data segments were initially reviewed by two experienced electroencephalographers using consensus to identify the presence or absence of ripples in the ordinary filtered EEG and an associated spectral blob in time-frequency analysis (Session A). These EEG data were subjected to numerical differentiation (the second derivative was denoted as EEG″). The EEG″ trace of each spike data segment was shown to two other electroencephalographers who judged independently whether there were clear ripple oscillations or uncertain ripple oscillations or an absence of oscillations (Session B).

Results

In Session A, ripples were identified in 57 spike data segments (Group A-R), but not in the other 443 data segments (Group A-N). In Session B, both reviewers identified clear ripples (strict criterion) in 11 spike data segments, all of which were in Group A-R (p < 0.0001 by Fisher’s exact test). When the extended criterion that included clear and/or uncertain ripples was used in Session B, both reviewers identified 25 spike data segments that fulfilled the criterion: 24 of these were in Group A-R (p < 0.0001).

Discussion

We have demonstrated that real ripples over scalp spikes exist in a certain proportion of patients. Ripples that were visualized consistently using both ordinary filters and the EEG″ method should be true, but failure to clarify ripples using the EEG″ method does not mean that true ripples are absent.

Conclusion

The numerical differentiation of EEG data provides convincing evidence that HFOs were detected in terms of the presence of such unusually fast oscillations over the scalp and the importance of this electrophysiological phenomenon.
A Quick and Easy Way to Estimate Entropy and Mutual Information for Neuroscience
Authors: Zbili Mickael , Rama Sylvain
Published: June 2021

Calculations of entropy of a signal or mutual information between two variables are valuable analytical tools in the field of neuroscience. They can be applied to all types of data, capture non-linear interactions and are model independent. Yet the limited size and number of recordings one can collect in a series of experiments makes their calculation highly prone to sampling bias. Mathematical methods to overcome this so-called “sampling disaster” exist, but require significant expertise, great time and computational costs. As such, there is a need for a simple, unbiased and computationally efficient tool for estimating the level of entropy and mutual information. In this article, we propose that application of entropy-encoding compression algorithms widely used in text and image compression fulfill these requirements. By simply saving the signal in PNG picture format and measuring the size of the file on the hard drive, we can estimate entropy changes through different conditions. Furthermore, with some simple modifications of the PNG file, we can also estimate the evolution of mutual information between a stimulus and the observed responses through different conditions. We first demonstrate the applicability of this method using white-noise-like signals. Then, while this method can be used in all kind of experimental conditions, we provide examples of its application in patch-clamp recordings, detection of place cells and histological data. Although this method does not give an absolute value of entropy or mutual information, it is mathematically correct, and its simplicity and broad use make it a powerful tool for their estimation through experiments.
Role of Cortisol and Testosterone in Risky Decision-Making: Deciphering Male Decision-Making in the Iowa Gambling Task
Authors: Singh Varsha
Published: June 2021

Despite the widely observed high risk-taking behaviors in males, studies using the Iowa gambling task (IGT) have suggested that males choose safe long-term rewards over risky short-term rewards. The role of sex and stress hormones in male decision-making is examined in the initial uncertainty and the latter risk phase of the IGT. The task was tested at peak hormone activity, with breath counting to facilitate cortisol regulation and its cognitive benefits. Results from IGT decision-making before and after counting with saliva samples from two all-male groups (breath vs. number counting) indicated that cortisol declined independent of counting. IGT decision-making showed phase-specific malleability: alteration in the uncertainty phase and stability in the risk phase. Working memory showed alteration, whereas inhibition task performance remained stable, potentially aligning with the phase-specific demands of working memory and inhibition. The results of hierarchical regression for the uncertainty and risk trials indicated that testosterone improved the model fit, cortisol was detrimental for decision-making in uncertainty, and decision-making in the risk trials was benefitted by testosterone. Cortisol regulation accentuated hormones’ phase-specific effects on decision-making. Aligned with the dual-hormone hypothesis, sex, and stress hormones might jointly regulate male long-term decision-making in the IGT.
Mammalian Neuronal mRNA Transport Complexes: The Few Knowns and the Many Unknowns
Authors: Rodrigues Elsa C. , Grawenhoff Julia , Baumann Sebastian J. , Lorenzon Nicola , Maurer Sebastian P.
Published: June 2021

Hundreds of messenger RNAs (mRNAs) are transported into neurites to provide templates for the assembly of local protein networks. These networks enable a neuron to configure different cellular domains for specialized functions. According to current evidence, mRNAs are mostly transported in rather small packages of one to three copies, rarely containing different transcripts. This opens up fascinating logistic problems: how are hundreds of different mRNA cargoes sorted into distinct packages and how are they coupled to and released from motor proteins to produce the observed mRNA distributions? Are all mRNAs transported by the same transport machinery, or are there different adaptors or motors for different transcripts or classes of mRNAs? A variety of often indirect evidence exists for the involvement of proteins in mRNA localization, but relatively little is known about the essential activities required for the actual transport process. Here, we summarize the different types of available evidence for interactions that connect mammalian mRNAs to motor proteins to highlight at which point further research is needed to uncover critical missing links. We further argue that a combination of discovery approaches reporting direct interactions, in vitro reconstitution, and fast perturbations in cells is an ideal future strategy to unravel essential interactions and specific functions of proteins in mRNA transport processes.
Conceptual and Methodological Pitfalls in Experimental Studies: An Overview, and the Case of Alzheimer’s Disease
Authors: Puzzo Daniela , Conti Fiorenzo
Published: June 2021

The main goal of scientific research is to uncover new knowledge to understand reality. In the field of life sciences, the aim of translational research—to transfer results “from bench to bedside”—has to contend with the problem that the knowledge acquired at the “bench” is often not reproducible at the “bedside,” raising the question whether scientific discoveries truly mirror the real world. As a result, researchers constantly struggle to overcome the dichotomy between methodological problems and expectations, as funding agencies and industries demand expandable and quick results whereas patients, who are uninterested in the epistemological dispute, only ask for an effective cure. Despite the numerous attempts made to address reproducibility and reliability issues, some essential pitfalls of scientific investigations are often overlooked. Here, we discuss some limitations of the conventional scientific method and how researcher cognitive bias and conceptual errors have the potential to steer an experimental study away from the search for thevera causaof a phenomenon. As an example, we focus on Alzheimer’s disease research and on some problems that may have undermined most of the clinical trials conducted to investigate it.