bluuebunny/crossref_metadata_2025 huggingface dataset:
POLISH-LATIN MACARONIC MIXTURE AND ‘SLAVONIC-RUTHENIAN’ LANGUAGE
Authors: Kyselov Roman
Published: August 2022

The paper focuses on the genesis of Ukrainian-Church Slavonic hybrid language, popular at the end of the 17th and during the 18th century among Ukrainian writers. Usually, this new love for the Church Slavonic, which led to the emergence of a hybrid literary form, is explained by two factors: piety to the Church Slavonic and the influence of Russian tradition, where the practice of mixing Church Slavonic with the vernacular was stable and almost unalterable. According to the paper’s author, the use of Church Slavonic as a religious and cultural marker, which had status advantages, was not a major and independent factor in the development of this practice. Th e poor knowledge of Church Slavonic in society and the lack of efforts to learn it, even among priests, undermine the notion that the sacralization of this language could lead to the creation of hybrid forms by itself. Th e Russian influence was not crucial as well, which is confirmed, in particular, by the proliferation of similar language use in the Right Bank Ukraine, free from tendencies of russification. The so-called ‘slovianoruska mova’ (Slavonic-Ruthenian language) was stimulated above all by the Latin-Polish macaronic mix, which, due to the local tradition of using such a language, and, importantly, through education, has been established in the public consciousness as a norm. The rhetoric courses and the practice of delivering occasional orations in Polish ensured the development of the trend. Therefore, both in Ukraine under Russian rule and in the Right Bank Ukraine within the Polish-Lithuanian Commonwealth, the creation of hybrid Ukrainian-Church Slavonic texts was just another way of actualizing one’s mental habit, produced by the regular use of the Polish-Latin language mixture.
A study of real-gas effect on SCO2 compressor performance using similitude method
Authors: Xu Pengcheng , Zou Zhengping
Published: August 2022

The drastic property changes of supercritical CO2 (SCO2) make the performance of SCO2 compressors different from that of conventional compressors. This study deals with the real-gas effect on the SCO2 compressor performance by theoretical analysis and numerical validation. A set of similitude parameters are firstly deduced by dimensional analysis. Then keeping these parameters unchanged, the performance variation of a SCO2 compressor is analyzed when the inlet flow condition changes in a certain temperature and pressure range. Results show that the proposed similitude method could accurately reflect the variation trend of SCO2 compressor performance under different inflow conditions. The real-gas effect enables the compressor to obtain higher pressure ratio with lower temperature rise. It is recommended that the inlet temperature of SCO2 compressor should be as close as possible to the critical temperature and the pressure should be about 150 kPa higher than the corresponding pseudo-critical pressure at the same temperature.
Perspectives on current models of Friedreich’s ataxia
Authors: Kelekçi Simge , Yıldız Abdullah Burak , Sevinç Kenan , Çimen Deniz Uğurlu , Önder Tamer
Published: August 2022

Friedreich’s ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.
Carbon quantum dots: An environmentally friendly and valued approach to sludge disposal
Authors: Rossi Bruno L. , Andrade Cláudia M. B. , Therézio Eralci M. , Ramos Romildo J. , Vasconcelos Leonardo G. , Terezo Ailton J. , De Siqueira Adriano B.
Published: August 2022

Sewage sludge, produced daily and inherent to urban development, presents problems of disposal that are still challenging today. Its disposal still offers palliative solutions, where the final destination is generally in landfills or, restrictively, to use in agriculture. The synthesis of carbon quantum dots (CQDs) from sewage sludge is a better alternative to use the stock of organic material present in the sludge. The present work aims to produce Carbon quantum dots (CQDs) using principles of green chemistry and to use an alternative raw material intrinsic stock of carbon present in sewage sludge, making its final disposal more sustainable. The material obtained has a core structure mainly composed of sp2 carbon and nitrogen. The surface functional groups containing sulfur, nitrogen, and oxygen of CQDs were investigated using FTIR and TG/DSC coupled FTIR techniques. The CQDs showed a luminescence decay time equivalent to fluorescent compounds and with satisfying quantum yield since no passive/oxidizing agent or material purification process was used. The photoluminescence spectroscopy analysis showed that the CDQs excitation λmax was at 360 nm and caused a λmax emission at 437 nm (CQDsa) and 430 nm (CQDsb). The CQDs obtained showed sizes of 9.69 ± 2.64 nm (CQDsa) and 10.92 ± 2.69 nm (CQDsb). In vitro experiments demonstrated the uptake of CQDs by the endothelial cell line EAhy 926 and their nontoxicity. However, the production of CQDs can be used for the sustainable disposal of sewage sludge.
The MELD-XI score predicts 3-year mortality in patients with chronic heart failure
Authors: Lin Zebin , Liu Xia , Xiao Li , Li Yin , Qi Chenlu , Song Siqi , Zhao Yiping , Zou Lili
Published: August 2022

Objectives

The relationship between the MELD-XI score, a modified version of the MELD score, and the long-term prognosis of hospitalized patients with chronic heart failure is unclear. The aim of this study was to determine the long-term prognostic relationship of MELD-XI score in patients with chronic heart failure.

Methods

This is a retrospective cohort study of patients with chronic heart failure who were initially hospitalized in the Second Affiliated Hospital of Chongqing Medical University from February 2017 to December 2017. The primary clinical outcome was all-cause mortality within 3 years. Cox regression and lasso regression were used to screen variables and build a prognostic model. Combined with the MELD-XI score, the final model was adjusted, and the predictive ability of the model was evaluated. Survival curves were estimated using the Kaplan–Meier method and compared by the log rank test.

Results

A total of 400 patients with chronic heart failure were included (median age 76 years, 51.5% female). During the 3-year follow-up period, there were 97 all-cause deaths, including 63 cardiac deaths. Six characteristic variables (NT-proBNP, BUN, RDW CV, Na+ and prealbumin) were selected by univariate Cox regression and lasso regression. Survival analysis results showed that elevated MELD-XI score at baseline predicted the risk of all-cause mortality at 3 years in patients (HR 3.19, 95% CI 2.11–4.82, P < 0.001; HRadjusted 1.79, 95% CI 1.09–2.92, P = 0.020). Subgroup analysis showed that MELD-XI score still had prognostic value in the subgroup without chronic kidney disease (HR 3.30 95%CI 2.01–5.42 P < 0.001; HRadjusted 1.88 95%CI 1.06–3.35 P = 0.032, P for interaction = 0.038).

Conclusions

This study proved that the MELD-XI score at admission was related to the poor prognosis of hospitalized patients with chronic heart failure within 3 years.
The semi-automatic classification of an open-ended question on panel survey motivation and its application in attrition analysis
Authors: Haensch Anna-Carolina , Weiß Bernd , Steins Patricia , Chyrva Priscilla , Bitz Katja
Published: August 2022

In this study, we demonstrate how supervised learning can extract interpretable survey motivation measurements from a large number of responses to an open-ended question. We manually coded a subsample of 5,000 responses to an open-ended question on survey motivation from the GESIS Panel (25,000 responses in total); we utilized supervised machine learning to classify the remaining responses. We can demonstrate that the responses on survey motivation in the GESIS Panel are particularly well suited for automated classification, since they are mostly one-dimensional. The evaluation of the test set also indicates very good overall performance. We present the pre-processing steps and methods we used for our data, and by discussing other popular options that might be more suitable in other cases, we also generalize beyond our use case. We also discuss various minor problems, such as a necessary spelling correction. Finally, we can showcase the analytic potential of the resulting categorization of panelists' motivation through an event history analysis of panel dropout. The analytical results allow a close look at respondents' motivations: they span a wide range, from the urge to help to interest in questions or the incentive and the wish to influence those in power through their participation. We conclude our paper by discussing the re-usability of the hand-coded responses for other surveys, including similar open questions to the GESIS Panel question.
A systematic review and Meta-analysis of urinary extracellular vesicles proteome in diabetic nephropathy
Authors: Ding Xiaonan , Wang Xiaochen , Du Junxia , Han Qiuxia , Zhang Dong , Zhu Hanyu
Published: August 2022

Diabetic nephropathy (DN) is a major microvascular complication of both type 1 and type 2 diabetes mellitus and is the most frequent cause of end-stage renal disease with an increasing prevalence. Presently there is no non-invasive method for differential diagnosis, and an efficient target therapy is lacking. Extracellular vesicles (EV), including exosomes, microvesicles, and apoptotic bodies, are present in various body fluids such as blood, cerebrospinal fluid, and urine. Proteins in EV are speculated to be involved in various processes of disease and reflect the original cells’ physiological states and pathological conditions. This systematic review is based on urinary extracellular vesicles studies, which enrolled patients with DN and investigated the proteins in urinary EV. We systematically reviewed articles from the PubMed, Embase, Web of Science databases, and China National Knowledge Infrastructure (CNKI) database until January 4, 2022. The article quality was appraised according to the Newcastle-Ottawa Quality Assessment Scale (NOS). The methodology of samples, isolation and purification techniques of urinary EV, and characterization methods are summarized. Molecular functions, biological processes, and pathways were enriched in all retrievable urinary EV proteins. Protein-protein interaction analysis (PPI) revealed pathways of potential biomarkers. A total of 539 articles were retrieved, and 13 eligible records were enrolled in this systematic review and meta-analysis. And two studies performed mass spectrometry to obtain the proteome profile. Two of them enrolled only T1DM patients, two studies enrolled both patients with T1DM and T2DM, and other the nine studies focused on T2DM patients. In total 988 participants were enrolled, and DN was diagnosed according to UACR, UAER, or decreased GFR. Totally 579 urinary EV proteins were detected and 28 of them showed a potential value to be biomarkers. The results of bioinformatics analysis revealed that urinary EV may participate in DN through various pathways such as angiogenesis, biogenesis of EV, renin-angiotensin system, fluid shear stress and atherosclerosis, collagen degradation, and immune system. Besides that, it is necessary to report results compliant with the guideline of ISEV, in orderto assure repeatability and help for further studies. This systematic review concordance with previous studies and the results of meta-analysis may help to value the methodology details when urinary EV proteins were reported, and also help to deepen the understanding of urinary EV proteins in DN.
Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue
Authors: Klein Hazebroek Marlou , Keipert Susanne
Published: August 2022

Metabolic diseases represent the major health burden of our modern society. With the need of novel therapeutic approaches, fibroblast growth factor 21 (FGF21) is a promising target, based on metabolic improvements upon FGF21 administration in mice and humans. Endogenous FGF21 serum levels, however, are increased during obesity-related diseases, suggesting the development of FGF21 resistance during obesity and thereby lowering FGF21 efficacy. In uncoupling protein 1 knockout (UCP1 KO) mice, however, elevated endogenous FGF21 levels mediate resistance against diet-induced obesity. Here, we show that after long-term high fat diet feeding (HFD), circulating FGF21 levels become similarly high in obese wildtype and obesity-resistant UCP1 KO mice, suggesting improved FGF21 sensitivity in UCP1 KO mice. To test this hypothesis, we injected FGF21 after long-term HFD and assessed the metabolic and molecular effects. The UCP1 KO mice lost weight directly upon FGF21 administration, whereas body weights of WT mice resisted weight loss in the initial phase of the treatment. The FGF21 treatment induced expression of liver Pck1, a typical FGF21-responsive gene, in both genotypes. In iWAT, FGF21-responsive genes were selectively induced in UCP1 KO mice, strongly associating FGF21-sensitivity in iWAT with healthy body weights. Thus, these data support the concept that FGF21-sensitivity in adipose tissue is key for metabolic improvements during obesogenic diets.
Epigenetics of functional hypothalamic amenorrhea
Authors: Fontana L. , Garzia E. , Marfia G. , Galiano V. , Miozzo M.
Published: August 2022

Functional hypothalamic amenorrhea (FHA) is a temporary infertility characterized by the suppression of the hypothalamic–pituitary–gonadal (HPG) axis, induced by the inhibition of the hypothalamic pulsatile secretion of the gonadotropin-releasing hormone (GnRH), in the presence of stressors, including eating disorders, excessive exercise, and psychological distress. Although the stressful factors that may lead to FHA are well-established, little is known about the inter-individual variability in response to stress and the consequent inhibition of the HPG axis. Not all women, indeed, manifest FHA in presence of stressful conditions. Recent studies highlighted a genetic contribution to FHA. Rare or polymorphic variants in genes that control the development and/or function of GnRH neurons may contribute, indeed, to the adaptability of the reproductive axis to stress factors. Also epigenetic changes have been associated with different pathways involved in the HPG axis and therefore, take part in FHA and confer a personal predisposition to anovulation consequent to a stressful event, or represent biological markers of response to stress. This review summarizes recent advances in the identification of the contribution of (epi)genetics to FHA and to long-term complications of functional amenorrhea, and reports insights into the involvement of additional genetic loci in FHA development on the bases of the clinical and molecular overlap with other gynecological and/or psychological conditions. Finally, we describe the promising application of induced pluripotent stem cells (iPSCs) as a new approach to investigate the molecular pathways involved in FHA.
The study of the relevance of macro- and microelements in the hair of young wrestlers depending on the style of wrestling
Authors: Zaborova Victoria , Zolnikov Oxana , Dzhakhaya Natiya , Bueverova Elena , Sedova Alla , Kurbatova Anastasia , Putilo Victor , Yakovleva Maria , Shantyr Igor , Kastyro Igor , Ozimek Mariusz , Korolev Dmitry , Krikheli Natella , Gurevich Konstantin , Heinrich Katie M.
Published: August 2022

While participating in an intensive training process, the athlete’s body requires not only energy, but also specific macro- and microelements. The purpose of this study was to show the meaning of monitoring the level of mineral trace elements in athletes-wrestlers during physical activity. As an experimental group, 66 male wrestlers aged 18-20 years with at least 3 years of intensive wrestling experience were examined. The control group consisted of 92 young cadets of military school aged 18-20 years, who had previous sports training, but were not engaged in wrestling. To determine the quantitative content of trace elements, the hair was cut from the back of the head for the entire length in an amount of at least 0.1 g. an examined using the mass spectrometer ICP-MS Agilent 7900. Strong positive correlations were found for sodium with potassium and rubidium, magnesium with calcium, potassium with rubidium, and rubidium with caesium among wrestlers. Wrestlers were found to have higher levels of a number of macro- and microelements, including toxic ones.
MHD williamson nanofluid flow in the rheology of thermal radiation, joule heating, and chemical reaction using the Levenberg–Marquardt neural network algorithm
Authors: Ali Aatif , Ahammad N. Ameer , Tag-Eldin Elsayed , Gamaoun Fehmi , Daradkeh Yousef Ibrahim , Yassen Mansour F.
Published: August 2022

Various studies have been conducted on the topic of predicting the thermal conductivity of nanofluids. Here, the thermal conductivity of nanofluids is determined using artificial neural networks since this approach is rapid and accurate, as well as cost-effective. To forecast the thermal conductivity of magnetohydrodynamic Williamson nanofluids flow through a vertical sheet, a feed-forward neural network with various numbers of neurons has been evaluated, and the best network based on the performance is selected. The fluid model incorporates the effects of Joule heating, heat generation absorption, thermal radiation, and a chemical reaction (MHD-WNF-HGA). A combination of heat radiation and reactive species improves the energy and solute profiles. The magnetic Reynolds number is assumed to be so small; therefore, the generated magnetic field has no effect. A postulate of similarity variables is used to convert the physical model in the form of nonlinear partial differential equations to an ordinary differential equation system. A supervised Levenberg–Marquardt backpropagation algorithm possesses a multilayer perceptron that is used for training the network, which is one of the top algorithms in machine learning. The bvp4c numerical technique is adopted to build the datasets for the construction of continuous neural network mapping. Flow, energy, and concentration profiles of the fluidic flow are constructed by adjusting several physical quantities such as the Williamson parameter, thermal radiation parameter, magnetic parameter, Eckert number, Darcy number, Brownian motion, and thermophoresis parameter. Analytical techniques such as error histogram graphs and regression-based statistical graphs are used to examine the accuracy of a suggested method. It has been found that the Levenberg–Marquardt backpropagation neural network mappings’ derivation, convergence, authentication, and consistency have been proven. Furthermore, thermal radiation assists the energy distribution to increase smoothly. Fluid velocity drops with the Williamson parameter, whereas thermophoresis impact enhances the strength of the nanofluid density.
The Effects of Engineered Aeration on Atmospheric Methane Flux From a Chesapeake Bay Tidal Tributary
Authors: Lapham Laura L. , Hobbs Edward A. , Testa Jeremy M. , Heyes Andrew , Forsyth Melinda K. , Hodgkins Casey , Szewczyk Curtis , Harris Lora A.
Published: August 2022

Engineered aeration is one solution for increasing oxygen concentrations in highly eutrophic estuaries that undergo seasonal hypoxia. Although there are various designs for engineered aeration, all approaches involve either destratification of the water column or direct injection of oxygen or air through fine bubble diffusion. To date, the effect of either approach on estuarine methane dynamics remains unknown. Here we tested the hypotheses that 1) bubble aeration will strip the water of methane and enhance the air-water methane flux to the atmosphere and 2) the addition of oxygen to the water column will enhance aerobic methane oxidation in the water column and potentially offset the air-water methane flux. These hypotheses were tested in Rock Creek, Maryland, a shallow-water sub-estuary to the Chesapeake Bay, using controlled, ecosystem-scale deoxygenation experiments where the water column and sediments were sampled in mid-summer, when aerators were ON, and then 1, 3, 7, and 13 days after the aerators were turned OFF. Experiments were performed under two system designs, large bubble and fine bubble approaches, using the same observational approach that combined discrete water sampling, long term water samplers (OsmoSamplers) and sediment porewater profiles. Regardless of aeration status, methane concentrations reached as high as 1,500 nmol L−1 in the water column during the experiments and remained near 1,000 nmol L−1 through the summer and into the fall. Since these concentrations are above atmospheric equilibrium of 3 nmol L−1, these data establish the sub-estuary as a source of methane to the atmosphere, with a maximum atmospheric flux as high as 1,500 µmol m−2 d−1, which is comparable to fluxes estimated for other estuaries. Air-water methane fluxes were higher when the aerators were ON, over short time frames, supporting the hypothesis that aeration enhanced the atmospheric methane flux. The fine-bubble approach showed lower air-water methane fluxes compared to the larger bubble, destratification system. We found that the primary source of the methane was the sediments, however, in situ methane production or an upstream methane source could not be ruled out. Overall, our measurements of methane concentrations were consistently high in all times and locations, supporting consistent methane flux to the atmosphere.
Evolution Characteristics of New Urbanization in the Provincial Capital Cities of Western China
Authors: Zou Yafeng , Deng Min , Wang Qi , Zhang Qian , Rong Yao
Published: August 2022

Urbanization is both a global concept and a project that is connected with all aspects of the society. China’s new urbanization process has been attracting wide attention internationally due to its rapid development and rich content. This new urbanization has significant impacts on hundreds of millions of people’s lives, as well as global wellbeing. Although Western China has always been in a relatively weak state of development when compared to the other parts of China, it has a large area and a significant amount of people, which all require a reasonable urbanization method. To show the development level of new urbanization in western China, we constructed an evaluation system and used entropy and weighted summation methods to get the development scores. We then obtained the correlation coefficient with the partial correlation analysis method. The results indicate that: 1) economic, land, and social urbanization are significant influencing factors; 2) temporal and spatial differences were significant during the 15-year period in these 11 cities; 3) among the factor layers, the score of social urbanization fluctuated the most, ecological civilization and economic urbanization showed an upward trend, and population urbanization and land urbanization have been relatively stable in the last few years; 4) for the western capitals, although economic urbanization and ecological civilization have achieved coordinated development in recent years, the endogenous power of the economy still needs to be tapped, and ecological development is facing greater pressure. Meanwhile the expansion of urban land has been too fast to respond well to population growth, which also damages the urban ecosystem to a certain extent. We conclude that it is necessary to realize the coordinated development of different factors in new urbanization, promote new urbanization, while considering the actual needs of the city and also developing the rural areas. This study can provide decision support for the development of new urbanization in the western region.
An inflammation-related signature could predict the prognosis of patients with kidney renal clear cell carcinoma
Authors: Yu Qingxin , Zhang Facai , Feng Dechao , Li Dengxiong , Xia Yuhui , Gan Mei-Fu
Published: August 2022

Background: Kidney renal clear cell carcinoma (KIRC) is an inflammation-related carcinoma, and inflammation has been recognized as an important factor in inducing carcinogenesis. To further explore the role of inflammation in KIRC, we developed an inflammation-related signature and verified its correlation with the tumor micro-environment.

Methods: After the differential inflammation-related prognostic genes were screened by Lasso regression, the inflammation-related signature (IRS) was constructed based on the risk score of multivariate Cox regression. Then, the prognostic value of the IRS was evaluated by Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis and multivariate Cox regression. Gene set variation analysis (GSVA) was applied to screen out enriched signaling pathways. Infiltrated immune cells, tumor mutational burden (TMB) and immune checkpoints were explored by CIBERSORTx and maftool.

Results: Four genes (TIMP1, PLAUR, CCL22, and IL15RA) were used to construct the IRS in patients with KIRC. Kaplan-Meier analysis and multivariate Cox regression identified that the IRS could independently predict the prognosis of patients with KIRC in the training and validation groups. The diagnostic value of the nomogram increased from 0.811 to 0.845 after adding the IRS to the multiparameter ROC analysis. The GSVA results indicated that IRS was closely related to primary immunodeficiency and antigen processing and presentation. The immune checkpoint LAG3 was highly expressed in patients with high-risk score (p < 0.05), while CD274 (PD-L1) and HAVCR2 were highly expressed in patients with low-risk score (p < 0.001). There was a significant positive correlation between the high-risk score group and CD8+ T, activated CD4+ memory T, gamma and delta regulatory T and M0 macrophage cells, while the low-risk score group was negatively associated with B memory, plasma, resting CD4+ memory T, activated NK, M1 macrophages and resting mast cells.

Conclusion: We found that the IRS might serve as a biomarker to predict the survival of KIRC. Moreover, patients with high or low-risk score might be sensitive to immune drugs at different immune checkpoints.
The Usefulness of a Targeted Next Generation Sequencing Gene Panel in Providing Molecular Diagnosis to Patients With a Broad Spectrum of Neurodevelopmental Disorders
Authors: Mellone Simona , Puricelli Chiara , Vurchio Denise , Ronzani Sara , Favini Simone , Maruzzi Arianna , Peruzzi Cinzia , Papa Amanda , Spano Alice , Sirchia Fabio , Mandrile Giorgia , Pelle Alessandra , Rasmini Paolo , Vercellino Fabiana , Zonta Andrea , Rabbone Ivana , Dianzani Umberto , Viri Maurizio , Giordano Mara
Published: August 2022

Background: Neurodevelopmental disorders comprise a clinically and genetically heterogeneous group of conditions that affect 2%–5% of children and represents a public health challenge due to complexity of the etiology. Only few patients with unexplained syndromic and non-syndromic NDDs receive a diagnosis through first-tier genetic tests as array-CGH and the search for FMR1 CGG expansion. The aim of this study was to evaluate the clinical performance of a targeted next-generation sequencing (NGS) gene panel as a second-tier test in a group of undiagnosed patients with NDDs.

Method: A 221-gene next-generation sequencing custom panel was designed and used to analyze a cohort of 338 patients with a broad spectrum of NDDs (202 males and 136 females) including Intellectual Disability (ID), Autism Spectrum Disorders (ASD), Epilepsy, language and motor disorders.

Results: A molecular diagnosis was established in 71 patients (21%) and a de novo origin was present in 38 (64.4%) of the available trios. The diagnostic yield was significantly higher in females than in males (29.4% vs. 15.3%; p = 0.0019) in particular in ASD (36.8% vs. 7.6%; p = 0.0026) and Epilepsy (38.9% vs. 14.4% p = 0.001). The most involved genes were SLC2A1, SCN1A, ANKRD11, ATP1A2, CACNA1A, FOXP1, and GNAS altered in more than two patients and accounting for the 19.7% of the diagnosis.

Conclusion: Our findings showed that this NGS panel represents a powerful and affordable clinical tool, significantly increasing the diagnostic yield in patients with different form of NDDs in a cost- and time-effective manner without the need of large investments in data storage and bioinformatic analysis.
Identification of pathogenic genes associated with CKD: An integrated bioinformatics approach
Authors: Ahmed Mohd Murshad , Shafat Zoya , Tazyeen Safia , Ali Rafat , Almashjary Majed N. , Al-Raddadi Rajaa , Harakeh Steve , Alam Aftab , Haque Shafiul , Ishrat Romana
Published: August 2022

Chronic kidney disease (CKD) is defined as a persistent abnormality in the structure and function of kidneys and leads to high morbidity and mortality in individuals across the world. Globally, approximately 8%–16% of the population is affected by CKD. Proper screening, staging, diagnosis, and the appropriate management of CKD by primary care clinicians are essential in preventing the adverse outcomes associated with CKD worldwide. In light of this, the identification of biomarkers for the appropriate management of CKD is urgently required. Growing evidence has suggested the role of mRNAs and microRNAs in CKD, however, the gene expression profile of CKD is presently uncertain. The present study aimed to identify diagnostic biomarkers and therapeutic targets for patients with CKD. The human microarray profile datasets, consisting of normal samples and treated samples were analyzed thoroughly to unveil the differentially expressed genes (DEGs). After selection, the interrelationship among DEGs was carried out to identify the overlapping DEGs, which were visualized using the Cytoscape program. Furthermore, the PPI network was constructed from the String database using the selected DEGs. Then, from the PPI network, significant modules and sub-networks were extracted by applying the different centralities methods (closeness, betweenness, stress, etc.) using MCODE, Cytohubba, and Centiserver. After sub-network analysis we identified six overlapped hub genes (RPS5, RPL37A, RPLP0, CXCL8, HLA-A, and ANXA1). Additionally, the enrichment analysis was undertaken on hub genes to determine their significant functions. Furthermore, these six genes were used to find their associated miRNAs and targeted drugs. Finally, two genes CXCL8 and HLA-A were common for Ribavirin drug (the gene-drug interaction), after docking studies HLA-A was selected for further investigation. To conclude our findings, we can say that the identified hub genes and their related miRNAs can serve as potential diagnostic biomarkers and therapeutic targets for CKD treatment strategies.
Identification of Ferroptosis-Related Molecular Clusters and Immune Characterization in Autism Spectrum Disorder
Authors: Liu Lichun , Lai Yongxing , Zhan Zhidong , Fu Qingxian , Jiang Yuelian
Published: August 2022

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with clinical presentation and prognostic heterogeneity. Ferroptosis is a regulated non-apoptotic cell death program implicated in the occurrence and progression of various diseases. Therefore, we aimed to explore ferroptosis-related molecular subtypes in ASD and further illustrate the potential mechanism.

Methods: A total of 201 normal samples and 293 ASD samples were obtained from the Gene Expression Omnibus (GEO) database. We used the unsupervised clustering analysis to identify the molecular subtypes based on ferroptosis-related genes (FRGs) and evaluate the immune characteristics between ferroptosis subtypes. Ferroptosis signatures were identified using the least absolute shrinkage and selection operator regression (LASSO) and recursive feature elimination for support vector machines (SVM-RFE) machine learning algorithms. The ferroptosis scores based on seven selected genes were constructed to evaluate the ferroptosis characteristics of ASD.

Results: We identified 16 differentially expressed FRGs in ASD children compared with controls. Two distinct molecular clusters associated with ferroptosis were identified in ASD. Analysis of immune infiltration revealed immune heterogeneity between the two clusters. Cluster2, characterized by a higher immune score and a larger number of infiltrated immune cells, exhibited a stronger immune response and was markedly enriched in immune response-related signaling pathways. Additionally, the ferroptosis scores model was capable of predicting ASD subtypes and immunity. Higher levels of ferroptosis scores were associated with immune activation, as seen in Cluster2. Lower ferroptosis scores were accompanied by relative immune downregulation, as seen in Cluster1.

Conclusion: Our study systematically elucidated the intricate correlation between ferroptosis and ASD and provided a promising ferroptosis score model to predict the molecular clusters and immune infiltration cell profiles of children with ASD.
Integrative analysis of a necroptosis-related gene signature of clinical value and heterogeneity in diffuse large B cell lymphoma
Authors: Pan Yu-Biao , Wang Wei , Cai Hong-Kai , Zhang Jia , Teng Ya , Xue Jiji , Zhu Min , Luo Wen-Da
Published: August 2022

Background: Diffuse large B-cell lymphoma (DLBCL), which is considered to be the most common subtype of lymphoma, is an aggressive tumor. Necroptosis, a novel type of programmed cell death, plays a bidirectional role in tumors and participates in the tumor microenvironment to influence tumor development. Targeting necroptosis is an intriguing direction, whereas its role in DLBCL needs to be further discussed.

Methods: We obtained 17 DLBCL-associated necroptosis-related genes by univariate cox regression screening. We clustered in GSE31312 depending on their expressions of these 17 genes and analyzed the differences in clinical characteristics between different clusters. To investigate the differences in prognosis across distinct clusters, the Kaplan-Meier method was utilized. The variations in the tumor immune microenvironment (TME) between distinct necroptosis-related clusters were investigated via “ESTIMATE”, “Cibersort” and single-sample geneset enrichment analysis (ssGSEA). Finally, we constructed a 6-gene prognostic model by lasso-cox regression and subsequently integrated clinical features to construct a prognostic nomogram.

Results: Our analysis indicated stable but distinct mechanism of action of necroptosis in DLBCL. Based on necroptosis-related genes and cluster-associated genes, we identified three groups of patients with significant differences in prognosis, TME, and chemotherapy drug sensitivity. Analysis of immune infiltration in the TME showed that cluster 1, which displayed the best prognosis, was significantly infiltrated by natural killer T cells, dendritic cells, CD8+ T cells, and M1 macrophages. Cluster 3 presented M2 macrophage infiltration and the worst prognosis. Importantly, the prognostic model successfully differentiated high-risk from low-risk patients, and could forecast the survival of DLBCL patients. And the constructed nomogram demonstrated a remarkable capacity to forecast the survival time of DLBCL patients after incorporating predictive clinical characteristics.

Conclusion: The different patterns of necroptosis explain its role in regulating the immune microenvironment of DLBCL and the response to R-CHOP treatment. Systematic assessment of necroptosis patterns in patients with DLBCL will help us understand the characteristics of tumor microenvironment cell infiltration and aid in the development of tailored therapy regimens.
Identification and validation of differentially expressed chromatin regulators for diagnosis of aortic dissection using integrated bioinformatics analysis and machine-learning algorithms
Authors: Liu Chunjiang , Zhou Yufei , Zhao Di , Yu Luchen , Zhou Yue , Xu Miaojun , Tang Liming
Published: August 2022

Background: Aortic dissection (AD) is a life-threatening disease. Chromatin regulators (CRs) are indispensable epigenetic regulators. We aimed to identify differentially expressed chromatin regulators (DECRs) for AD diagnosis.

Methods: We downloaded the GSE52093 and GSE190635 datasets from the Gene Expression Omnibus database. Following the merging and processing of datasets, bioinformatics analysis was applied to select candidate DECRs for AD diagnosis: CRs exertion; DECR identification using the “Limma” package; analyses of enrichment of function and signaling pathways; construction of protein–protein interaction (PPI) networks; application of machine-learning algorithms; evaluation of receiver operating characteristic (ROC) curves. GSE98770 served as the validation dataset to filter DECRs. Moreover, we collected peripheral-blood samples to further validate expression of DECRs by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Finally, a nomogram was built for clinical use.

Results: A total of 841 CRs were extracted from the merged dataset. Analyses of functional enrichment of 23 DECRs identified using Limma showed that DECRs were enriched mainly in epigenetic-regulation processes. From the PPI network, 17 DECRs were selected as node DECRs. After machine-learning calculations, eight DECRs were chosen from the intersection of 13 DECRs identified using support vector machine recursive feature elimination (SVM-RFE) and the top-10 DECRs selected using random forest. DECR expression between the control group and AD group were considerably different. Moreover, the area under the ROC curve (AUC) of each DECR was >0.75, and four DECRs (tumor protein 53 (TP53), chromobox protein homolog 7 (CBX7), Janus kinase 2 (JAK2) and cyclin-dependent kinase 5 (CDK5)) were selected as candidate biomarkers after validation using the external dataset and clinical samples. Furthermore, a nomogram with robust diagnostic value was established (AUC = 0.960).

Conclusion: TP53, CBX7, JAK2, and CDK5 might serve as diagnostic DECRs for AD diagnosis. These DECRs were enriched predominantly in regulating epigenetic processes.
Modulation of sol mRNA expression by the long non-coding RNA Assolrna in Clostridium saccharoperbutylacetonicum affects solvent formation
Authors: Baur Saskia Tabea , Poehlein Anja , Renz Niklas Jan , Hollitzer Stefanie Karolina , Montoya Solano José David , Schiel-Bengelsdorf Bettina , Daniel Rolf , Dürre Peter
Published: August 2022

Solvents such as butanol are important platform chemicals and are often produced from petrochemical sources. Production of butanol and other compounds from renewable and sustainable resources can be achieved by solventogenic bacteria, such as the hyper-butanol producer Clostridium saccharoperbutylacetonicum. Its sol operon consists of the genes encoding butyraldehyde dehydrogenase, CoA transferase, and acetoacetate decarboxylase (bld, ctfA, ctfB, adc) and the gene products are involved in butanol and acetone formation. It is important to understand its regulation to further optimize the solvent production. In this study, a new long non-coding antisense transcript complementary to the complete sol operon, now called Assolrna, was identified by transcriptomic analysis and the regulatory mechanism of Assolrna was investigated. For this purpose, the promoter-exchange strain C. saccharoperbutylacetonicum ΔPasr::Pasr** was constructed. Additionally, Assolrna was expressed plasmid-based under control of the native Pasr promoter and the lactose-inducible PbgaL promoter in both the wild type and the promoter-exchange strain. Solvent formation was strongly decreased for all strains based on C. saccharoperbutylacetonicum ΔPasr::Pasr** and growth could not be restored by plasmid-based complementation of the exchanged promoter. Interestingly, very little sol mRNA expression was detected in the strain C. saccharoperbutylacetonicum ΔPasr::Pasr** lacking Assolrna expression. Butanol titers were further increased for the overexpression strain C. saccharoperbutylacetonicum [pMTL83151_asr_PbgaL] compared to the wild type. These results suggest that Assolrna has a positive effect on sol operon expression. Therefore, a possible stabilization mechanism of the sol mRNA by Assolrna under physiological concentrations is proposed.
Characterization of CD41+ cells in the lymph node
Authors: Dai Li , Uehara Mayuko , Li Xiaofei , LaBarre Brenna A. , Banouni Naima , Ichimura Takaharu , Lee-Sundlov Melissa M. , Kasinath Vivek , Sullivan Jade A. , Ni Heyu , Barone Francesca , Giannini Silvia , Bahmani Baharak , Sage Peter T. , Patsopoulos Nikolaos A. , Tsokos George C. , Bromberg Jonathan S. , Hoffmeister Karin , Jiang Liwei , Abdi Reza
Published: August 2022

Lymph nodes (LNs) are the critical sites of immunity, and the stromal cells of LNs are crucial to their function. Our understanding of the stromal compartment of the LN has deepened recently with the characterization of nontraditional stromal cells. CD41 (integrin αIIb) is known to be expressed by platelets and hematolymphoid cells. We identified two distinct populations of CD41+Lyve1+ and CD41+Lyve1- cells in the LNs. CD41+Lyve1- cells appear in the LN mostly at the later stages of the lives of mice. We identified CD41+ cells in human LNs as well. We demonstrated that murine CD41+ cells express mesodermal markers, such as Sca-1, CD105 and CD29, but lack platelet markers. We did not observe the presence of platelets around the HEVs or within proximity to fibroblastic reticular cells of the LN. Examination of thoracic duct lymph fluid showed the presence of CD41+Lyve1- cells, suggesting that these cells recirculate throughout the body. FTY720 reduced their trafficking to lymph fluid, suggesting that their egress is controlled by the S1P1 pathway. CD41+Lyve1- cells of the LNs were sensitive to radiation, suggestive of their replicative nature. Single cell RNA sequencing data showed that the CD41+ cell population in naïve mouse LNs expressed largely stromal cell markers. Further studies are required to examine more deeply the role of CD41+ cells in the function of LNs.
A Novel Tolerogenic Antibody Targeting Disulfide-Modified Autoantigen Effectively Prevents Type 1 Diabetes in NOD Mice
Authors: Li Wei , Zhang Yan , Li Ronghui , Wang Yang , Chen Lan , Dai Shaodong
Published: August 2022

Increasing evidence suggested that the islet amyloid polypeptide (IAPP) is an essential autoantigen in the pathogenesis of type 1 diabetes (T1D) in humans and non-obese diabetic (NOD) mice. A unique disulfide containing IAPP-derived peptide KS20 is one of the highly diabetogenic peptides in NOD mice. The KS20-reactive T cells, including prototypic pathogenic BDC5.2.9, accumulate in the pancreas of prediabetic and diabetic mice and contribute to disease development. We generated a monoclonal antibody (LD96.24) that interacts with IAg7-KS20 complexes with high affinity and specificity. LD96.24 recognized the IAg7-KS20 disulfide loop and blocked the interaction between IAg7-KS20 tetramers and cognate T cells but not other autoantigen-reactive T cells. Thein vivoLD96.24 studies, at either early or late stages, drastically induced tolerance and delayed the onset of T1D disease in NOD mice by reducing the infiltration of not only IAPP-specific T cells but also chromogranin A and insulin-specific T cells in the pancreas, together with B cells and dendritic cells. LD96.24 can also significantly increase the ratio of Foxp3+regulatory T cells with Interferon-gamma-secreting effector T cells. Our data suggested the important role of disulfide-modified peptides in the development of T1D. Targeting the complexes of Major histocompatibility complex (MHC)/disulfide modified antigens would influence the thiol redox balance and could be a novel immunotherapy for T1D.
Aging-based molecular classification and score system in ccRCC uncovers distinct prognosis, tumor immunogenicity, and treatment sensitivity
Authors: Zhu Maoshu , Huang Chaoqun , Wu Xinhong , Gu Ying , Hu Xiaoxu , Ma Dongna , Zhong Weimin
Published: August 2022

Objective

Aging is a complex biological process and a major risk factor for cancer development. This study was conducted to develop a novel aging-based molecular classification and score system in clear cell renal cell carcinoma (ccRCC).

Methods

Integrative analysis of aging-associated genes was performed among ccRCC patients in the TCGA and E-MTAB-1980 cohorts. In accordance with the transcriptional expression matrix of 173 prognostic aging-associated genes, aging phenotypes were clustered with the consensus clustering approach. The agingScore was generated to quantify aging phenotypes with principal component analysis. Tumor-infiltrating immune cells and the cancer immunity cycle were quantified with the ssGSEA approach. Immunotherapy response was estimated through the TIDE algorithm, and a series of tumor immunogenicity indicators were computed. Drug sensitivity analysis was separately conducted based on the GDSC, CTRP, and PRISM analyses.

Results

Three aging phenotypes were established for ccRCC, with diverse prognosis, clinical features, immune cell infiltration, tumor immunogenicity, immunotherapeutic response, and sensitivity to targeted drugs. The agingScore was developed, which enabled to reliably and independently predict ccRCC prognosis. Low agingScore patients presented more undesirable survival outcomes. Several small molecular compounds and three therapeutic targets, namely, CYP11A1, SAA1, and GRIK4, were determined for the low agingScore patients. Additionally, the high agingScore patients were more likely to respond to immunotherapy.

Conclusion

Overall, our findings introduced an aging-based molecular classification and agingScore system into the risk stratification and treatment decision-making in ccRCC.