bluuebunny/crossref_metadata_2025 huggingface dataset:
BİREYLERİN DİJİTAL BAĞIMLILIKLARI İLE YALNIZLIK DÜZEYLERİ ARASINDAKİ İLİŞKİNİN İNCELENMESİ: BİR META-ANALİZ ÇALIŞMASI
Authors: SEKİ Tolga , KURNAZ M. Furkan
Published: December 2021

Günümüzde teknolojinin insan hayatına etkisi sonucu oldukça yaygınlık kazanan dijital bağımlılık türleri ile yalnızlık arasındaki ilişkinin incelendiği bu araştırmada, literatürde bulunan çalışmalardan hareketle genel bir kanıya varmak amaçlanmıştır. Bu araştırmada en yaygın dijital bağımlılık çeşitleri olan internet bağımlılığı, akıllı telefon bağımlılığı, sosyal medya bağımlılığı ve dijital oyun bağımlılığı ile yalnızlık arasındaki ilişkiyi inceleyen çalışmalar incelenmiştir. Araştırmaya Türkiye örnekleminde gerçekleştirilmiş Türkçe veya İngilizce yazılmış ve etki büyüklüğünü hesaplayabilecek sayısal verileri içeren çalışmalar dahil edilmiştir. Bu dahil edilme ktirerleri doğrultusunda 101 araştırmadan elde edilen 104 korelasyon değeri analiz edilerek her bir bağımlılık türü ile yalnızlık arasındaki ilişkinin yayın yanlılığı, heterojenlik ve etki büyüklüğü (r) değerleri hesaplanmıştır. Araştırmada yalnızlık ile araştırma kapsamında incelenen internet bağımlılığı, akıllı telefon bağımlılığı, sosyal medya bağımlılığı ve dijital oyun bağımlılığı arasındaki ilişkilere ait çalışmaların yayın yanlılığı olmadığı bulunmuştur. Ayrıca yalnızlık ile ilişkisi incelenen her bir dijital bağımlılık türlerine ait çalışmaların heterojen dağılım gösterdiği bulunmuştur. Analiz sonuçlarına göre yalnızlık ile internet bağımlılığı, akıllı telefon bağımlılığı ve dijital oyun bağımlılığı arasında pozitif yönlü ve zayıf düzeyde bir ilişki bulunmuştur. Yalnızlık ile sosyal medya bağımlılığı arasında ise pozitif yönlü orta düzeyde bir ilişki bulunmuştur. Araştırmada Türkiye’de yalnız olan bireylerin dijital bağımlılıklarının daha fazla olduğu sonucuna ulaşılmıştır. Araştırmadan elde edilen sonuçlar literatürde yapılan çalışmalar incelenerek tartışılmıştır.
On the Solutions of the Higher Order Fractional Differential Equations of Riesz Space Derivative with Anti-Periodic Boundary Conditions
Authors: TOPRAKSEVEN Şuayip
Published: December 2021

We present existence and uniqueness results for a class of higher order anti-periodic fractional boundary value problems with Riesz space derivative which is two-sided fractional operator. The obtained results are established by applying some fixed point theorems. Various numerical examples are given to illustrate the obtained results.
A Nonlinear $r(x)$-Kirchhoff Type Hyperbolic Equation: Stability Result and Blow up of Solutions with Positive Initial Energy
Authors: SHAHROUZİ Mohammad , FERREIRA Jorge
Published: December 2021

In this paper we consider $r(x)-$Kirchhoff type equation with variable-exponent nonlinearity of the form $$ u_{tt}-\Delta u-\big(a+b\int_{\Omega}\frac{1}{r(x)}|\nabla u|^{r(x)}dx\big)\Delta_{r(x)}u+\beta u_{t}=|u|^{p(x)-2}u, $$ associated with initial and Dirichlet boundary conditions. Under appropriate conditions on $r(.)$ and $p(.)$, stability result along the solution energy is proved. It is also shown that regarding arbitrary positive initial energy and suitable range of variable exponents, solutions blow-up in a finite time.
Results on the Behavior of the Solutions for Linear Impulsive Neutral Delay Differential Equations with Constant Coefficients
Authors: YENİÇERİOĞLU Ali Fuat
Published: December 2021

We have given some results regarding the behavior of solutions for first order linear impulsive neutral delay
differential equations with constant coefficients. These results were obtained using two different real roots of the
corresponding characteristic equation. Finally, two examples are given for solutions of impulsive neutral delay
differential equations.
Authorship, Co-Production, Plagiarism: Issues of Origin and Provenance in the Korean Studies Community
Authors: Winstanley-Chesters Robert
Published: December 2021

The long controversy and struggle over Charles Armstrong’s Tyranny of the Weak may have, for the Korean Studies community felt uniquely transgressive and offensive, but the malfeasance and academic corruption of the episode is not by far the only instance of productive difficulty in the recent history of the academic field. This paper not only attempts to think through questions of authenticity and intellectual ownership in Korean Studies’ difficulties with the writer formerly known as Professor Charles Armstrong, but also to explore other moments of complexity, both historical and contemporary, in the discipline.
US Hegemony in Korean Studies and the Soviet Role in Early Postwar Korea
Authors: Weathersby Kathryn
Published: December 2021

This paper examines some of the ways the US-centric framework of Anglophone Korean studies has distorted scholarship on post-colonial Korean history. First, an over-emphasis on the American role in the division of Korea has exaggerated the possibility that the US and USSR could have compromised to create a unified government for the peninsula. The Soviet documentary record reveals that Moscow was determined to obstruct such an outcome if it endangered Soviet security. Second, by focusing on the serious damage the American occupation inflicted on the South, scholars have understated the control Soviet occupation authorities exercised in the North.
DETERMINATION OF THE OPTIMAL NUMBER OF EMPLOYEES USING THE FULL TIME EQUIVALENT (FTE) METHOD AT PT. XYZ
Authors: Dahlan Muhammad , Rauf Nurhayati , Mahenra Yusril , Alisyahbana Takdir , Ahmad Arfandi , Pawennari Andi , Lantara Dirgahayu , Malik Rahmaniah
Published: December 2021

Determining the optimal number of employees in a company is a basic condition that must be concern into account when drafting a work plan. The work design process ultimately aims for balance the physical and mental aspects of humans in completing certain tasks so that. Determination of the number of employees whit the existing workload will support employees performance in perform their duties optimally. The purpose of this research is to determine the optimal number of salesman based on the workload calculated using the Full Time Equivlent method. Based on the results of research at PT. Xyz used the method FTE is know that the workload of the 4 salesman is classified as overloaded. Where is sales I has a workload of 1.48, sales II has a workload of 1.70, sales III has a workload of 1.66, sales IV get a workload of 1.42. Based on the table of labor requirements to the FTE value, the number of initial salesman was 4 sales and the addition of the number of salesman is as many as 10 salesmen. So, the optimal number of salesmen in Makassar city is 14 salesmen.
Impact action of a projectiles on special protective structures and ways to increase their protective capacity
Authors: Andrukhiv A. , Baranov A. , Huzyk N. , Sokil B. , Sokil M.
Published: December 2021

A method for studying the reaction of elastic elements of protective structures to a series of impact actions of shells has been developed. In the work, the elastic elements of the protective structure are modeled by homogeneous beams, and the dynamic action of the shells is simulated by instantaneous point-applied forces. A mathematical model of this dynamic process is constructed, which is a boundary value problem for a hyperbolic equation with an irregular right-hand side. The latter is described using Dirac delta functions. Cases of both fixed and free ends of protective elements are considered. The main ideas of perturbation methods are used for the researches carried out in the work. Analytical dependences for the description of elastic deformations of a protective element which are basic for definition of its strength characteristics are received. They and the graphical dependences built on their basis for specific cases show that the dynamic deformations of the protective element for the fixed ends are greater in the case of the projectile closer to its middle, at the same time for the free ends – closer to the end. With regard to the modernization of protective structures, the dynamic effect on their elements can be reduced by using elastic reinforcement or changing the method of fixing the ends of the protective element: elastic or with a certain angle of inclination of the bearing surfaces. It is proposed to use special plastics, soil layer, flexible wood flooring, etc. as elastic reinforcement. The technique used in the work is the basis for determining the strength characteristics of protective elements, and from so – to check the reliability of the protective structure; study of the dynamics of protective and similar types of structures, taking into account the nonlinear characteristics of the elastic elements of protective structures; study of more complex oscillations of elements of protective structures. In the case of a series of impacts, it is obvious that the amplitude of deflection of the protective element after each impact will increase over time, because the model does not take into account the force of viscoelastic friction. These tasks will be the subject of further research.
Survey among Russian doctors on routine electroencephalography
Authors: Bogdanova E. P. , Elshina O. D. , Sinkin M. V.
Published: December 2021

The aim of the work was to assess how accurately specialists, performing EEG, apply the recommendations in their daily practice.

Materials and Methods. An anonymous survey was conducted of 210 specialists in functional diagnostics and neurologists performing routine electroencephalography. The survey consisted of nine mandatory single-choice questions.

Results. Only 9 respondents out of 210 (4.3%) perform routine EEG completely in accordance with the Recommendations of the Expert Council of Neurophysiology of the Russian Anti-Epileptic League on performing the routine EEG.' Of these, only three specialists (1.4% of the total number of respondents) answered that a functional diagnostics doctor is present throughout the entire examination.

Conclusion: Despite the wide distribution and extensive experience in the use of EEG, there is no uniform practice of its implementation by doctors in the Russian Federation. Standardization of the methodology of its performance will increase confidence in EEG results among doctors of clinical specialties, increase the degree of inter-expert agreement among functional diagnostics physicians, and improve the quality of diagnosis of central nervous system diseases. To do this, it is necessary to develop webinar and educational programs on the methodology of EEG under the auspices of professional associations of doctors of functional diagnostics, neurophysiologists, neurologists.
Rules for a routine electroencephalogram recording
Authors: Sinkin M. V. , Bogdanova E. P. , Elshina O. D. , Troitskiy A. A.
Published: December 2021

Electroencephalography (EEG) is the primary method for functional assessment of the brain bioelectrical activity. It is the most effective for epilepsy diagnosing, and also used for localization of the epileptogenic zone in presurgical evaluation for pharmaco-resistant epilepsy and in critical care medicine. In practice, the most common type is a 'routine' EEG, the informative value of which depends largely on the accuracy of its performance. The paper briefly outlines the rules for performing a routine EEG and lists the most common mistakes that can affect its interpretation.
Power spectrum of electroencephalogram: Mistakes and Practical Application
Authors: Ivanov L. B.
Published: December 2021

In this lecture, the state of the practical use of spectral analysis of EEG is analyzed in detail. The author focuses on the reasons for the slow introduction of spectral analysis into everyday practice and identifies ways to overcome this deficiency. The reason for the need to master this useful analysis technique has been substantiated. The algorithm for performing spectral analysis of EEG in practice, both at the stage of processing and at the stage of data interpretation, is presented in detail. In the lecture, the author outlined the features of the options for the spatial organization of the alpha rhythm and their relationship with the characteristics of the human psyche. One of the reasons that hinders the use of EEG spectral analysis in practice is the lag of the software of electroencephalographic computer systems of leading manufacturers from modern requirements of the time.
Samples of standard operating procedures performed by mid-level workers in departments and rooms of functional diagnostics
Authors: Pugachev M. V. , Ibatova O. V. , Korotina E. V. , Sinkin V. M.
Published: December 2021

As an example standard operating procedures performed by nurses in functional diagnostics departments are given. Methods of registration of electrocardiogram, electroencephalogram, spirogram, setting of recorders for Holter monitoring and blood pressure monitoring are considered.
EM DIREÇÃO À MATEMATIZAÇÃO EM ATIVIDADES DE MODELAGEM MATEMÁTICA: INTERVENÇÕES MEDIADAS PELA AVALIAÇÃO EM FASES
Authors: Silva Karina Alessandra Pessoa da , Borssoi Adriana Helena , Dalto Jader Otavio
Published: December 2021

Este artigo tem como objetivo investigar a seguinte questão: Como ocorre matematização em um processo de avaliação em fases em Modelagem Matemática? Com esse propósito, pautamo-nos em aportes teóricos da Modelagem Matemática, como uma possibilidade de abarcar conteúdos matemáticos, focando na matematização bem como em pesquisas que versam sobre avaliação em modelagem. Consideramos a avaliação em fases como um subsídio para regular a matematização realizada por um grupo de alunos numa disciplina de Cálculo Diferencial e Integral de cursos de Engenharia de uma universidade federal do Paraná. A análise qualitativa, inspirada na Research Design, revelou que o acompanhamento possibilitado pela avaliação em fases permitiu diagnosticar que a matematização, em alguns momentos, foi orientada pelos professores e outras vezes foi requerida de forma imperativa pelos professores. As intervenções e diálogos nas diferentes fases da avaliação permitiu diagnosticar que os alunos não estavam conseguindo vincular a matemática estudada na disciplina de Cálculo com a matemática necessária para descrever o problema.
Pandemics, Delays, and Pure Data: on ‘afterlives’ (2020), for Flute and Live Electronics and Visuals
Authors: Padovani José
Published: December 2021

The essay addresses creative and technical aspects of the piece ‘afterlives’ (2020), for flute and live electronics and visuals. Composed and premiered in the context of the COVID-19 pandemic, the composition employs audiovisual processes based on different audiovisual techniques: phase-vocoders, buffer-based granulations, Ambisonics spatialization, and variable delay of video streams. The resulting sounds and images allude to typical situations of social interaction via video conferencing applications. ‘Afterlives’ relies on an interplay between current, almost-current, and past moments of the audiovisual streams, which dephase the performer’s images and sounds. I have avoided, in text, delving deeper into the Pure Data abstractions and or into the musical analysis of my composition. The main purpose of the text is rather to present compositional/technical elements of ‘afterlives’ and discuss how they enable new experiences of time.
Discurso periodístico: análisis e interpretación de las asociaciones texto-imagen acerca de las protestas de 2019 en Chile en “El Mercurio” y “La Tercera”
Authors: Nuesch Enrique , Santos Cindy Annielli
Published: December 2021

El 25 de octubre de 2019, en Santiago de Chile, ocurrió una de las más grandes protestas políticas de la historia del país. El hecho fue reportado por la prensa internacional, así como por los periódicos nacionales. Entre éstos, “El Mercurio” y “La Tercera”, dos de los más tradicionales periódicos del país, registraron la marcha en fotografía y texto en sus portadas del 26/10. Este artículo rescata la historia de estos periódicos y analiza cómo se asocian los textos y las imágenes en sus portadas. Se usan aportes teóricos de Roland Barthes y Arlindo Machado.
Regeneration of Subcutaneous Cartilage in a Swine Model Using Autologous Auricular Chondrocytes and Electrospun Nanofiber Membranes Under Conditions of Varying Gelatin/PCL Ratios
Authors: Zheng Rui , Wang Xiaoyun , Xue Jixin , Yao Lin , Wu Gaoyang , Yi Bingcheng , Hou Mengjie , Xu Hui , Zhang Ruhong , Chen Jie , Shen Zhengyu , Liu Yu , Zhou Guangdong
Published: December 2021

The scarcity of ideal biocompatible scaffolds makes the regeneration of cartilage in the subcutaneous environment of large animals difficult. We have previously reported the successful regeneration of good-quality cartilage in a nude mouse model using the electrospun gelatin/polycaprolactone (GT/PCL) nanofiber membranes. The GT/PCL ratios were varied to generate different sets of membranes to conduct the experiments. However, it is unknown whether these GT/PCL membranes can support the process of cartilage regeneration in an immunocompetent large animal model. We seeded swine auricular chondrocytes onto different GT/PCL nanofiber membranes (GT:PCL = 30:70, 50:50, and 70:30) under the sandwich cell-seeding mode. Prior to subcutaneously implanting the samples into an autologous host, they were cultured in vitro over a period of 2 weeks. The results revealed that the nanofiber membranes with different GT/PCL ratios could support the process of subcutaneous cartilage regeneration in an autologous swine model. The maximum extent of homogeneity in the cartilage tissues was achieved when the G5P5 (GT: PC = 50: 50) group was used for the regeneration of cartilage. The formed homogeneous cartilage tissues were characterized by the maximum cartilage formation ratio. The extents of the ingrowth of the fibrous tissues realized and the extents of infiltration of inflammatory cells achieved were found to be the minimum in this case. Quantitative analyses were conducted to determine the wet weight, cartilage-specific extracellular matrix content, and Young’s modulus. The results indicated that the optimal extent of cartilage formation was observed in the G5P5 group. These results indicated that the GT/PCL nanofiber membranes could serve as a potential scaffold for supporting subcutaneous cartilage regeneration under clinical settings. An optimum GT/PCL ratio can promote cartilage formation.
Microbial-Derived Polyhydroxyalkanoate-Based Scaffolds for Bone Tissue Engineering: Biosynthesis, Properties, and Perspectives
Authors: Li Jian , Zhang Xu , Udduttula Anjaneyulu , Fan Zhi Shan , Chen Jian Hai , Sun Antonia RuJia , Zhang Peng
Published: December 2021

Polyhydroxyalkanoates (PHAs) are a class of structurally diverse natural biopolyesters, synthesized by various microbes under unbalanced culture conditions. PHAs as biomedical materials have been fabricated in various forms to apply to tissue engineering for the past years due to their excellent biodegradability, inherent biocompatibility, modifiable mechanical properties, and thermo-processability. However, there remain some bottlenecks in terms of PHA production on a large scale, the purification process, mechanical properties, and biodegradability of PHA, which need to be further resolved. Therefore, scientists are making great efforts via synthetic biology and metabolic engineering tools to improve the properties and the product yields of PHA at a lower cost for the development of various PHA-based scaffold fabrication technologies to widen biomedical applications, especially in bone tissue engineering. This review aims to outline the biosynthesis, structures, properties, and the bone tissue engineering applications of PHA scaffolds with different manufacturing technologies. The latest advances will provide an insight into future outlooks in PHA-based scaffolds for bone tissue engineering.
Comprehensive Review on Thermoelectric Electrodeposits: Enhancing Thermoelectric Performance Through Nanoengineering
Authors: Wu Tingjun , Kim Jiwon , Lim Jae-Hong , Kim Min-Seok , Myung Nosang V.
Published: December 2021

Thermoelectric devices based power generation and cooling systemsystem have lot of advantages over conventional refrigerator and power generators, becausebecause of solid-state devicesdevices, compact size, good scalability, nono-emissions and low maintenance requirement with long operating lifetime. However, the applications of thermoelectric devices have been limited owingowing to their low energy conversion efficiency. It has drawn tremendous attention in the field of thermoelectric materials and devices in the 21st century because of the need of sustainable energy harvesting technology and the ability to develop higher performance thermoelectric materials through nanoscale science and defect engineering. Among various fabrication methods, electrodeposition is one of the most promising synthesis methods to fabricate devices because of its ability to control morphology, composition, crystallinity, and crystal structure of materials through controlling electrodeposition parameters. Additionally, it is an additive manufacturing technique with minimum waste materials that operates at near room temperature. Furthermore, its growth rate is significantly higher (i.e.,a few hundred microns per hour) than the vacuum processes, which allows device fabrication in cost effective matter. In this paper, the latest development of various electrodeposited thermoelectric materials (i.e.,Te, PbTe, Bi2Te3and their derivatives, BiSe, BiS, Sb2Te3) in different forms including thin films, nanowires, and nanocomposites were comprehensively reviewed. Additionally, their thermoelectric properties are correlated to the composition, morphology, and crystal structure.
The Role of Cardiovascular Magnetic Resonance Imaging in the Assessment of Myocardial Fibrosis in Young and Veteran Athletes: Insights From a Meta-Analysis
Authors: Androulakis Emmanuel , Mouselimis Dimitrios , Tsarouchas Anastasios , Antonopoulos Alexios , Bakogiannis Constantinos , Papagkikas Panagiotis , Vlachopoulos Charalambos
Published: December 2021

Background: Cardiac magnetic resonance (CMR) combined with late gadolinium enhancement (LGE) has revealed a non-negligible increased incidence of myocardial fibrosis (MF) in athletes compared to healthy sedentary controls.

Objective: The aim of this systematic research and meta-analysis is to investigate and present our perspective regarding CMR indices in athletes compared to sedentary controls, including T1 values, myocardial extracellular volume (ECV) and positive LGE indicative of non-specific fibrosis, also to discuss the differences between young and veteran athletes.

Methods: The protocol included searching, up to October 2021, of MEDLINE, EMBASE, SPORTDiscus, Web of Science and Cochrane databases for original studies assessing fibrosis via CMR in athletes. A mean age of 40 years differentiated studies' athletic populations to veteran and young.

Results: The research yielded 14 studies including in total 1,312 individuals. There was a statistically significant difference in LGE fibrosis between the 118/759 athletes and 16/553 controls (Z = 5.2, P < 0.001, I2 = 0%, PI = 0.45). Notably, LGE fibrosis differed significantly between 546 (14.6%) veteran and 140 (25.7%) young athletes (P = 0.002). At 1.5T, T1 values differed between 117 athletes and 48 controls (P < 0.0001). A statistically significant difference was also shown at 3T (110 athletes vs. 41 controls, P = 0.0004), as well as when pooling both 1.5T and 3T populations (P < 0.00001). Mean ECV showed no statistically significant difference between these groups.

Conclusions: Based on currently available data, we reported that overall LGE based non-specific fibrosis and T1 values differ between athletes and sedentary controls, in contrast to ECV values. Age of athletes seems to have impact on the incidence of MF. Future prospective studies should focus on the investigation of the underlying pathophysiological mechanisms.
DroughtCast: A Machine Learning Forecast of the United States Drought Monitor
Authors: Brust Colin , Kimball John S. , Maneta Marco P. , Jencso Kelsey , Reichle Rolf H.
Published: December 2021

Drought is one of the most ecologically and economically devastating natural phenomena affecting the United States, causing the U.S. economy billions of dollars in damage, and driving widespread degradation of ecosystem health. Many drought indices are implemented to monitor the current extent and status of drought so stakeholders such as farmers and local governments can appropriately respond. Methods to forecast drought conditions weeks to months in advance are less common but would provide a more effective early warning system to enhance drought response, mitigation, and adaptation planning. To resolve this issue, we introduce DroughtCast, a machine learning framework for forecasting the United States Drought Monitor (USDM). DroughtCast operates on the knowledge that recent anomalies in hydrology and meteorology drive future changes in drought conditions. We use simulated meteorology and satellite observed soil moisture as inputs into a recurrent neural network to accurately forecast the USDM between 1 and 12 weeks into the future. Our analysis shows that precipitation, soil moisture, and temperature are the most important input variables when forecasting future drought conditions. Additionally, a case study of the 2017 Northern Plains Flash Drought shows that DroughtCast was able to forecast a very extreme drought event up to 12 weeks before its onset. Given the favorable forecasting skill of the model, DroughtCast may provide a promising tool for land managers and local governments in preparing for and mitigating the effects of drought.
Progress on the Function and Application of Thymosin β4
Authors: Xing Yuan , Ye Yumeng , Zuo Hongyan , Li Yang
Published: December 2021

Thymosin β4 (Tβ4) is a multifunctional and widely distributed peptide that plays a pivotal role in several physiological and pathological processes in the body, namely, increasing angiogenesis and proliferation and inhibiting apoptosis and inflammation. Moreover, Tβ4 is effectively utilized for several indications in animal experiments or clinical trials, such as myocardial infarction and myocardial ischemia-reperfusion injury, xerophthalmia, liver and renal fibrosis, ulcerative colitis and colon cancer, and skin trauma. Recent studies have reported the potential application of Tβ4 and its underlying mechanisms. The present study reveals the progress regarding functions and applications of Tβ4.
FSHB Genotype Identified as a Relevant Diagnostic Parameter Revealed by Cluster Analysis of Men With Idiopathic Infertility
Authors: Krenz Henrike , Sansone Andrea , Kliesch Sabine , Gromoll Joerg , Schubert Maria
Published: December 2021

Introduction and Objectives

About 30-75% of infertile men are diagnosed with idiopathic infertility, thereby lacking major causative factors to explain their impaired fertility status. In this study, we used a large cohort of idiopathic infertile men to determine whether subgroups could be identified by an unbiased clustering approach and whether underlying etiologic factors could be delineated.

Patients and Methods

From our in-house database Androbase®, we retrospectively selected patients (from 2008 to 2018) with idiopathic male infertility (azoo- to normozoospermia) who fit the following selection criteria: FSH ≥ 1 IU/l, testosterone ≥ 8 nmol/l, ejaculate volume ≥ 1.5 ml. Patients with genetic abnormalities or partners with female factors were excluded.

For the identified study population (n=2742), we used common andrologic features (somatic, semen and hormonal parameters, including the FSHB c.-211G>T (rs10835638) single nucleotide polymorphism) for subsequent analyses. Cluster analyses were performed for the entire study population and for two sub-cohorts, which were separated by total sperm count (TSC) thresholds: Cohort A (TSC ≥ 1 mill/ejac; n=2422) and Cohort B (TSC < 1 mill/ejac; n=320). For clustering, the partitioning around medoids method was employed, and the quality was evaluated by average silhouette width.

Results

The applied cluster approach for the whole study population yielded two separate clusters, which showed significantly different distributions in bi-testicular volume, FSH and FSHB genotype. Cluster 1 contained all men homozygous for G (wildtype) in FSHB c.-211G>T (100%), while Cluster 2 contained most patients carrying a T allele (>96.6%). In the analyses of sub-cohorts A/B, two clusters each were formed too. Again, the strongest segregation markers between the respective clusters were bi-testicular volume, FSH and FSHB c.-211G>T.

Conclusion

With this first unbiased approach for revealing putative subgroups within a heterogenous group of idiopathic infertile men, we did indeed identify distinct patient clusters. Surprisingly, across all diverse phenotypes of infertility, the strongest segregation markers were FSHB c.-211G>T, FSH, and bi-testicular volume. Further, Cohorts A and B were significantly separated by FSHB genotype (wildtype vs. T-allele carriers), which supports the notion of a contributing genetic factor. Consequently, FSHB genotyping should be implemented as diagnostic routine in patients with idiopathic infertility.
Research Progress on the Effect of Epilepsy and Antiseizure Medications on PCOS Through HPO Axis
Authors: Li Shuang , Zhang Linhai , Wei Nian , Tai Zhenzhen , Yu Changyin , Xu Zucai
Published: December 2021

Epilepsy is a common chronic neurological disease that manifests as recurrent seizures. The incidence and prevalence of epilepsy in women are slightly lower than those in men. Polycystic ovary syndrome (PCOS), a reproductive endocrine system disease, is a complication that women with epilepsy are susceptible to, and its total prevalence is 8%–13% in the female population and sometimes as high as 26% in female epilepsy patients. The rate of PCOS increased markedly in female patients who chose valproate (VPA), to 1.95 times higher than that of other drugs. In addition, patients receiving other anti-seizure medications (ASMs), such as lamotrigine (LTG), oxcarbazepine (OXC), and carbamazepine (CBZ), also have reproductive endocrine abnormalities. Some scholars believe that the increase in incidence is related not only to epilepsy itself but also to ASMs. Epileptiform discharges can affect the activity of the pulse generator and then interfere with the reproductive endocrine system by breaking the balance of the hypothalamic–pituitary–ovarian (HPO) axis. ASMs may also cause PCOS-like disorders of the reproductive endocrine system through the HPO axis. Moreover, other factors such as hormone metabolism and related signalling pathways also play a role in it.
Prenatal Diagnosis and Genetic Analysis of 21q21.1–q21.2 Aberrations in Seven Chinese Pedigrees
Authors: Hu Huamei , Zhang Rong , Ma Yongyi , Luo Yanmei , Pan Yan , Xu Juchun , Jiang Lupin , Wang Dan
Published: December 2021

Background: Chromosomal aberrations contribute to human phenotypic diversity and disease susceptibility, but it is difficult to assess their pathogenic effects in the clinic. Therefore, it is of great value to report new cases of chromosomal aberrations associated with normal phenotypes or clinical abnormalities.

Methods: This was a retrospective analysis of seven pedigrees that carried 21q21.1–q21.2 aberrations. G-banding and single-nucleotide polymorphism array techniques were used to analyze chromosomal karyotypes and copy number variations in the fetuses and their family members.

Results: All fetuses and their family members showed normal karyotypes in seven pedigrees. Here, it was revealed that six fetuses carried maternally inherited 21q21.1–q21.2 duplications, ranging from 1 to 2.7 Mb, but none of the mothers had an abnormal phenotype. In one fetus, an 8.7 Mb deletion of 21q21.1–q21.2 was found. An analysis of the pedigree showed that the deletion was also observed in the mother, brother, and maternal grandmother, but no abnormal phenotypes were found.

Conclusion: This study identified 21q21.1–q21.2 aberrations in Chinese pedigrees. The carriers of 21q21.1–q21.2 duplications had no clinical consequences based on their phenotypes, and the 21q21.1–q21.2 deletion was transmitted through three generations of normal individuals. This provides benign clinical evidence for pathogenic assessment of 21q21.1–q21.2 duplication and deletion, which was considered a variant of uncertain significance and a likely pathogenic variant in previous reports.
The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity
Authors: Tesi Niccolò , Hulsman Marc , van der Lee Sven J. , Jansen Iris E. , Stringa Najada , van Schoor Natasja M. , Scheltens Philip , van der Flier Wiesje M. , Huisman Martijn , Reinders Marcel J. T. , Holstege Henne
Published: December 2021

Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.
Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort
Authors: Yao Ruen , Zhou Yunqing , Tang Jie , Li Niu , Yu Tingting , He Yingzhong , Wang Cuijin , Wang Jiwen , Wang Jian
Published: December 2021

Childhood epilepsy is a considerably heterogeneous neurological condition with a high worldwide incidence. Genetic diagnosis of childhood epilepsy provides the most accurate pathogenetic evidence; however, a large proportion of highly suspected cases remain undiagnosed. Accumulation of rare variants at the exome level as a multigenic burden contributing to childhood epilepsy should be further evaluated. In this retrospective analysis, exome-level sequencing was used to depict the mutation spectra of 294 childhood epilepsy patients from Shanghai Children’s Medical Center, Department of Neurology. Furthermore, variant information from exome sequencing data was analyzed apart from monogenic diagnostic purposes to elucidate the possible multigenic burden of rare variants related to epilepsy pathogenesis. Exome sequencing reached a diagnostic rate of 30.61% and identified six genes not currently listed in the epilepsy-associated gene list. A multigenic burden study revealed a three-fold possibility that deleterious missense mutations in ion channel and synaptic genes in the undiagnosed cohort may contribute to the genetic risk of childhood epilepsy, whereas variants in the gene categories of cell growth, metabolic, and regulatory function showed no significant difference. Our study provides a comprehensive overview of the genetic diagnosis of a Chinese childhood epilepsy cohort and provides novel insights into the genetic background of these patients. Harmful missense mutations in genes related to ion channels and synapses are most likely to produce a multigenic burden in childhood epilepsy.
Artificial Neural Network Analysis-Based Immune-Related Signatures of Primary Non-Response to Infliximab in Patients With Ulcerative Colitis
Authors: Chen Xuanfu , Jiang Lingjuan , Han Wei , Bai Xiaoyin , Ruan Gechong , Guo Mingyue , Zhou Runing , Liang Haozheng , Yang Hong , Qian Jiaming
Published: December 2021

Infliximab (IFX) is an effective medication for ulcerative colitis (UC) patients. However, one-third of UC patients show primary non-response (PNR) to IFX. Our study analyzed three Gene Expression Omnibus (GEO) datasets and used the RobustRankAggreg (RRA) algorithm to assist in identifying differentially expressed genes (DEGs) between IFX responders and non-responders. Then, an artificial intelligence (AI) technology, artificial neural network (ANN) analysis, was applied to validate the predictive value of the selected genes. The results showed that the combination of CDX2, CHP2, HSD11B2, RANK, NOX4, and VDR is a good predictor of patients’ response to IFX therapy. The range of repeated overall area under the receiver-operating characteristic curve (AUC) was 0.850 ± 0.103. Moreover, we used an independent GEO dataset to further verify the value of the six DEGs in predicting PNR to IFX, which has a range of overall AUC of 0.759 ± 0.065. Since protein detection did not require fresh tissue and can avoid multiple biopsies, our study tried to discover whether the key information, analyzed by RNA levels, is suitable for protein detection. Therefore, immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with IFX and a receiver-operating characteristic (ROC) analysis were used to further explore the clinical application value of the six DEGs at the protein level. The IHC staining of colon tissues from UC patients confirmed that VDR and RANK are significantly associated with IFX efficacy. Total IHC scores lower than 5 for VDR and lower than 7 for RANK had an AUC of 0.828 (95% CI: 0.665–0.991, p = 0.013) in predicting PNR to IFX. Collectively, we identified a predictive RNA model for PNR to IFX and explored an immune-related protein model based on the RNA model, including VDR and RANK, as a predictor of IFX non-response, and determined the cutoff value. The result showed a connection between the RNA and protein model, and both two models were available. However, the composite signature of VDR and RANK is more conducive to clinical application, which could be used to guide the preselection of patients who might benefit from pharmacological treatment in the future.
The Role of Heparin and Glycocalyx in Blood–Brain Barrier Dysfunction
Authors: Yang Rui , Chen Mingming , Zheng Jiayin , Li Xin , Zhang Xiaojuan
Published: December 2021

The blood-brain barrier (BBB) functions as a dynamic boundary that protects the central nervous system from blood and plays an important role in maintaining the homeostasis of the brain. Dysfunction of the BBB is a pathophysiological characteristic of multiple neurologic diseases. Glycocalyx covers the luminal side of vascular endothelial cells(ECs). Damage of glycocalyx leads to disruption of the BBB, while inhibiting glycocalyx degradation maintains BBB integrity. Heparin has been recognized as an anticoagulant and it protects endothelial glycocalyx from destruction. In this review, we summarize the role of glycocalyx in BBB formation and the therapeutic potency of heparin to provide a theoretical basis for the treatment of neurological diseases related to BBB breakdown.
The Pathogenic Roles of IL-22 in Colitis: Its Transcription Regulation by Musculin in T Helper Subsets and Innate Lymphoid Cells
Authors: Yan Jun , Yu Jing , Liu Ke , Liu Yijia , Mao Changchuin , Gao Wenda
Published: December 2021

IL-22 plays a crucial role in promoting inflammation, antimicrobial immunity and tissue repair at barrier surfaces. The role of IL-22 in colitis is still controversial: while IL-22 has a protective effect on gut epithelium in acute injuries, it also enhances colitis in a context-dependent manner. Here, we summarize the Yin and Yang of IL-22 in colitis. Particularly, we emphasize the role of innate lymphoid cells (ILCs) in IL-22 production and regulation. A previously underappreciated transcription factor, Musculin (MSC), has been recently identified to be expressed in not only Th17 cells, but also RORγt+/Id2+ IL-22-producing group 3 ILCs in the gut of naïve mice. We hypothesize that the co-expression and interaction of MSC with the key transcription repressor Id2 in developing lymphoid cells (e.g., in LTi cells) and ILC precursors might fine tune the developmental programs or regulate the plasticity of adaptive Th subset and innate ILCs. The much-elevated expression of IL-22 in MSC-/- ILC3s suggests that MSC may function as: 1) a transcription suppressor for cytokines, particularly for IL-22, and/or 2) a gatekeeper for specific lineages of Th cells and innate ILCs as well. Amelioration of colitis symptoms in MSC-/- mice by IL-22-blocking agent IL-22BP-Fc suggests a counterintuitive pathogenic role of IL-22 in the absence of MSC as a checkpoint. The theory that exuberant production of IL-22 under pathological conditions (e.g., in human inflammatory bowel disease, IBD) may cause epithelial inflammation due to endoplasmic reticulum (ER) stress response is worth further investigation. Rheostatic regulation of IL-22 may be of therapeutic value to restore homeostatic balance and promote intestinal health in human colitis.
Sphingosine-1-Phosphate and Its Signal Modulators Alleviate Psoriasis-Like Dermatitis: Preclinical and Clinical Evidence and Possible Mechanisms
Authors: Liu Liu , Wang Jiao , Li Hong-jin , Zhang Shuo , Jin Meng-zhu , Chen Si-ting , Sun Xiao-ying , Zhou Ya-qiong , Lu Yi , Yang Dan , Luo Ying , Ru Yi , Li Bin , Li Xin
Published: December 2021

Background

Psoriasis is an autoimmune skin disease associated with lipid metabolism. Sphingosine-1-phosphate (S1P) is a bioactive lipid that plays a key role in the development of autoimmune diseases. However, there is currently a lack of comprehensive evidence of the effectiveness of S1P on psoriasis.

Objective

To assess the efficacy and possible mechanism of S1P and its signal modulators in the treatment of psoriasis-like dermatitis.

Methods

Six databases were searched through May 8, 2021, for studies reporting S1P and its signal modulators. Two reviewers independently extracted information from the enrolled studies. Methodological quality was assessed using SYRCLE’s risk of bias tool. RevMan 5.3 software was used to analyze the data. For clinical studies, the Psoriasis Area and Severity Index score were the main outcomes. For preclinical studies, we clarified the role of S1P and its regulators in psoriasis in terms of phenotype and mechanism.

Results

One randomized double-blind placebo-controlled trial and nine animal studies were included in this study. The pooled results showed that compared with control treatment, S1P receptor agonists [mean difference (MD): −6.80; 95% confidence interval (CI): −8.23 to −5.38; p<0.00001], and sphingosine kinase 2 inhibitors (MD: −0.95; 95% CI: −1.26 to −0.65; p<0.00001) alleviated psoriasis-like dermatitis in mice. The mechanism of S1P receptor agonists in treating psoriasis might be related to a decrease in the number of white blood cells, topical lymph node weight, interleukin-23 mRNA levels, and percentage of CD3+ T cells (p<0.05). Sphingosine kinase 2 inhibitors ameliorated psoriasis in mice, possibly by reducing spleen weight and cell numbers (p<0.05).

Conclusions

S1P receptor agonists and sphingosine kinase 2 inhibitors could be potential methods for treating psoriasis by decreasing immune responses and inflammatory factors.
Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation of Monocytes and Reduces IL-1β Secretion by Urate Crystal Stimulated Gout PBMCs
Authors: ElSayed Sandy , Jay Gregory D. , Cabezas Ralph , Qadri Marwa , Schmidt Tannin A. , Elsaid Khaled A.
Published: December 2021

Objectives

To compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes.

Methods

Acute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU (200μg/mL) stimulated IL-1β secretion was determined by ELISA. Reactive oxygen species (ROS) generation in monocytes was determined fluorometrically. PBMCs were incubated with IL-1RA (250ng/mL) or rhPRG4 (200μg/mL) and bead phagocytosis by monocytes was determined. THP-1 monocytes were treated with MSU crystals ± rhPRG4 and cellular levels of NLRP3 protein, pro-IL-1β, secreted IL-1β, and activities of caspase-1 and protein phosphatase-2A (PP2A) were quantified. The peritoneal influx of inflammatory and anti-inflammatory monocytes and neutrophils in Prg4 deficient mice was studied and the impact of rhPRG4 on immune cell trafficking was assessed.

Results

Enhanced phagocytic activation of gout monocytes under basal conditions (p<0.001) was associated with ROS generation and MSU stimulated IL-1β secretion (p<0.05). rhPRG4 reduced bead phagocytosis by normal and gout monocytes compared to IL-1RA and both treatments were efficacious in reducing IL-1β secretion (p<0.05). rhPRG4 reduced pro-IL-1β content, caspase-1 activity, conversion of pro-IL-1β to mature IL-1β and restored PP2A activity in monocytes (p<0.05). PP2A inhibition reversed rhPRG4’s effects on pro-IL-1β and mature IL-1β in MSU stimulated monocytes. Neutrophils accumulated in peritoneal cavities of Prg4 deficient mice (p<0.01) and rhPRG4 treatment reduced neutrophil accumulation and enhanced anti-inflammatory monocyte influx (p<0.05).

Conclusions

MSU phagocytosis was higher in gout monocytes resulting in higher ROS and IL-1β secretion. rhPRG4 reduced monocyte phagocytic activation to a greater extent than IL-1RA and reduced IL-1β secretion. The anti-inflammatory activity of rhPRG4 in monocytes is partially mediated by PP2A, and in vivo, PRG4 plays a role in regulating the trafficking of immune cells into the site of a gout flare.