bluuebunny/crossref_metadata_2025 huggingface dataset:
The Meaning of Sexual Violence and Society Stigma Against Victims of Sexual Violence
Authors: Mas'udah Siti
Published: June 2022

Sexual violence is a serious issue that is becoming more common in various forms. The number of victims of sexual violence is growing, and its forms are becoming more diverse. This study aims to reveal the meaning of sexual violence to victims or survivors and the social sanctions they face. This study employed mixed-method research, with 377 respondents interviewed. According to the findings of this study, victims perceive sexual violence as a bad, embarrassing, and inappropriate experience. The victims were subjected to social sanctions from the community, including friends, neighbors, and social media users. The Law of Sexual Violence Crime Number 12 of 2022 demonstrates the state’s efforts to achieve gender justice. This study recommends the need to protect victims of sexual violence from families, communities, society, and the state to realize gender equality.
MODELING OF PROCESSES OF FORMATION OF STARTUP ECOSYSTEMS ON THE BASIS OF CLUSTER ANALYSIS: ENTREPRENEURIAL ASPECT
Authors: Dymchenko O. , Smachylo V. , Rudachenko O. , Dril N.
Published: June 2022

The aim of the article is to model the processes of formation of startup ecosystems on the basis of cluster analysis as a basis for developing strategies for their development. The development of startup ecosystems is due to various support systems that are implemented at different levels: international, national, regional, local.
The article considers the peculiarities of starting a startup ecosystem in Ukraine and abroad. It is proved that the topic of startups is quite popular in Ukrainian business, as startups are the largest number of innovative and innovative products or services, which is a significant prospect for attracting domestic and foreign investment in the economy.
The main approaches to the definition of "startup" and "ecosystem" are analyzed. In a startup ecosystem, all actors involved are connected. Entrepreneurs come together to share ideas and interact with universities to attract future employees, and investors learn to understand which types of entrepreneurs, teams and startups are most likely to succeed and exit, investing in startups to raise new capital.
Models of cluster analysis of processes of formation of startup ecosystems are constructed, which gave the chance to generalize ratings of ecosystems of the countries on 5 clusters. The purpose of cluster analysis is the formation of relatively homogeneous groups (clusters) in the space of variables based on a set of models and methods of aggregation of rows of the data matrix. The use of cluster analysis has a certain sequence of actions and involves the use of several methods. The grouping included 96 countries (4 countries that were included in the ranking for the first time were excluded automatically), which created 5 clusters that differ from each other, but have common characteristics within the selected groups. Each cluster is characterized by features. This division into clusters allowed to highlight the features of the development of startup ecosystems, provide characteristics of each group of countries and in the future will be the basis for developing recommendations and formulating strategies for the development of startup ecosystems.
THEORETICAL PRINCIPLES AND PROSPECTS OF USING MODELS OF FUNCTIONING OF SOCIALLY RESPONSIBLE BUSINESS
Authors: Romanovska A. , Velichko V.
Published: June 2022

The article considers the features, disadvantages and advantages of existing models of socially responsible business. The state of socially responsible business in Ukraine is also analyzed, the main obstacles to development are identified. Based on the results obtained, ways to overcome obstacles and prospects for dissemination are proposed. The main incentives for the implementation of CSR would be the introduction of preferential taxation, reducing administrative pressure on local authorities and providing them with proposals for social development programs in the region.
In the context of globalization of the modern market, an increasing number of large enterprises in developed countries are paying attention to issues of socially oriented business. Corporate citizens, along with their core business activities, carry out activities aimed at solving social, environmental and other problems in the community. Corporate social responsibility is beginning to be used as one of the indicators of ensuring the competitiveness of the enterprise.
Such changes in the socio-economic environment require a more detailed analysis of the criteria of socially responsible and socially oriented business to build an effective model of operation of the entity.
In world practice, there are several models of socially responsible business, due to national and cultural characteristics of doing business. They correspond to three models of corporate governance. These are American, European and Japanese models.
These models of CSR are quite common and are based on the cultural traditions of countries, economic and environmental situation.
As for Ukrainian enterprises, companies do not perceive CSR as a policy that is integrated into the company's business strategy and is a factor of competitive advantage in the market. To develop CSR, it is necessary to develop a legal framework that would promote these activities, raise awareness of responsible business behavior, introduce CSR courses in university programs and increase the participation of business associations in promoting practices.
Design and Build a Web App-Based Conference Registration System Using the Waterfall Model
Authors: Fawaidul Badri  , Maulana Ridwan , Khotimah Khusnul , Budiarti Rizqi Putri Nourma , Andhyka Awang
Published: June 2022

During the pandemic, many events are held online. conference registration (webinars, seminars, workshops) which basically will cause its complexity for admins if there are excess registrants or over participants from achieving the registration quota target. In addition, the admin must monitor regularly to ensure that there are no excess registrants that result in inefficient. The method used in the development of this application is the waterfall method. The purpose of this research is to build a web-based conference registration system that can make it easier for admins/organizers to manage the registration process. The results of this study the system can display the results of the recap from the admin so that the user can see the quota from the conference registration organized by the committee as well as testing of users from several tests to produce an application system that runs well.
Powszechność w głosowaniu korespondencyjnym w dobie COVID-19. Wybrane zagadnienia
Authors: Kobylski Piotr
Published: June 2022

W artykule omówiono jedną z instytucji systemu wyborczego w dobie pandemii COVID-19. Wybory to proces wybierania przez obywateli przedstawicieli na określone stanowiska. Istotne w tym kontekście są sposób i zasady przeprowadzania elekcji, tak by zachowana została jej fundamentalna reguła - powszechność. Chociaż od 1989 r. obowiązywało kilkanaście ordynacji wyborczych, a tradycyjny model oddania głosu w lokalu wyborczym nadal funkcjonował, to polski ustawodawca przewidział także głosowanie korespondencyjne oraz za pośrednictwem pełnomocnika. Z uwagi na ryzyko związane z pandemią COVID-19 wydawać by się mogło, że dalsze zmiany w polskim Kodeksie wyborczym będą niezbędne. Dostosowanie nowych przepisów do Konstytucji RP z 1997 r. okazało się jednak dla krajowego ustawodawcy zbyt ambitnym zadaniem. Niniejsze opracowanie ma charakter empiryczny - to studium przypadku konkretnego działania legislacyjnego pokazanego w ujęciu porównawczym na przykładzie Polski i Stanów Zjednoczonych Ameryki Północnej.
Wybory korespondencyjne w Bawarii 29 marca 2020 r. a COVID-19. Analiza empiryczna na tle debaty o zasadności organizacji wyborów w czasie pandemii
Authors: Radwan Arkadiusz , Horonziak Sonia
Published: June 2022

W marcu 2020 r., a więc w czasie trwania pandemii COVID-19, w Bawarii odbyły się wybory samorządowe: 15 marca - pierwsza tura wyborów (w formie tradycyjnej oraz korespondencyjnej), a 29 marca - druga tura (jedynie w formie korespondencyjnej). Zmiana reguł głosowania między I a II turą nastąpiła w atmosferze politycznej zgody, za aprobatą wszystkich frakcji parlamentarnych. Druga tura była zorganizowana w okręgach, w których głosowanie w pierwszej turze nie przyniosło rozstrzygnięcia. Takich okręgów było 34, spośród ogólnej liczby 96 bawarskich okręgów wyborczych. W ten sposób wytworzyła się próba badawcza obejmująca wspomniane 34 okręgi, losowo i równomiernie rozproszone po terytorium całego landu, oraz próba kontrolna obejmująca pozostałe 62 okręgi. Celem niniejszego artykułu jest zweryfikowanie hipotezy głoszącej, że zorganizowanie w Bawarii w marcu 2020 r., tj. w czasie trwania pandemii, wyborów w formie korespondencyjnej doprowadziło do wzrostu liczby przypadków COVID-19. Wyniki tego badania mogą być interesujące dla toczonej w Polsce w kwietniu i maju 2020 r. - i nigdy ostatecznie nierozstrzygniętej - dyskusji na temat zasadności organizacji wyborów korespondencyjnych w czasie pandemii pod względem bezpieczeństwa epidemiologicznego. Przykład Bawarii był bowiem przywoływany zarówno przez zwolenników, jak i przeciwników zorganizowania w Polsce wyborów prezydenckich w formie wyborów "kopertowych" - odpowiednio jako argument na rzecz albo przeciwko przeprowadzeniu głosowania zgodnie z pierwotnie przyjętym kalendarzem wyborczym. W niniejszym artykule zaprezentowano dane empiryczne oraz zaproponowano ich interpretację celem weryfikacji sformułowanej wyżej hipotezy, a przez to rozstrzygnięcie wzmiankowanej dyskusji na temat epidemiologicznego wymiaru wyborów korespondencyjnych.
ACTITUDES DE LOS DOCENTES HACIA LA EDUCACIÓN INCLUSIVA. ANÁLISIS DE LAS VARIABLES QUE INFLUYEN EN SU CONFIGURACIÓN
Authors: Lacruz-Pérez Irene , Fernández-Andrés Ma. Inmaculada , Tárraga-Mínguez Raúl
Published: June 2022

El propósito de este trabajo fue analizar las actitudes de los docentes hacia la educación inclusiva en educación infantil y primaria, y determinar algunos de los factores que infuyen en la confguración de estas actitudes. Ciento veintiocho docentes de diferentesescuelas de la Comunidad Valenciana (España) completaron un cuestionario que evalúa las actitudes del profesorado hacia la inclusión. Se analizó mediante un ANOVA la infuencia del puesto de trabajo (maestro/a generalista o especialista de educación especial) y del modelo inclusivo de centro educativo donde desarrollaban su trabajo. Asimismo, se realizaron correlaciones entre las actitudes hacia la inclusión, y dos variables sobre la trayectoria de los docentes: su experiencia con alumnado con necesidades específcas de apoyo educativo (NEAE) y sus años totales de experiencia docente. Los resultados muestran que estos cuatro factores están estrechamente relacionados con las actitudes del profesorado hacia la educación inclusiva. El artículo concluye con algunasrecomendaciones en el ámbito de la formación inicial y continua del profesorado, y además destaca la necesidad de intensifcar la formación en materia de inclusión para todos los docentes (no solo para los especialistas en educación especial), y la conveniencia de desarrollar en la formación inicial prácticas escolares en contextos inclusivos.

Palabras claveActitudes, educación inclusiva, formación de profesorado, maestros, necesidades específcas de apoyo educativo.

AbstractThe aim of this study was to analyze the attitudes towards inclusive education of early childhood and primary education teachers and to determine some of the factors that infuence the shaping of these attitudes. One hundred and twenty-eight teachers from diferent schools in the Valencian Community (Spain) flled in a questionnaire that assesses the attitudes of teachers towards inclusion. The infuence of the job position (mainstream teacher or special education specialist) and the inclusive model of the school where they worked were analyzed through ANOVA. Likewise, correlations were made between attitudes towards inclusion and two variables on the teachers’ trajectory: their experience with students with specifc needs of educational support (SNES) and their years of teaching experience. The results show that these four factors were closely related to teachers attitudes towards inclusive education. Thepaper concludes with some recommendations in the feld of initial and continuing teacher training, highlighting the need to intensify training on inclusion for all teachers (not only for specialists in special education), and the convenience of developing school internships in inclusive contexts during the initial teaching training.

KeywordsAttitudes, inclusive education, specifc needs of educational support, teachers, teacher training
GAMBARAN MEKANISME KOPING IBU YANG MEMILIKI ANAK BERKEBUTUHAN KHUSUS DI SLB NEGERI 2 INDRAMAYU
Authors: Husnaniyah Dedeh , Kamsari Kamsari , Nursoleha Nia
Published: June 2022

Coping mechanisms are the means by which individuals solve problems and changes. Parents who have ABK (children with special needs) result in the emerge new changes in the family and cause different coping mechanisms of each mother. This research is to know how to describe the coping mechanism of mother who have children with special needs in SLB Negeri 2 Indramayu.The research design used is quantitative research with descriptive approach. The population of mothers who have children in SLB Negeri 2 Indramayu. The data analysis using univariate. The population is 91 respondents.The results showed that in general the mechanism of coping mother includes 52.4% of respondents who have adaptive coping mechanism. Mother coping mechanism based on final adult category 61,0% of respondents have adaptive coping mechanism. Mechanism of coping mother based on education with high school education category 54,1% of respondents have adaptive coping mechanism. Mechanism of coping mother based on occupation category of housewife 52,4% of respondents have adaptive coping mechanism.Conclusion of research entitled Description of Mechanism of Mother Coping Who Have Children with Special Needs In SLB Negeri 2 Indramayu is adaptive coping mechanism.
PROFIL PENGELOLAAN EMERGENCY TROLLEY DI INSTALASI GAWAT DARURAT (IGD) RUMAH SAKIT UMUM DAERAH Dr.M.YUNUS BENGKULU
Authors: Sihotang Febrianti
Published: June 2022

Emergency trolley is a trolley that contains equipment and medicines for emergencies, where there is a sudden and unexpected deterioration in the clinical condition of the patient which can immediately cause death or cause long-term health so that immediate intervention or resuscitation is needed. Good management of emergency trolley can improve the quality of health services in the environment of Dr. M.Yunus Bengkulu Hospital, especially emergency services. The research has been conducted on the management of emergency trolley in the Emergency Room of Dr. M.Yunus Bengkulu Hospital. Emergency trolley at Dr. M.Yunus Bengkulu Hospital guides and applies emergency trolley management standards according to procedures so that the quantity and quality of storage and completeness are maintained. The purpose of this research is to determine the readiness and availability of emergency trolley management standards, especially in the Emergency Room Installation  Dr. M.Yunus Bengkulu Hospital. This research is descriptive in nature with a qualitative approach, primary data collection through direct observation, comprising of observing human resources, facilities and infrastructure as well as the process of managing an emergency trolley at RSUD Dr. M.Yunus Bengkulu Hospital. Secondary data collection is conducted through tracing guidelines or procedures for managing emergency trolley used, as well as documents related to management of emergency trolley at RSUD Dr. M.Yunus Bengkulu Hospital. The results of the study are compiled and presented in the form of a checklist table of observations and in the form of a narrative about human resources, facilities and infrastructure as well as the process of managing an emergency trolley at Dr. M.Yunus Bengkulu  Hospital.
Effects of Nitrogen and Phosphorus Concentrations on the Growth and Lipid Accumulation of Microalgae Scenedesmus obliquus
Authors: USLU Leyla , IŞIK Oya , BARIŞ Yasemin , SAYIN Selin
Published: June 2022

In the study, Scenedesmus obliquus green algae was cultivated under laboratory conditions at 21±2°C, 16:8 (light:dark) photoperiod and continuous aeration in different nitrogen and phosphorus ratio nutrient medium and its growth was determined. Dry weight, cell density (optical density) and chlorophyll a and b were used to determine the growth of the algae. The best growth was determined in the group consisting of 30 ml NaNO3+10 ml PO4. The amount of biomass obtained was determined as 1.549 gL-1 in this group. The lowest values were the group containing 5 ml NaNO3+5 ml PO4. With the decrease in the amount of nitrogen in the medium, an increase in the amount of carotene and a decrease in the amount of chl a and b were detected. The highest lipid values were determined as 36.7% in the group containing 5 ml NaNO3+5 ml PO4 and 36.2% in the group containing 5 ml NaNO3+10 ml PO4.
Carotenoid Composition and Investigation of the Antioxidant Activity of Phormidium sp.
Authors: ALUÇ Yaşar
Published: June 2022

Microalgae metabolites are used for health, feed additives, cosmetic industries, food and biodiesel production. Phormidium species have an important position in medical studies because they contain essential components. In this study, carotenoid profile and content were analyzed using the HPLC method. Antioxidant activities for Phormidium sp. were determined using DPPH and FRAP assays. BHT and ASC were used as control samples in antioxidant assays. The method used to resolve a number of carotenoids from saponified Phormidium sp. proved acceptable separation, as evidenced by retention factor (k) values of 0.54 to 3.83 and separation factor (α) values greater than 1. Main carotenoids were dominated by the two main derivatives, all-trans form of lutein 41.35% (1.25 mg/g) and 9-or 9’-cis-β-carotene 36.43% (1.10 mg/g). Auroxanthin and cis neoxanthin were identified as epoxy-containing compounds. It is also understood that considering the DPPH assay, the extract of Phormidium sp. (IC50:127.6 mg/L) exhibited clearly low radical scavenging activity compared to the standards ASC (IC50: 0.02 mg/L) and BHT (IC50: 0.19 mg/L). In the FRAP antioxidant experiment, the mean ASC and BHT equivalent amounts were determined as 828.6 and 124.6 mg/L, respectively. Quantitatively, Phormidium sp. was predominated by cis-Lutein as a major constituent, being 41.35% (3.02 mg/g) in total carotenoids (Tc). The antioxidant capacity of Phormidium sp. that considering the DPPH and FRAP were compared to control standards were showed considerably low effects.
Phonological Awareness in Arabic among Early Grade Teachers
Authors: Bani Hani Hanady
Published: June 2022

Early-grade teachers’ ability to incorporate high-quality explicit phonological
awareness (PA) instruction into the classroom helps children succeed in early reading
endeavors and significantly reduces reading difficulties among children at risk for reading
problems. Teachers’ deep knowledge of teaching PA is expected to affect their reading
instructional practices inside the classrooms. This study aims to gain perspective on early
grade teachers’ perceptions, knowledge, and practices related to teaching PA skills in the
Arabic language. To this end, a modified survey instrument was completed by 109 Arabic
language teachers at kindergarten and primary grade levels. Results reveal that although
teachers recognize the significance of PA for reading development, many show poor
knowledge of certain PA fundamentals and do not formally assess PA or provide adequate
and explicit PA instruction in their classrooms. Furthermore, results show that teachers
with more teaching experience provide their students with more chances to complete PA
activities in the classroom. These findings suggest a need to provide Arabic language
teachers with adequate knowledge and training as well as assessment and teaching
materials to enable them to provide the required PA skills, as a crucial reading skill, in the
classroom..
From “My Dovecote” to “My Building”:
Intertextuality in Jarrar’s “The Story of My Building”
Authors: Abu Amrieh Yousef
Published: June 2022

This paper aims at investigating how Arab American writer Randa Jarrar’s
short story “The Story of My Building” (2016) appropriates events, themes, tropes and
motifs employed by Russian writer Isaac Babel in his short story “The Story of My
Dovecote” (1925) to portray the hard conditions and circumstances that Palestinians
endure due to recurrent Israeli military attacks on the Gaza Strip. Jarrar’s story alludes
to anti-Semitic violence, known as pogroms, that marred the lives of Jews in Russia in the
nineteenth century and early twentieth century. Through strategic employment of
intertextuality, Jarrar’s story vividly portrays how a child’s dream of building a dovecote
has turned into a nightmare due to the demolition of his house by Israeli tanks. Borrowing
certain episodes from Babel’s story, Jarrar sets up a link between her story and Babel’s,
creating a parallelism between Palestinian people’s aches and anguishes at the hands of
Israeli military forces at the start of the twenty-first century and Russian Jews’ sufferings
and torments at the hands of pogromists almost a century ago. The connection between
the stories is made even stronger as each story is narrated by a smart ten-year-old boy
who is traumatized by the pillage and carnage he witnesses and experiences. In Jarrar’s
story, Israeli tanks destroy the protagonist’s house and kill civilians; similarly, pogromists
loot the protagonist’s house and murder his grandfather. Eventually, the two boys are
reunited with their families who have taken refuge at a friend’s house. Yet, while Babel’s
protagonist does not lose his house, in Jarrar’s story the protagonist’s family along with
several other Palestinian families become homeless and displaced..
Translating Children’s Literature Using a Pivot Language
Authors: Abdel-Fattah Mahmoud
Published: June 2022

Any attempt to translate a text may result in distortion(s) of the meaning intended
by the original author, and sometimes it may even lead to loss of original meaning. This
effect may be amplified if it is necessary to work through a pivot language. However,
communication between the translators and, if possible, the authors of the original texts
will facilitate the process of translation and may eliminate much of the possible distortion
of meaning and other unwanted translation flavors. The phenomenon of “mediated
translation” is explored here through reflections on translated works of a variety of
children’s literature from and into Arabic through English into Gaelic and vice versa. The
study first provides a brief introduction to and definition of mediated translation, and then
gives an account of the pros and cons of mediated translation, before proceeding to consider
the main challenges of translating for children, in particular, when a pivot language is
involved. The study will also focus on such issues as cross-cultural communication and
translation.
.
Nuclear Mechanosensation and Mechanotransduction in Vascular Cells
Authors: Salvador Jocelynda , Iruela-Arispe M. Luisa
Published: June 2022

Vascular cells are constantly subjected to physical forces associated with the rhythmic activities of the heart, which combined with the individual geometry of vessels further imposes oscillatory, turbulent, or laminar shear stresses on vascular cells. These hemodynamic forces play an important role in regulating the transcriptional program and phenotype of endothelial and smooth muscle cells in different regions of the vascular tree. Within the aorta, the lesser curvature of the arch is characterized by disturbed, oscillatory flow. There, endothelial cells become activated, adopting pro-inflammatory and athero-prone phenotypes. This contrasts the descending aorta where flow is laminar and endothelial cells maintain a quiescent and atheroprotective phenotype. While still unclear, the specific mechanisms involved in mechanosensing flow patterns and their molecular mechanotransduction directly impact the nucleus with consequences to transcriptional and epigenetic states. The linker of nucleoskeleton and cytoskeleton (LINC) protein complex transmits both internal and external forces, including shear stress, through the cytoskeleton to the nucleus. These forces can ultimately lead to changes in nuclear integrity, chromatin organization, and gene expression that significantly impact emergence of pathology such as the high incidence of atherosclerosis in progeria. Therefore, there is strong motivation to understand how endothelial nuclei can sense and respond to physical signals and how abnormal responses to mechanical cues can lead to disease. Here, we review the evidence for a critical role of the nucleus as a mechanosensor and the importance of maintaining nuclear integrity in response to continuous biophysical forces, specifically shear stress, for proper vascular function and stability.
Molecular Dissection of a Conserved Cluster of miRNAs Identifies Critical Structural Determinants That Mediate Differential Processing
Authors: Pandey Manish , Luhur Arthur , Sokol Nicholas S. , Chawla Geetanjali
Published: June 2022

Differential processing is a hallmark of clustered microRNAs (miRNAs) and the role of position and order of miRNAs in a cluster together with the contribution of stem-base and terminal loops has not been explored extensively within the context of a polycistronic transcript. To elucidate the structural attributes of a polycistronic transcript that contribute towards the differences in efficiencies of processing of the co-transcribed miRNAs, we constructed a series of chimeric variants of Drosophila let-7-Complex that encodes three evolutionary conserved and differentially expressed miRNAs (miR-100, let-7 and miR-125) and examined the expression and biological activity of the encoded miRNAs. The kinetic effects of Drosha and Dicer processing on the chimeric precursors were examined by in vitro processing assays. Our results highlight the importance of stem-base and terminal loop sequences in differential expression of polycistronic miRNAs and provide evidence that processing of a particular miRNA in a polycistronic transcript is in part determined by the kinetics of processing of adjacent miRNAs in the same cluster. Overall, this analysis provides specific guidelines for achieving differential expression of a particular miRNA in a cluster by structurally induced changes in primary miRNA (pri-miRNA) sequences.
Single-Cell Transcriptome Analysis Reveals Changes of Tumor Immune Microenvironment in Oral Squamous Cell Carcinoma After Chemotherapy
Authors: Song Hao , Lou Chao , Ma Jie , Gong Qiyu , Tian Zhuowei , You Yuanhe , Ren Guoxin , Guo Wei , Wang Yanan , He Kunyan , Xiao Meng
Published: June 2022

Induction chemotherapy in oral squamous cell carcinoma is a controversial issue in clinical practice. To investigate the evolution of cancer cells and tumor microenvironment (TME) response to chemotherapy in oral squamous cell carcinoma, single-cell transcriptome analysis was performed in a post-chemotherapy squamous cell carcinoma located in oral cavity. The main cell types were identified based on gene expression patterns determined using dimensionality reduction and unsupervised cell clustering. Non-negative matrix factorization clustering of the gene expression of Cancer-associated fibroblasts (CAFs) and macrophages was performed. Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene set enrichment analysis were performed to explore significant functional pathways. CellPhoneDB and NicheNet were used to detect the intercellular communication between cell types. CAFs were divided into “inflammatory CAFs,” “antigen-presenting CAFs” and “myofibroblastic CAFs.” Three classic subgroups of tumor-associated macrophages (TAMs) were detected, namely C1Q (+), FCN1 (+) and SPP1(+) TAMs. The inflammatory cytokine expression is elevated, and several molecular pathways, such as PI3K/Akt/mTORC1, TNF-α via NFκB, TGF-β, IL-6/JAK2/STAT3 and CXCL12/CXCR4 axis associated with epithelial-mesenchymal transition were enriched in TME. Also, CD74-MIF/COPA/APP interactions were expressed in TME of oral squamous cell carcinoma after chemotherapy. The results revealed the characteristics of TME in post-chemotherapy oral squamous cell carcinoma at single-cell transcriptome level, providing new insights and clues for further investigation.
Characterization of Ligand-Receptor Pair in Bladder Cancer Develops a Validated Scoring Model for Prognosis and Treatment Response
Authors: Wang Chuang , Wan Honglei , Zhang Han , Yang Bo , Huang Wen-Kuan , Sun Wenguo
Published: June 2022

The role of ligand-receptor (LR) pairs in disease progression has been explored in bladder cancer. However, the relationship of LR pairs with cancer prognosis and treatment response remains poorly understood. We characterized the LR pair network and identified three distinct molecular subtypes with distinct biologic features based on the TCGA database (n = 406) and validated in GSE13507 (n = 165) and GSE32894 (n = 224). Three subtypes were compared for differences in patient clinical characteristics, genomic, and transcriptomic features. A multivariate Lasso Cox regression model was applied to construct an LR pairs-based scoring model to stratify the prognostic risk of patients. We demonstrated the high LR. score patients had better responses in chemotherapy, while low LR. score patients may benefit from immune checkpoint blockade (ICB). Collectively, we identified three LR pair-related subtypes associated with prognosis. We constructed and validated a LR pairs-based gene signature, which helps to predict prognosis and differentiate the susceptible population to chemotherapy and immunotherapy in patients with bladder cancer. Among the LR pairs significantly related to prognosis, ANAX1−EGFR axis was found to be potential therapeutic target for treatment of bladder cancer.
Synthesis and Biological Activity Evaluation of 2-Cyanopyrrole Derivatives as Potential Tyrosinase Inhibitors
Authors: Hu Ya-Guang , Gao Zhu-Peng , Zheng Ying-Ying , Hu Chun-Mei , Lin Jing , Wu Xiao-Zheng , Zhang Xin , Zhou Yong-Sheng , Xiong Zhuang , Zhu Dao-Yong
Published: June 2022

In order to find potential inhibitors of tyrosinase, two series of pyrrole derivatives A (1–17) and B (1–8) were synthesized and screened for their inhibitory activities on tyrosinase. Most of the 2-cyanopyrrole derivatives exhibited effective inhibitory activities. In particular, A12 exhibited the strongest inhibitory activities, with the IC50 values of 0.97 μM, which is ∼30 times stronger than the reference inhibitor kojic acid (IC50: 28.72 μM). The inhibitory mechanism analysis results revealed that A12 was a reversible and mixed-type inhibitor. Molecular docking experiments clarified the interaction between A12 with tyrosinase. Furthermore, A12 (100 μM) presented effective inhibitory effect on tyrosinase in B16 melanoma cells with inhibition of 33.48%, which was equivalent to that of Kojic acid (39.81%). Accordingly, compound A12 may serve as the lead structure for the further design of potent tyrosinase inhibitors. Molecular docking studies confirmed the interaction between the compound and tyrosinase.
An Unusual U2AF2 Inhibits Splicing and Attenuates the Virulence of the Human Protozoan Parasite Entamoeba histolytica
Authors: González-Blanco Gretter , García-Rivera Guillermina , Talmás-Rohana Patricia , Orozco Ester , Galindo-Rosales José Manuel , Vélez Cristina , Salucedo-Cárdenas Odila , Azuara-Liceaga Elisa , Rodríguez-Rodríguez Mario Alberto , Nozaki Tomoyoshi , Valdés Jesús
Published: June 2022

E. histolytica is the etiological agent of intestinal amebiasis and liver abscesses, which still poses public health threat globally. Metronidazole is the drug of choice against amebiasis. However, metronidazole-resistant amoebic clinical isolates and strains have been reported recently, challenging the efforts for amebiasis eradication. In search of alternative treatments, E. histolytica transcriptomes have shown the association of genes involved in RNA metabolism with the virulence of the parasite. Among the upregulated genes in amoebic liver abscesses are the splicing factors EhU2AF2 and a paralog of EhSF3B1. For this reason and because EhU2AF2 contains unusual KH-QUA2 (84KQ) motifs in its lengthened C-terminus domain, here we investigated how the role of EhU2AF2 in pre-mRNA processing impacts the virulence of the parasite. We found that 84KQ is involved in splicing inhibition/intron retention of several virulence and non-virulence-related genes. The 84KQ domain interacts with the same domain of the constitutive splicing factor SF1 (SF1KQ), both in solution and when SF1KQ is bound to branchpoint signal RNA probes. The 84KQ–SF1KQ interaction prevents splicing complex E to A transition, thus inhibiting splicing. Surprisingly, the deletion of the 84KQ domain in EhU2AF2 amoeba transformants increased splicing and enhanced the in vitro and in vivo virulence phenotypes. We conclude that the interaction of the 84KQ and SF1KQ domains, probably involving additional factors, tunes down Entamoeba virulence by favoring intron retention.
Spatio-Temporal Patterns and Source-Dispersion Modeling Towards Sloth Bear–Human Conflict Management in Central India
Authors: Chaudhuri Sankarshan , Bandyopadhyay Meghna , Rajaraman Rajasekar , Kalyanasundaram Sankar , Sathyakumar Sambandam , Krishnamurthy Ramesh
Published: June 2022

The impact of humans on biodiversity, in the form of the spatially extensive occurrence of humans and subsequent habitat degradation, leads to negative interactions between humans and native wildlife. However, knowledge of the spatial and temporal interface between humans and wildlife is necessary to understand the root cause of such negative interactions, yet considerably understudied in the context of human-dominated landscapes in south and south-eastern Asia. We took this opportunity, gaining insights on seasonal spatial interaction and spatio-temporal overlap between sloth bears (Melursus ursinus) and humans, and subsequently predicted the conflict source sites and dispersion (i.e., hotspots) based on the robust geographic profiling (GP) method in the Sanjay Tiger Reserve (STR), a human-dominated landscape of central India. Detection data of sloth bear and human were obtained from camera trap survey conducted for two years (2017–2018) and records of conflict incidents (2009–2019) were collected from forest department. We found that sloth bears can co-occur with humans independently of seasons, based on occupancy models. However, during summer, higher temporal overlap (Δ4 = 0.46) and lower spatial overlap (0.31) were observed between sloth bears and humans. Contrastingly, lower temporal overlap (Δ4 = 0.29) and higher spatial overlap (0.44) were observed between the same two during winter. The activity patterns of sloth bears and humans differed significantly across seasons and within the same species in different seasons. Our findings indicated that significant changes in human activity, especially during summer, increased the likelihood of sloth bear-human interaction and subsequent conflict incidents. The mapping of conflict source and dispersion (with high accuracy) also predicted a greater probability of conflict during summer, compared to winter, and thus showed the successful application of GP models in this field. Also, camera trap data alone were able to predict the occurrence of hotspots, demonstrating the use of camera trap records in the successful prediction of source-dispersion of conflict. This study would be useful for decision-makers to alleviate sloth bear–human conflict based on insights on seasonal variation of spatio-temporal overlap between the two and direct conservation efforts accordingly.
Comprehensive Proteomics Profiling Identifies Patients With Late Gadolinium Enhancement on Cardiac Magnetic Resonance Imaging in the Hypertrophic Cardiomyopathy Population
Authors: Lander Bradley S. , Zhao Yanling , Hasegawa Kohei , Maurer Mathew S. , Tower-Rader Albree , Fifer Michael A. , Reilly Muredach P. , Shimada Yuichi J.
Published: June 2022

Introduction

In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) represents myocardial fibrosis and is associated with sudden cardiac death. However, CMR requires particular expertise and is expensive and time-consuming. Therefore, it is important to specify patients with a high pre-test probability of having LGE as the utility of CMR is higher in such cases. The objective was to determine whether plasma proteomics profiling can distinguish patients with and without LGE on CMR in the HCM population.

Materials and Methods

We performed a multicenter case-control (LGE vs. no LGE) study of 147 patients with HCM. We performed plasma proteomics profiling of 4,979 proteins. Using the 17 most discriminant proteins, we performed logistic regression analysis with elastic net regularization to develop a discrimination model with data from one institution (the training set; n = 111) and tested the discriminative ability in independent samples from the other institution (the test set; n = 36). We calculated the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity.

Results

Overall, 82 of the 147 patients (56%) had LGE on CMR. The AUC of the 17-protein model was 0.83 (95% confidence interval [CI], 0.75–0.90) in the training set and 0.71 in the independent test set for validation (95% CI, 0.54–0.88). The sensitivity of the training model was 0.72 (95% CI, 0.61–0.83) and the specificity was 0.78 (95% CI, 0.66–0.90). The sensitivity was 0.71 (95% CI, 0.49–0.92) and the specificity was 0.74 (95% CI, 0.54–0.93) in the test set. Based on the discrimination model derived from the training set, patients in the test set who had high probability of having LGE had a significantly higher odds of having LGE compared to those who had low probability (odds ratio 29.6; 95% CI, 1.6–948.5; p = 0.03).

Conclusions

In this multi-center case-control study of patients with HCM, comprehensive proteomics profiling of 4,979 proteins demonstrated a high discriminative ability to distinguish patients with and without LGE. By identifying patients with a high pretest probability of having LGE, the present study serves as the first step to establishing a panel of circulating protein biomarkers to better inform clinical decisions regarding CMR utilization.
Colchicine for the Treatment of Cardiac Injury in Hospitalized Patients With Coronavirus Disease-19
Authors: Rabbani Amir , Rafique Asim , Wang Xiaoyan , Campbell Danielle , Wang Daniel , Brownell Nicholas , Capdevilla Kenia , Garabedian Victoria , Chaparro Sandra , Herrera Raul , Parikh Rushi V. , Ardehali Reza
Published: June 2022

Introduction

The impact of colchicine on hospitalized patients with Coronavirus disease-19 (COVID-19) related cardiac injury is unknown.

Materials and Methods

In this multicenter randomized controlled open-label clinical trial, we randomized hospitalized adult patients with documented COVID-19 and evidence of cardiac injury in a 1:1 ratio to either colchicine 0.6 mg po twice daily for 30 days plus standard of care or standard of care alone. Cardiac injury was defined as elevated cardiac biomarkers, new arrhythmia, new/worsened left ventricular dysfunction, or new pericardial effusion. The primary endpoint was the composite of all-cause mortality, need for mechanical ventilation, or need for mechanical circulatory support (MCS) at 90 days. Key secondary endpoints included the individual components of the primary endpoint and change in and at least 2-grade reduction in the World Health Organization (WHO) Ordinal Scale at 30 days. The trial is registered with clinicaltrials.gov (NCT04355143).

Results

We enrolled 93 patients, 48 patients in the colchicine arm and 45 in the control arm. There was no significant difference in the primary outcome between the colchicine and control arms (19 vs. 15%, p = 0.78), nor in the individual components of all-cause mortality (17 vs. 15%, p = 1.0) and need for mechanical ventilation (8 vs. 5%, p = 0.68); no patients in either group required MCS. The change in (−1.8 ± 2.4 vs. −1.2 ± 2.0, p = 0.12) and at least 2-grade reduction (75 vs. 75%, p = 1.0) in the WHO ordinal scale was also similar between groups.

Conclusion

Patients hospitalized with COVID-19 and evidence of cardiac injury did not benefit from colchicine therapy.
Significance and Determinants of Plasma Apelin in Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: Yang Chengzhi , Zhang Changlin , Jia Ruofei , Qiao Shubin , Yuan Jiansong , Jin Zening
Published: June 2022

Background

Recent studies suggest apelin has multiple protective effects in some cardiovascular diseases. However, there are few data concerning apelin levels in patients with obstructive hypertrophic cardiomyopathy (OHCM) or the relationship between apelin levels and severity of OHCM.

Methods

We studied 88 patients with OHCM and 32 control subjects with matched age and sex distribution. Complete medical history was collected and related examinations were performed. Cardiac magnetic resonance (CMR) and echocardiography were employed to characterize cardiac morphology and function. Plasma apelin was measured by enzyme-linked immunosorbent assay (ELISA).

Results

Plasma apelin levels were significantly lower in patients with OHCM than those in control subjects (96.6 ± 34.3 vs. 169.4 ± 62.5 μg/L, p < 0.001). When patients with OHCM were divided into two groups according to the mean value of plasma apelin, patients with lower apelin levels (plasma apelin ≤ 96.6 μg/L) had greater septal wall thickness (SWT; 25.6 ± 5.5 vs. 23.2 ± 4.3 mm, p = 0.035) and less right ventricular end-diastolic diameter (RVEDD; 20.4 ± 3.3 vs. 23.0 ± 3.6 mm, p = 0.001). Consistently, plasma apelin levels were inversely correlated with SWT (r = −0.334, p = 0.002) and positively correlated with RVEDD (r = 0.368, p < 0.001). Besides, plasma apelin levels were inversely correlated with Ln (NT-proBNP) (r = −0.307, p = 0.008) and positively correlated with body mass index (BMI; r = 0.287, p = 0.008). On multivariate analysis, the SWT was independently associated with decreasing plasma apelin, while the RVEDD was independently associated with increasing plasma apelin.

Conclusion

Plasma apelin levels are reduced in patients with OHCM. The apelin levels are inversely related to SWT and positively related to RVEDD.
Renin-Angiotensin-System Inhibitors Are Associated With Lower In-hospital Mortality in COVID-19 Patients Aged 80 and Older
Authors: Spannella Francesco , Giulietti Federico , Di Pentima Chiara , Allevi Massimiliano , Bordoni Valentina , Filipponi Andrea , Falzetti Sara , Garbuglia Caterina , Scorcella Samuele , Giordano Piero , Sarzani Riccardo
Published: June 2022

Background

Older adults are at higher risk of morbidity and mortality for coronavirus disease 2019 (COVID-19). Renin-angiotensin-system inhibitors (RASi) were found to have a neutral or protective effect against mortality in COVID-19 adult patients.

Aims

We investigated whether this association was confirmed also in COVID-19 older patients.

Methods

This is a prospective observational study on 337 hospitalized older adults (aged 80 years and older). We classified the study population according to usage of RASi before and during hospitalization. A propensity score analysis was also performed to confirm the findings.

Results

The mean age was 87.4 ± 6.1 years. Patients taking RASi at home were 147 (43.6%). During hospitalization, 38 patients (11.3% of the entire study population) discontinued RASi, while 57 patients (16.9% of the entire study population) started RASi. In-hospital mortality was 43.9%. Patients taking RASi during hospitalization (patients who maintained their home RASi therapy + patients who started RASi during hospitalization) had a significantly lower in-hospital mortality than untreated patients [HR 0.48 (95% CI: 0.34–0.67)], even after adjustment for required respiratory support, functional status, albumin, inflammation, and cardiac biomarkers. The analysis of the groups derived from the “propensity score matching” (58 patients in each group) confirmed these results [HR 0.46 (95% CI: 0.23–0.91)].

Discussion

Despite the high risk of death in older COVID-19 patients, RASi therapy during hospitalization was associated with a clinically relevant lower in-hospital mortality, likely due to the benefit of RAS modulation on the cardiopulmonary system during the acute phase of the disease.

Conclusion

Our findings confirm the protective role of RASi even in COVID-19 patients aged 80 years and older.
Alterations of Cardiac Protein Kinases in Cyclic Nucleotide-Dependent Signaling Pathways in Human Ischemic Heart Failure
Authors: Wang Chunguang , Taskinen Juuso H. , Segersvärd Heli , Immonen Katariina , Kosonen Riikka , Tolva Johanna M. , Mäyränpää Mikko I. , Kovanen Petri T. , Olkkonen Vesa M. , Sinisalo Juha , Laine Mika , Tikkanen Ilkka , Lakkisto Päivi
Published: June 2022

Objectives

Impaired protein kinase signaling is a hallmark of ischemic heart disease (IHD). Inadequate understanding of the pathological mechanisms limits the development of therapeutic approaches. We aimed to identify the key cardiac kinases and signaling pathways in patients with IHD with an effort to discover potential therapeutic strategies.

Methods

Cardiac kinase activity in IHD left ventricle (LV) and the related signaling pathways were investigated by kinomics, transcriptomics, proteomics, and integrated multi-omics approach.

Results

Protein kinase A (PKA) and protein kinase G (PKG) ranked on top in the activity shift among the cardiac kinases. In the IHD LVs, PKA activity decreased markedly compared with that of controls (62% reduction, p = 0.0034), whereas PKG activity remained stable, although the amount of PKG protein increased remarkably (65%, p = 0.003). mRNA levels of adenylate cyclases (ADCY 1, 3, 5, 9) and cAMP-hydrolysing phosphodiesterases (PDE4A, PDE4D) decreased significantly, although no statistically significant alterations were observed in that of PKGs (PRKG1 and PRKG2) and guanylate cyclases (GUCYs). The gene expression of natriuretic peptide CNP decreased remarkably, whereas those of BNP, ANP, and neprilysin increased significantly in the IHD LVs. Proteomics analysis revealed a significant reduction in protein levels of “Energy metabolism” and “Muscle contraction” in the patients. Multi-omics integration highlighted intracellular signaling by second messengers as the top enriched Reactome pathway.

Conclusion

The deficiency in cAMP/PKA signaling pathway is strongly implicated in the pathogenesis of IHD. Natriuretic peptide CNP could be a potential therapeutic target for the modulation of cGMP/PKG signaling.