bluuebunny/crossref_metadata_2025 huggingface dataset:
THE ROLE OF THE «MIZRACHI» POLITICAL PARTY IN THE DEVELOPMENT OF JEWISH PRIVATE SCHOOLING IN INTERWAR POLAND
Authors: RUDA Oksana
Published: April 2021

The activity of the Jewish party «Mizrachi» in the 20s and the 30s of the 20th century, aimed at developing private Jewish schooling with Hebrew as the medium of instruction, is analyzed. In interwar Poland, Jewish students were deprived of the opportunity to receive primary education in public schools in the mother tongue as the medium of instruction, as government officials only partially implemented the Little Treaty of Versailles of 1919. The development of Jewish schooling was also complicated by the Polonization policy, the cultural and linguistic heterogeneity of Poland's Jews. Polish-speaking «szabasówka», who implemented a nationwide program of educating Jewish students in the spirit of loyalty to the government, facilitated their assimilation. That part of the Jewish community, which perceived these schools as an assimilation factor, actively participated in expanding the network of private Jewish schools with Yiddish or Hebrew mediums of instruction. An important part in the development of such religious and national educational institutions took the Mizrachi party, whose program principles combined the Jewish religious tradition with activities aimed at forming a Jewish state in Palestine. The author examines the activities of the Jewish cultural and educational societies «Jabne» and «Micyjon tejce Tora», which were cared for by «Mizrachi». The societies took part in establishing preschools, primary and secondary schools, teachers' seminaries, evening courses, public universities, reading clubs, libraries, and more. Both Judaic and secular subjects were taught in these educational institutions. Paying due attention to the teaching of Hebrew, Jewish literature, and Jewish history in schools helped preserve Jewish students' national identity.

Keywords
«Mizrachi» political party, Poland, cultural and educational societies, religious and national schools, Hebrew, Yiddish.
CONTROLLING THE MUHAMMADIYAH LHOKSEUMAWE ORPHANAGE IN FORMING INDEPENDENT CHARACTER OF FOSTER CHILDREN
Authors: Almuhajir Almuhajir
Published: April 2021

The formation of children's independent character is one of the goals of education that is wanted to be realized in the educational process, both in formal, non-formal and informal educational institutions. This study aims to explain controlling the Muhammadiyah Lhokseumawe Orphanage in forming the independent character of foster children. This research is a qualitative research using a phenomenological approach. The results showed that controlling the Muhammadiyah Lhokseumawe Orphanage in forming an independent character included controlling the Chair of the Caregivers which consisted of the Caregiver's personality and materials or learning methods with two approaches, namely direct confirmation of Caregiver and foster children in formal and non-formal situations. Caregiver Controlling of Foster Children which consists of cognitive aspects, namely the ability to understand and master learning material, affective aspects, namely changes in the behavior of foster children in their daily life, and psychomotor aspects, namely the ability of foster children to develop skills or talents.
Deleuze and the Third World
Authors: Taek-Gwang Lee Alex
Published: April 2021

The purpose of this essay is to discuss Deleuze and Guattari's concept of the Third World. For Deleuze and Guattari, however, the Third World is not only a geographical term, but also one that denotes the linguistic zones, another term of the minority. The essay argues that the concept of the Third World is related to minor literature, the minor or intense use of language. This ‘transcendental exercise’ of writing is an opposition to the initial purpose of language, namely representation. Language must escape from its normative usage, and then be liberated to a new spatio-temporality, in other words, the linguistic Third World zones. My conclusion is that the creation of Third World linguistic zones is the repetition of differences against the generalisation of representation, such as becoming non-human and non-European, not in imitation of the molar form of the animal or a non-continent extending terrestrial power into the ocean, but as the right way to invent the people missing in the Third World. Inventing the people of the Third World is the right condition in which alternative political subjects can be produced through desubjectification, not domestication, by capitalist axiomatics. In this way, Deleuze's political philosophy aims to use the virtual politics of the Third World to radicalise the actual representation of the existing Left.
Development of Fluorescent and Biotin Probes Targeting NLRP3
Authors: Keuler Tim , Gatterdam Karl , Akbal Anil , Lovotti Marta , Marleaux Michael , Geyer Matthias , Latz Eicke , Gütschow Michael
Published: April 2021

Extracellular signals drive the nucleation of the NLRP3 inflammasome which leads to the release of cytokines and causes inflammatory events. Hence, the inflammasome has gained enormous momentum in biomedical basic research. The detailed mechanisms of inflammasome generation and regulation remain to be elucidated. Our study was directed toward the design, convergent synthesis, and initial biochemical evaluation of activity-based probes addressing NLRP3. For this purpose, probes were assembled from a CRID3/MCC950-related NLRP3-binding unit, a linker portion and a coumarin 343 fluorophore or biotin. The affinity of our probes to NLRP3 was demonstrated through SPR measurements and their cellular activity was confirmed by reduction of the interleukin 1β release from stimulated bone marrow-derived macrophages. The initial characterizations of NLRP3-targeting probes highlighted the coumarin probe 2 as a suitable tool compound for the cellular and biochemical analysis of the NLRP3 inflammasome.
The Effects of ESL Immersion and Proficiency on Learners’ Pronunciation Development
Authors: Kostromitina Maria , Kang Okim
Published: April 2021

Despite the efforts of existing studies in the domain of L2 phonology to examine ESL learners’ pronunciation development, little research has comprehensively demonstrated ESL learners’ pronunciation improvement in academic immersion contexts. Similarly, few studies have focused on learners’ proficiency levels linked to their developmental success. The current exploratory study investigated the changes of learners’ pronunciation constructs as a result of their ESL program. Seventy-five newly arrived ESL students (25 in each proficiency; beginner, intermediate, and advanced) enrolled in an Intensive English Program in the United States provided their speech responses (to the placement and exit tests from the program). One hundred fifty speaking samples were linguistically analyzed for the following suprasegmental features: fluency (speech rates and pauses) and prosody (prominence and pitch range). Segmental features were analyzed by employing a functional load approach with randomly selected 90 speech files. Findings revealed different developmental patterns among phonological features and proficiency levels; that is, the upper-level learners improved more in fluency and prominence than the lower-level learners. Segmental changes were minimal, suggesting that both high functional and low functional load sounds involve a complex process in learning. Overall findings provide important implications for ESL curriculum planning and development: 1) intonation acquisition can be difficult; 2) skill improvement differs by proficiency level; and 3) level-specific curriculum may be needed.
Can You Develop New Interests? an Improved Instrument for Measuring Implicit Theories of Interest Development
Authors: Jahner Erik Erwin
Published: April 2021

O’Keefe et al. (2018) did not sufficiently narrow the implicit theory-of-interest development to accurately address the targeted domain: potential development of an entirely new interest. This was revealed when current participants expressed alternative interpretations of the word “change” in the indicator’s stem. This study therefore sought to first characterize a way to think about implicit theories of interest and refine the wording. However, the revised items revealed low reliability in a targeted population of Singaporeans. Was this due to the manipulation of the questions or the new test population? This was evaluated by following the same sampling procedure as O’Keefe et al. (2018) and participants were presented with both the revised and the original versions of the items. Factor analysis revealed a preferred factor structure for both versions having potential implications for understand implicit theories, as well as the dimensions of implicit theories-of-interests specifically.
Migration in the Time of COVID-19—Policy Responses and Practices in Croatia Concerning the Western Balkan Routes and Readiness for the Post-COVID-19 Society in Which the Right to Health Care for the Most Vulnerable Is Guaranteed
Authors: Roksandić Sunčana , Mamić Krešimir , Mikac Robert
Published: April 2021

This research article aims to provide answers on how COVID-19 pandemics influenced migration law, policy responses, and practices in Croatia, particularly concerning migrants on the Western Balkan route. Throughout the EU, governments have reinstituted border controls in the Schengen region and any “nonessential travel” to the EU has been suspended. In this study, it is analyzed whether asylum seekers have been denied entry in violation of international refugee law and whether immigration officers held detainees because of the risks posed by COVID-19 alongside Croatian borders. In addition, the study addresses the question whether and to what degree the COVID-19 pandemic influenced the overall approach toward migrants and their access to services, primarily the right to health care. Also, it is researched whether facilities for migrants and asylum seekers have appropriate health care and whether the measures imposed by the Croatian Institute of Public Health and by the National Emergency Response Team are respected when dealing with migrants. In addition, it is researched whether the EU, UN, and WHO policies and recommendation concerning COVID-19 and migrants, where applicable, are respected in the Republic of Croatia and whether specific policies concerning migrants and COVID-19 were introduced. All legislation, policy responses, and practices will be critically approached and examined. The text will make proposals for implementation of best practices and policy responses for migrants in the context of COVID-19. All statistical data that are necessary for this research are requested from the Ministry of the Interior of the Republic of Croatia.
Investigation of Extracellular Vesicles From SARS-CoV-2 Infected Specimens: A Safety Perspective
Authors: Nunez Lopez Yury O. , Casu Anna , Pratley Richard E.
Published: April 2021

The coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, is wreaking havoc around the world. Considering that extracellular vesicles (EVs) released from SARS-CoV-2 infected cells might play a role in a viremic phase contributing to disease progression and that standard methods for EV isolation have been reported to co-isolate viral particles, we would like to recommend the use of heightened laboratory safety measures during the isolation of EVs derived from SARS-CoV-2 infected tissue and blood from COVID-19 patients. Research needs to be conducted to better understand the role of EVs in SARS-CoV-2 infectivity, disease progression, and transmission. EV isolation procedures should include approaches for protection from SARS-CoV-2 contamination. We recommend the EV and virology scientific communities develop collaborative projects where relationships between endogenous EVs and potentially lethal enveloped viruses are addressed to better understand the risks and pathobiology involved.
Bile Acids Elevated in Chronic Periaortitis Could Activate Farnesoid-X-Receptor to Suppress IL-6 Production by Macrophages
Authors: Cao Shan , Meng Xinyu , Li Yixuan , Sun Li , Jiang Lindi , Xuan Hanqing , Chen Xiaoxiang
Published: April 2021

Chronic periaortitis (CP) is a rare autoimmune disease without effective treatment. By analyzing the serum bile acid spectrum in 28 CP patients with the ultra-performance liquid chromatography-tandem mass spectrometry, we found that the bile acids were significantly altered in CP patients, with significant increases in chenodeoxycholic acid (CDCA) and glycochenodeoxycholic acid (GCDCA) and decrease in deoxycholic acid (DCA). Signaling pathway enrichment analysis from the RNA sequencing results suggested that the altered gene sets in PBMC of CP patients were associated with bile acid metabolism. Furthermore, we found that pathological concentration of CDCA could significantly inhibited IL-6 expression in RAW 264.7 cells after LPS stimulation. Since CDCA is a well-known natural high-affinity ligand for the bile acid receptor farnesoid-x-receptor (FXR) while GW4064 is the synthetic specific agonist of this receptor, we then revealed that GW4064 significantly decreased IL-6 expression in RAW 264.7 cells and bone marrow-derived macrophages but not in FXR-/- macrophages upon LPS stimulation. The western blot results with the anti-FXR antibody showed significantly increased expression in the nuclear proportion, suggesting that FXR agonist promoted the transportation of FXR into the nucleus but did not increase the FXR expression in macrophages. Dual-luciferase report assay and ChIP assay demonstrated that upon activation, FXR could directly bind to the promoter site of IL-6, leading to the decreased expression of IL-6. Thus, bile acids, especially CDCA, may operate to damp inflammation via FXR-mediated downregulation of IL-6 in mononuclear cells and provide a protective mechanism for CP patients.
Neutrophil Elastase Defects in Congenital Neutropenia
Authors: Rydzynska Zuzanna , Pawlik Bartlomiej , Krzyzanowski Damian , Mlynarski Wojciech , Madzio Joanna
Published: April 2021

Severe congenital neutropenia (SCN) is a rare hematological condition with heterogenous genetic background. Neutrophil elastase (NE) encoded byELANEgene is mutated in over half of the SCN cases. The role of NE defects in myelocytes maturation arrest in bone marrow is widely investigated; however, the mechanism underlying this phenomenon has still remained unclear. In this review, we sum up the studies exploring mechanisms of neutrophil deficiency, biological role of NE in neutrophil and the effects ofELANEmutation and neutropenia pathogenesis. We also explain the hypotheses presented so far and summarize options of neutropenia therapy.
PD-L1 Blockade During Allergen Sensitization Inhibits the Synthesis of Specific Antibodies and Decreases Mast Cell Activation in a Murine Model of Active Cutaneous Anaphylaxis
Authors: Bonamichi-Santos Rafael , Aun Marcelo Vivolo , Kalil Jorge , Castells Mariana Concepcion , Giavina-Bianchi Pedro
Published: April 2021

Programmed cell death ligand 1(PDL-1) is known for its inhibitory effect on the cellular immune response. Even though it is expressed on the surface of mast cells, its role in allergic diseases is unknown. We analyzed the effects of PD-L1 blockade in a murine model of active cutaneous anaphylaxis (ACA). C57BL/6 mice were sensitized and challenged with ovalbumin (OVA). Blood samples were collected to measure specific immunoglobulins. The mice were divided into six groups that underwent the active cutaneous anaphylaxis procedure. Group 1 (negative control) received 50 μl of phosphate-buffered saline (PBS) subcutaneously, and the other five groups were sensitized with 50 μg of OVA subcutaneously. Group 2 was the positive control, and the others received the anti-PD-L1 antibody or its isotype during sensitization (groups 3 and 4) or during the challenge (groups 5 and 6). All animals that underwent ACA on the ears with OVA and PBS were sacrificed, and the reaction was evaluated by extravasation of Evans blue (measured by spectrophotometry) and histological analysis of the collected fragments. Anti-PD-L1 blockade during the sensitization phase led to a reduction in specific IgE and IgG1 levels, allergic reaction intensity at the ACA site, and mast cell degranulation in the tissue. There was no significant biological effect of anti-PD-L1 administration on the challenge phase. PD-L1 blockade during allergen sensitization inhibited the synthesis of specific IgE and IgG1 and decreased mast cell activation in this murine model of anaphylaxis.
Enhancing the Prefusion Conformational Stability of SARS-CoV-2 Spike Protein Through Structure-Guided Design
Authors: Riley Timothy P. , Chou Hui-Ting , Hu Ruozhen , Bzymek Krzysztof P. , Correia Ana R. , Partin Alexander C. , Li Danqing , Gong Danyang , Wang Zhulun , Yu Xinchao , Manzanillo Paolo , Garces Fernando
Published: April 2021

The worldwide pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented and the impact on public health and the global economy continues to be devastating. Although early therapies such as prophylactic antibodies and vaccines show great promise, there are concerns about the long-term efficacy and universal applicability of these therapies as the virus continues to mutate. Thus, protein-based immunogens that can quickly respond to viral changes remain of continued interest. The Spike protein, the main immunogen of this virus, displays a highly dynamic trimeric structure that presents a challenge for therapeutic development. Here, guided by the structure of the Spike trimer, we rationally design new Spike constructs that show a uniquely high stability profile while simultaneously remaining locked into the immunogen-desirable prefusion state. Furthermore, our approach emphasizes the relationship between the highly conserved S2 region and structurally dynamic Receptor Binding Domains (RBD) to enable vaccine development as well as the generation of antibodies able to resist viral mutation.
Capturing T Lymphocytes’ Dynamic Interactions With Human Neural Cells Using Time-Lapse Microscopy
Authors: Lemaître Florent , Carmena Moratalla Ana , Farzam-kia Negar , Carpentier Solorio Yves , Tastet Olivier , Cleret-Buhot Aurélie , Guimond Jean Victor , Haddad Elie , Arbour Nathalie
Published: April 2021

To fully perform their functions, T lymphocytes migrate within organs’ parenchyma and interact with local cells. Infiltration of T lymphocytes within the central nervous system (CNS) is associated with numerous neurodegenerative disorders. Nevertheless, how these immune cells communicate and respond to neural cells remains unresolved. To investigate the behavior of T lymphocytes that reach the CNS, we have established an in vitro co-culture model and analyzed the spatiotemporal interactions between human activated CD8+ T lymphocytes and primary human astrocytes and neurons using time-lapse microscopy. By combining multiple variables extracted from individual CD8+ T cell tracking, we show that CD8+ T lymphocytes adopt a more motile and exploratory behavior upon interacting with astrocytes than with neurons. Pretreatment of astrocytes or neurons with IL-1β to mimic in vivo inflammation significantly increases CD8+ T lymphocyte motility. Using visual interpretation and analysis of numerical variables extracted from CD8+ T cell tracking, we identified four distinct CD8+ T lymphocyte behaviors: scanning, dancing, poking and round. IL-1β-pretreatment significantly increases the proportion of scanning CD8+ T lymphocytes, which are characterized by active exploration, and reduces the proportion of round CD8+ T lymphocytes, which are less active. Blocking MHC class I on astrocytes significantly diminishes the proportion of poking CD8+ T lymphocytes, which exhibit synapse-like interactions. Lastly, our co-culture time-lapse model is easily adaptable and sufficiently sensitive and powerful to characterize and quantify spatiotemporal interactions between human T lymphocytes and primary human cells in different conditions while preserving viability of fragile cells such as neurons and astrocytes.
Geographical Latitude Remains as an Important Factor for the Prevalence of Some Myositis Autoantibodies: A Systematic Review
Authors: Aguilar-Vazquez Andrea , Chavarria-Avila Efrain , Pizano-Martinez Oscar , Ramos-Hernandez Alejandra , Andrade-Ortega Lilia , Rubio-Arellano Edy-David , Vazquez-Del Mercado Monica
Published: April 2021

The idiopathic inflammatory myopathies (IIM) are characterized by muscular weakness, cutaneous manifestations, muscle damage revealed by increase of muscular enzymes, muscle biopsy, electromyography and changes on magnetic resonance imaging. However, the hallmark of these IIM, is the development of myositis specific antibodies (MSA) or myositis associated antibodies (MAA). The theories about their presence in the serum of IIM is not known. Some studies have suggested that some of these MSA, such as anti-Mi-2 increases according to the intensity of UV radiation. There is scarce information about the environmental factors that might contribute in order to be considered as triggering factors as UV radiation might be. In this review, we analyzed the reported prevalence of MSAs and MAAs regarding to their geographical location and the possible relation with UV radiation. We collected the prevalence data of fifteen MSA and thirteen MAA from 22 countries around the world and we were able to observe a difference in prevalence between countries and continents. We found differences in anti-PL7, anti-Ro52, anti-La and anti-Ku prevalence according to UV radiation level. Otherwise, we observed that anti-Mi-2 prevalence increases near to the Equator meanwhile anti-MJ/NXP2 and anti-ARS prevalence had an opposite behavior increasing their prevalence in the geographical locations farther to the Equator. Our results highlighted the importance to include the UV radiation and other environmental factors in IIM studies, in order to clarify its association with MSA and MAA prevalence as well as its possible role in the immunopathogenesis of these diseases.
Quantitative Phosphoproteomic Analysis Reveals Dendritic Cell- Specific STAT Signaling After α2-3–Linked Sialic Acid Ligand Binding
Authors: Li Rui-Jún Eveline , de Haas Aram , Rodríguez Ernesto , Kalay Hakan , Zaal Anouk , Jimenez Connie R. , Piersma Sander R. , Pham Thang V. , Henneman Alex A. , de Goeij-de Haas Richard R. , van Vliet Sandra J. , van Kooyk Yvette
Published: April 2021

Dendritic cells (DCs) are key initiators of the adaptive immunity, and upon recognition of pathogens are able to skew T cell differentiation to elicit appropriate responses. DCs possess this extraordinary capacity to discern external signals using receptors that recognize pathogen-associated molecular patterns. These can be glycan-binding receptors that recognize carbohydrate structures on pathogens or pathogen-associated patterns that additionally bind receptors, such as Toll-like receptors (TLRs). This study explores the early signaling events in DCs upon binding of α2-3 sialic acid (α2-3sia) that are recognized by Immune inhibitory Sialic acid binding immunoglobulin type lectins. α2-3sias are commonly found on bacteria, e.g. Group B Streptococcus, but can also be expressed by tumor cells. We investigated whether α2-3sia conjugated to a dendrimeric core alters DC signaling properties. Through phosphoproteomic analysis, we found differential signaling profiles in DCs after α2-3sia binding alone or in combination with LPS/TLR4 co-stimulation. α2-3sia was able to modulate the TLR4 signaling cascade, resulting in 109 altered phosphoproteins. These phosphoproteins were annotated to seven biological processes, including the regulation of the IL-12 cytokine pathway. Secretion of IL-10, the inhibitory regulator of IL-12 production, by DCs was found upregulated after overnight stimulation with the α2-3sia dendrimer. Analysis of kinase activity revealed altered signatures in the JAK-STAT signaling pathway. PhosphoSTAT3 (Ser727) and phosphoSTAT5A (Ser780), involved in the regulation of the IL-12 pathway, were both downregulated. Flow cytometric quantification indeed revealed de- phosphorylation over time upon stimulation with α2-3sia, but no α2-6sia. Inhibition of both STAT3 and -5A in moDCs resulted in a similar cytokine secretion profile as α-3sia triggered DCs. Conclusively, this study revealed a specific alteration of the JAK-STAT pathway in DCs upon simultaneous α2-3sia and LPS stimulation, altering the IL10:IL-12 cytokine secretion profile associated with reduction of inflammation. Targeted control of the STAT phosphorylation status is therefore an interesting lead for the abrogation of immune escape that bacteria or tumors impose on the host.
Age-Related Changes in Thymic Central Tolerance
Authors: Srinivasan Jayashree , Lancaster Jessica N. , Singarapu Nandini , Hale Laura P. , Ehrlich Lauren I. R. , Richie Ellen R.
Published: April 2021

Thymic epithelial cells (TECs) and hematopoietic antigen presenting cells (HAPCs) in the thymus microenvironment provide essential signals to self-reactive thymocytes that induce either negative selection or generation of regulatory T cells (Treg), both of which are required to establish and maintain central tolerance throughout life. HAPCs and TECs are comprised of multiple subsets that play distinct and overlapping roles in central tolerance. Changes that occur in the composition and function of TEC and HAPC subsets across the lifespan have potential consequences for central tolerance. In keeping with this possibility, there are age-associated changes in the cellular composition and function of T cells and Treg. This review summarizes changes in T cell and Treg function during the perinatal to adult transition and in the course of normal aging, and relates these changes to age-associated alterations in thymic HAPC and TEC subsets.
Induced Autophagy of Macrophages and the Regulation of Inflammatory Effects by Perovskite Nanomaterial LaNiO3
Authors: Wei Yang , Gao Xuejiao , Zhao Feng , Baimanov Didar , Cong Yalin , Jiang Yingying , Hameed Saima , Ouyang Yixin , Gao Xingfa , Lin Xiaoying , Wang Liming
Published: April 2021

Perovskite nanomaterials (NMs) possess excellent physicochemical properties and have promising applications in light-emitting diodes (LEDs), lasers, photodetectors, and artificial synapse electronics. Potential exposure to these NMs happens in the manufacture and application of the perovskite-based products, however, the biological safety of these NMs is still unknown. Here, we used the LaNiO3 NM (LNO), a typical kind of perovskite nanostructures to study the interaction with macrophages (J774A.1) and to explore its biological effects at the cellular level. Firstly, we characterized the properties of LNO including the size, shape, and crystal structure using Transmission electronic microscope (TEM), Dynamic lighting scattering (DLS), and X-ray diffraction (XRD). Secondly, to gain a better understanding of the biological effect, we evaluated the effect of LNO on cell viability and found that LNO induced cell autophagy at a concentration of 5 μg/ml and influenced the inflammatory response based on RT-PCR result. Finally, we demonstrated the mechanism that LNO causes cell autophagy and immune response is probably due to the metal ions released from LNO in acidic lysosomes, which triggered ROS and increased lysosomal membrane permeation. This study indicates the safety aspect of perovskite NMs and may guide the rational design of perovskite NMs with more biocompatibility during their manufacture and application.
Preparation and Characterization of Sodium Aluminum Silicate-Polymer Composites and Effects of Surface Roughness and Scratch Directions on Their Flexural Strengths
Authors: Cui Bencang , Sun Fengbo , Ding Qian , Wang Huining , Lin Yuanhua , Shen Yang , Li Ming , Deng Xuliang , Zhang Lei , Nan Cewen
Published: April 2021

Although efforts have been put into the research in polymer-infiltrated ceramic network composites (PICNs), data are needed to understand the relationship between surface roughness and flexural strength. In this work, a novel dental restorative composite was fabricated via infiltrating mixtures of Bis-GMA/TEGDMA and UDMA/TEGDMA into partially sintered porous sodium aluminum silicate blocks and curing. Bars with different surface conditions were produced by sanding with abrasive and polishing. Flexural strength was measured using three-point-bending. Scanning electron microscopy (SEM) was employed to observe the microstructure of surface areas. One-way analysis of variance was applied for statistical calculations, with p < 0.05 being considered significant. Weibull plots were used to evaluate the reliability of flexural strength. The results demonstrated that the flexural strength of the resultant composites was affected by the scratch direction and the value of roughness. The flexural strength increased with decrease of surface roughness. A higher strength value was found for parallel types than for vertical types with nearly the same surface roughness. A large roughness value and a scratch direction perpendicular to tensile stress produced a low Weibull modulus. Of particular importance with this work is that these factors should be taken into consideration when using PICNs as dental restorative composites.
Application of Artificial Neural Network to Preoperative 18F-FDG PET/CT for Predicting Pathological Nodal Involvement in Non-small-cell Lung Cancer Patients
Authors: Taralli Silvia , Scolozzi Valentina , Boldrini Luca , Lenkowicz Jacopo , Pelliccioni Armando , Lorusso Margherita , Attieh Ola , Ricciardi Sara , Carleo Francesco , Cardillo Giuseppe , Calcagni Maria Lucia
Published: April 2021

Purpose: To evaluate the performance of artificial neural networks (aNN) applied to preoperative 18F-FDG PET/CT for predicting nodal involvement in non-small-cell lung cancer (NSCLC) patients.

Methods: We retrospectively analyzed data from 540 clinically resectable NSCLC patients (333 M; 67.4 ± 9 years) undergone preoperative 18F-FDG PET/CT and pulmonary resection with hilo-mediastinal lymphadenectomy. A 3-layers NN model was applied (dataset randomly splitted into 2/3 training and 1/3 testing). Using histopathological reference standard, NN performance for nodal involvement (N0/N+ patient) was calculated by ROC analysis in terms of: area under the curve (AUC), accuracy (ACC), sensitivity (SE), specificity (SP), positive and negative predictive values (PPV, NPV). Diagnostic performance of PET visual analysis (N+ patient: at least one node with uptake ≥ mediastinal blood-pool) and of logistic regression (LR) was evaluated.

Results: Histology proved 108/540 (20%) nodal-metastatic patients. Among all collected data, relevant features selected as input parameters were: patients' age, tumor parameters (size, PET visual and semiquantitative features, histotype, grading), PET visual nodal result (patient-based, as N0/N+ and N0/N1/N2). Training and testing NN performance (AUC = 0.849, 0.769): ACC = 80 and 77%; SE = 72 and 58%; SP = 81 and 81%; PPV = 50 and 44%; NPV = 92 and 89%, respectively. Visual PET performance: ACC = 82%, SE = 32%, SP = 94%; PPV = 57%, NPV = 85%. Training and testing LR performance (AUC = 0.795, 0.763): ACC = 75 and 77%; SE = 68 and 55%; SP = 77 and 82%; PPV = 43 and 43%; NPV = 90 and 88%, respectively.

Conclusions: aNN application to preoperative 18F-FDG PET/CT provides overall good performance for predicting nodal involvement in NSCLC patients candidate to surgery, especially for ruling out nodal metastases, being NPV the best diagnostic result; a high NPV was also reached by PET qualitative assessment. Moreover, in such population with low a priori nodal involvement probability, aNN better identify the relatively few and unexpected nodal-metastatic patients than PET analysis, so supporting the additional aNN use in case of PET-negative images.
Proteomic Analysis of Non-human Primate Peripheral Blood Mononuclear Cells During Burkholderia mallei Infection Reveals a Role of Ezrin in Glanders Pathogenesis
Authors: Chiang Chih-Yuan , Zhong Yang , Ward Michael D. , Lane Douglas J. , Kenny Tara , Rosario-Acevedo Raysa , Eaton Brett P. , Treviño Sylvia R. , Chance Taylor B. , Hu Meghan , Worsham Patricia L. , Waag David M. , Moore Richard T. , Cazares Lisa H. , Cote Christopher K. , Zhou Yingyao , Panchal Rekha G.
Published: April 2021

Burkholderia mallei, the causative agent of glanders, is a gram-negative intracellular bacterium. Depending on different routes of infection, the disease is manifested by pneumonia, septicemia, and chronic infections of the skin. B. mallei poses a serious biological threat due to its ability to infect via aerosol route, resistance to multiple antibiotics and to date there are no US Food and Drug Administration (FDA) approved vaccines available. Induction of innate immunity, inflammatory cytokines and chemokines following B. mallei infection, have been observed in in vitro and small rodent models; however, a global characterization of host responses has never been systematically investigated using a non-human primate (NHP) model. Here, using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach, we identified alterations in expression levels of host proteins in peripheral blood mononuclear cells (PBMCs) originating from naïve rhesus macaques (Macaca mulatta), African green monkeys (Chlorocebus sabaeus), and cynomolgus macaques (Macaca fascicularis) exposed to aerosolized B. mallei. Gene ontology (GO) analysis identified several statistically significant overrepresented biological annotations including complement and coagulation cascade, nucleoside metabolic process, vesicle-mediated transport, intracellular signal transduction and cytoskeletal protein binding. By integrating an LC-MS/MS derived proteomics dataset with a previously published B. mallei host-pathogen interaction dataset, a statistically significant predictive protein-protein interaction (PPI) network was constructed. Pharmacological perturbation of one component of the PPI network, specifically ezrin, reduced B. mallei mediated interleukin-1β (IL-1β). On the contrary, the expression of IL-1β receptor antagonist (IL-1Ra) was upregulated upon pretreatment with the ezrin inhibitor. Taken together, inflammasome activation as demonstrated by IL-1β production and the homeostasis of inflammatory response is critical during the pathogenesis of glanders. Furthermore, the topology of the network reflects the underlying molecular mechanism of B. mallei infections in the NHP model.
Resveratrol Improves Mitochondrial Biogenesis Function and Activates PGC-1α Pathway in a Preclinical Model of Early Brain Injury Following Subarachnoid Hemorrhage
Authors: Zhou Jian , Yang Zaijia , Shen Ruiming , Zhong Wangwang , Zheng Huiduan , Chen Zhenggang , Tang Jianjian , Zhu Juan
Published: April 2021

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) has been shown to play a pivotal role in the regulation of mitochondrial biogenesis in diseases. Resveratrol (RSV), a natural polyphenolic reagent, has powerful antioxidant properties and the ability to scavenge mitochondrial reactive oxygen species (ROS) in a variety of central nervous system diseases. However, the underlying molecular mechanisms of RSV on mitochondrial biogenesis in early brain injury (EBI) following subarachnoid hemorrhage (SAH) remain poorly understood. This study aimed to explore the potential neuroprotective effects of RSV on mitochondrial biogenesis and function by activation of the PGC-1α signaling pathway in a prechiasmatic cistern SAH model. PGC-1α expression and related mitochondrial biogenesis were detected. Amounts of nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) were determined to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis after SAH were observed in the temporal cortex. Resveratrol increased the expression of PGC-1α, NRF1, and TFAM, and promoted PGC-1α nuclear translocation. Moreover, RSV could scavenge excess ROS, increase the activity of superoxide dismutase (SOD), enhance the potential of mitochondrial membrane and ATP levels, reduce the number of mitochondrial DNA copy, and decrease the level of malondialdehyde (MDA). RSV significantly ameliorated the release of apoptosis-related cytokines, namely P53, cleaved caspase-3, cytochrome c, and BAX, leading to the amelioration of neuronal apoptosis, brain edema, and neurological impairment 24 h after SAH. These results indicate that resveratrol promotes mitochondrial biogenesis and function by activation of the PGC-1α signaling pathway in EBI following SAH.
Intranasal Delivery of Collagen-Loaded Neprilysin Clears Beta-Amyloid Plaques in a Transgenic Alzheimer Mouse Model
Authors: Humpel Christian
Published: April 2021

Alzheimer’s disease (AD) is pathologically characterized by extracellular beta-amyloid (Aβ) plaques and intraneuronal tau tangles in the brain. A therapeutic strategy aims to prevent or clear these Aβ plaques and the Aβ-degrading enzyme neprilysin is a potent drug to degrade plaques. The major challenge is to deliver bioactive neprilysin into the brain via the blood-brain barrier. The aim of the present study is to explore if intranasal delivery of neprilysin can eliminate plaques in a transgenic AD mouse model (APP_SweDI). We will test if collagen or platelets are useful vehicles to deliver neprilysin into the brain. Using organotypic brain slices from adult transgenic APP_SweDI mice, we show that neprilysin alone or loaded in collagen hydrogels or in platelets cleared cortical plaques. Intransasal delivery of neprilysin alone increased small Aβ depositions in the middle and caudal cortex in transgenic mice. Platelets loaded with neprilysin cleared plaques in the frontal cortex after intranasal application. Intranasal delivery of collagen-loaded neprilysin was very potent to clear plaques especially in the middle and caudal parts of the cortex. Our data support that the Aβ degrading enzyme neprilysin delivered to the mouse brain can clear Aβ plaques and intranasal delivery (especially with collagen as a vehicle) is a fast and easy application. However, it must be considered that intranasal neprilysin may also activate more plaque production in the transgenic mouse brain as a side effect.
An Analysis of the Potential Relationship of Triglyceride Glucose and Body Mass Index With Stroke Prognosis
Authors: Hou Zongyi , Pan Yuesong , Yang Yindong , Yang Xiaofan , Xiang Xianglong , Wang Yilong , Li Zixiao , Zhao Xingquan , Li Hao , Meng Xia , Wang Yongjun
Published: April 2021

Background: The inverse association between obesity and outcome in stroke patients (known as the obesity paradox) has been widely reported, yet mechanistic details explaining the paradox are limited. The triglyceride glucose (TYG) index has been proposed as a marker of insulin resistance. We sought to explore possible associations of the TYG index, body mass index (BMI), and stroke outcome.

Methods: We identified 12,964 ischemic stroke patients without a history of diabetes mellitus from the China National Stroke Registry and classified patients as either low/normal weight, defined as a BMI <25 kg/m2, or overweight/obese, defined as a BMI ≥ 25 kg/m2. We calculated TYG index and based on which the patients were divided into four groups. A Cox or logistic regression model was used to evaluate the association between BMI and TYG index and its influence on stroke outcomes, including stroke recurrence all-cause mortality and poor outcome (modified Rankin Scale score of 3–6) at 12 months.

Results: Among the patients, 63.3% were male, and 36.7% were female, and the mean age of the patient cohort was 64.8 years old. The median TYG index was 8.62 (interquartile range, 8.25–9.05). After adjusting for multiple potential covariates, the all-cause mortality of overweight/obese patients was significantly lower than that of the low/normal weight patients (6.17 vs. 9.32%; adjusted hazard ratio, 0.847; 95% CI 0.732–0.981). The difference in mortality in overweight/obese and low/normal weight patients with ischemic stroke was not associated with TYG index, and no association between BMI and TYG index was found.

Conclusion: Overweight/obese patients with ischemic stroke have better survival than patients with low/normal weight. The association of BMI and stroke outcome is not changed by TYG index.
Triadin Decrease Impairs the Expression of E-C Coupling Related Proteins in Muscles of MPTP-Induced Parkinson’s Disease Mice
Authors: Seo Min Hyung , Yeo Sujung
Published: April 2021

Parkinson’s disease (PD), caused by destruction of dopaminergic neurons in the brain, leads to motor symptoms like bradykinesia, tremor, and walking impairments. While most research effort focuses on changes in neuronal pathology we examined how muscle proteins were altered in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. A Ca2+ release channel complex, consisting of ryanodine receptors (RYR), triadin (TRDN), and calsequestrin (CSQ1), is important for excitation-contraction coupling in the sarcoplasmic reticulum membrane in muscles. Thus, we investigated changes in the RYR Ca2+ release channel components in PD mice model. Based on a report that TRDN deletion impairs skeletal muscle function, we also investigated how the knock-down of TRDN affects other components of the RYR channel in the PD model. In this study, the expression levels of the components of RYR channels decreased in the quadriceps femoris muscle of MPTP-induced PD mice and in C2C12 cells treated with 1-methyl-4-phenylpyridinium. We show that decreased TRDN levels decrease RYR and CSQ1 levels. These results suggest that the levels of proteins related to Ca2+ channel function decreased in this model, which could impair muscle function. We conclude that muscle function alterations could add to the bradykinesia and tremor in this model of PD.
Regulation of Drosophila Long-Term Courtship Memory by Ecdysis Triggering Hormone
Authors: Lee Sang Soo , Adams Michael E.
Published: April 2021

Endocrine state is an important determinant of learning and memory in animals. InDrosophila, rejection of male courtship overtures by mated females leads to an aversive response manifested as courtship memory. Here we report that ecdysis triggering hormone (ETH) is an obligatory enabler of long-term courtship memory (LTM). ETH deficiency suppresses LTM, whereas augmented ETH release reduces the minimum training period required for LTM induction. ETH receptor knockdown either in the mushroom body (MB) γ lobe or in octopaminergic dorsal-anterior-lateral (DAL) neurons impairs memory performance, indicating its direct action in these brain areas. Consistent with these findings, brain exposure to ETH mobilizes calcium in MB γ lobe neuropils and DAL neurons. ETH receptor (ETHR) knockdown in the corpus allatum (CA) to create juvenile hormone (JH) deficiency also suppresses LTM, as does knockdown of the JH receptor Met in the MB γ lobe, indicating a convergence of ETH and JH signaling in this region of the brain. Our findings identify endocrine-enabled neural circuit components in the brain that are critical for persistent behavioral changes resulting from aversive social experience.
Stress-Induced Enhanced Long-Term Potentiation and Reduced Threshold for N-Methyl-D-Aspartate Receptor- and β-Adrenergic Receptor-Mediated Synaptic Plasticity in Rodent Ventral Subiculum
Authors: Bartsch Julia C. , von Cramon Monique , Gruber David , Heinemann Uwe , Behr Joachim
Published: April 2021

Stress is a biologically relevant signal and can modulate hippocampal synaptic plasticity. The subiculum is the major output station of the hippocampus and serves as a critical hub in the stress response network. However, stress-associated synaptic plasticity in the ventral subiculum has not been adequately addressed. Therefore, we investigated the impact of a single exposure to an inherently stressful two-way active avoidance conditioning on the induction of long-term potentiation (LTP) at CA1—subiculum synapses in ventral hippocampal slices from young adult rats 1 day after stressor exposure. We found that acute stress enhanced LTP and lowered the induction threshold for a late-onset LTP at excitatory CA1 to subicular burst-spiking neuron synapses. This late-onset LTP was dependent on the activation of β-adrenergic and glutamatergic N-methyl-D-aspartate receptors and independent of D1/D5 dopamine receptor activation. Thereby, we present a cellular mechanism that might contribute to behavioral stress adaptation after acute stressor exposure.
MicroRNA Signature in Melanoma: Biomarkers and Therapeutic Targets
Authors: Ghafouri-Fard Soudeh , Gholipour Mahdi , Taheri Mohammad
Published: April 2021

Melanoma is the utmost fatal kind of skin neoplasms. Molecular changes occurring during the pathogenic processes of initiation and progression of melanoma are diverse and include activating mutations in BRAF and NRAS genes, hyper-activation of PI3K/AKT pathway, inactivation of p53 and alterations in CDK4/CDKN2A axis. Moreover, several miRNAs have been identified to be implicated in the biology of melanoma through modulation of expression of genes being involved in these pathways. In the current review, we provide a summary of the bulk of information about the role of miRNAs in the pathobiology of melanoma, their possible application as biomarkers and their emerging role as therapeutic targets for this kind of skin cancer.
Identification of VWF as a Novel Biomarker in Lung Adenocarcinoma by Comprehensive Analysis
Authors: He Yi , Liu Ruijie , Yang Mei , Bi Wu , Zhou Liuyin , Zhang Sai , Jin Jin , Liang Xujun , Zhang Pengfei
Published: April 2021

Lung adenocarcinoma (LUAD) is one of the most malignant tumors with high morbidity and mortality worldwide due to the lack of reliable methods for early diagnosis and effective treatment. It’s imperative to study the mechanism of its development and explore new biomarkers for early detection of LUAD. In this study, the Gene Expression Omnibus (GEO) dataset GSE43458 and The Cancer Genome Atlas (TCGA) were used to explore the differential co-expressed genes between LUAD and normal samples. Three hundred sixity-six co-expressed genes were identified by differential gene expression analysis and Weighted Gene Co-expression Network Analysis (WGCNA) method. Those genes were mainly enriched in ameboidal-type cell migration (biological process), collagen-containing extracellular matrix (cell component), and extracellular matrix structure constituent (molecular function). The protein-protein network (PPI) was constructed and 10 hub genes were identified, including IL6, VWF, CDH5, PECAM1, EDN1, BDNF, CAV1, SPP1, TEK, and SELE. The expression level of hub genes was validated in the GEPIA database, compared with normal tissues, VWF is lowly expressed and SPP1 is upregulated in LUAD tissues. The survival analysis showed increased expression of SPP1 indicated unfavorable prognosis whereas high expression of VWF suggested favorable prognosis in LUAD (p < 0.05). Based on the immune infiltration analysis, the relationship between SPP1 and VWF expression and macrophage, neutrophil, and dendritic cell infiltration was weak in LUAD. Quantitative real-time PCR (qRT-PCR) and western blotting were used to validate the expression of VWF and SPP1 in normal human bronchial epithelial (HBE) cell and three LUAD cell lines, H1299, H1975, and A549. Immunohistochemistry (IHC) was further performed to detect the expression of VWF in 10 cases LUAD samples and matched normal tissues. In summary, the data suggest that VWF is a potential novel biomarker for prognosis of LUAD.