bluuebunny/crossref_metadata_2025 huggingface dataset:
FAKTOR YANG MEMPENGARUHI MOTIVASI BELAJAR SISWA SEKOLAH DASAR PADA MASA PANDEMI COVID-19
Authors: Handayani Silvia , Marlina Marlina , Desyandri Desyandri
Published: January 2022

Studi ini bertujuan untuk mengetahui faktor-faktor yang mempengaruhi motivasi belajar siswa sekolah dasar dimasa pandemi covid-19 (corona virus disease). Studi ini dilakukan dengan metode studi literatur. Literatur yang dikaji dapat berupa artikel, laporan, majalah, berita, dan lain sebagainya yang dapat dijadikan landasan dalam pengkajian sebuah topik. Hasil dari kajian yang dilakukan menunjukkan bahwa terdapat beberapa faktor yang mempengaruhi motivasi belajar siswa sekolah dasar di masa pandemi seperti faktor pola asuh orang tua, penyajian pembelajaran jarak jauh yang dilakukan oleh guru, dan adanya dukungan dari pemerintah dalam mendukung dan membantu dalam pelaksanaan pembelajaran jarak jauh.
IMPLEMENTASI SUPERVISI AKADEMIK UNTUK MENINGKATKAN KINERJA GURU PADA MASA PANDEMI COVID-19
Authors: Mukroni Siti
Published: January 2022

Berdasarkan pengamatan sementara di SMA Negeri 2 Sentajo Raya Kabupaten Kuantan Singingi, ditemukan fenomena antara lain; Adanya sebagian guru yang belum melengkapi perangkat pembelajarannya, seperti Rencana  Pelaksanaan Pembelajaran (RPP) dan sebagainya. Adanya sebagian guru yang tidak menjalankan tugas sesuai dengan ketentuan-ketentuan yang telah ditentukan, hal ini terlihat adanya guru yang meninggalkan sekolah ketika jam mengajar. Kurangnya inisiatif guru dalam mengembangkan model atau metode pembelajaran yang lebih menarik bagi anak. Kurangnya kreatifitas guru dalam penyediaan media dan sumber belajar yang bervariasi, termasuk menggunakan aplikasi pembelajaran online. Jenis penelitian ini adalah Penelitian Tindakan Sekolah (PTS) berlokasi di SMA Negeri 2 Sentajo Raya Kabupaten Kuantan Singingi, yang ditujukan pada guru-guru. Adapun alasan  utamanya adalah dari hasil pengamatan dan  informasi dari guru, bahwa kinerja guru pada masa pandemi tergolong kurang. Tempat penelitian adalah di SMA Negeri 2 Sentajo Raya Kabupaten Kuantan Singingi. Waktu penelitian ini dilaksanakan pada bulan maret 2021. Jumlah sampel yang ditetapkan dalam penelitian ini adalah 26 orang guru. Dari uraian pengolahan data dan pembahasan didapatkan kesimpulan bahwa kinerja guru didapatkan pada siklus I sebesar 60% dengan kategori baik dan pada siklus II meningkat menjadi 91% dengan kategori baik. Artinya bahwa Kegiatan Supervisi dapat Meningkatkan Kinerja Guru di SMA Negeri 2 Sentajo Raya Kabupaten Kuantan Singingi dikatakan berhasil.
Iowa Experience on Local Calibration of AASHTOWare Pavement ME Design (PMED) for Jointed Plain Concrete Pavements
Authors: Kaya Orhan , Sai Praveen Gopisetti Leela , Ceylan Halil , Kim Sunghwan , Cetin Bora
Published: January 2022

The AASHTO Mechanistic-Empirical Pavement Design Guide (MEPDG) pavement performance models and the associated AASHTOWare pavement ME design (PMED) software are nationally calibrated using design inputs and distress data largely obtained from National Long-Term Pavement Performance (LTPP) to predict Jointed Plain Concrete Pavement (JPCP) performance measures. To improve the accuracy of nationally-calibrated JPCP performance models for various local conditions, further calibration and validation studies in accordance with the local conditions are highly recommended, and multiple updates have been made to the PMED since its initial release in 2011, with the latest version (i.e., Ver. 2.5.X) becoming available in 2019. Validation of JPCP performance models after such software updates is necessary as part of PMED implementation, and such local calibration and validation activities have been identified as the most difficult or challenging parts of PMED implementation. As one of the states at the forefront of implementing the MEPDG and PMED, Iowa has conducted local calibration of JPCP performance models extending from MEPDG to updated versions of PMED. The required MEPDG and PMED inputs and the historical performance data for the selected JPCP sections were extracted from a variety of sources and the accuracy of the nationally-calibrated MEPDG and PMED performance prediction models for Iowa conditions was evaluated. To improve the accuracy of model predictions, local calibration factors of MEPDG and PMED performance prediction models were identified and gained local calibration experiences of MEPDG and PMED in Iowa are presented and discussed here to provide insight of local calibration for other State Highway Agencies (SHAs).
A Users Guide to Performance Engineered Mixtures
Authors: Grove Jim , Praul Michael , Gudimettla Jagan , Conway Robert , Taylor Peter
Published: January 2022

Performance Engineered Mixtures is an initiative, spearheaded by the Federal Highway Administration and the National Concrete Pavement Technology Center, in cooperation with state Departments of Transportation and the concrete paving industry, to develop a comprehensive approach to modernizing the way concrete is specified, tested, and accepted. It focusses on three components: testing of six critical concrete properties, a robust approach to quality control, and the replacement of prescriptive specifications. Many new tests have been recently developed that provide the ability to test concrete properties more easily and quicker than in the past. This paper provides background of how this initiative began. It elaborates on each of the six properties of concrete that are the focus of PEM. The new tests that are integral to the PEM process are described. The effects PEM will have on the acceptance process and the quality control responsibilities are outlined. Finally, tables are included which list the properties and the tests that are associated with each property, as well as how each is applied to each step of the paving process.
Construction Practices of Short Paneled Concrete Pavements (SPCP) for High Volume Roads
Authors: Kasu Sridhar , Mupireddy Amaranatha , Mitra Nilanjan
Published: January 2022

The state of research on narrow and non-dowel short jointed paneled concrete pavements (SPCP) is gaining attention on a large scale across the different parts of the world especially in Chile, the USA, and India. The jointed plain concrete pavements (JPCP), which are designed with slab sizes around 3.5 m x 4.5 m results in thicker slabs with a thickness of paving quality concrete (PQC) layer ranging from 280-330 mm depending on load and temperature stresses on Indian highways. In addition to thicker slabs, JPCP requires dowelled joints, which increases the initial cost of pavement. In order to reduce the thickness and initial cost of construction, the use of cast-in-situ SPCP laid on a strong foundation consisting of a dry lean concrete (DLC) base, cement treated sub base (CTSB) and subgrade is being studied. The square short slabs of size: 1 m, 1.5 m and 2 m joint spacing and of thickness 180 to 220 mm were designed and constructed as two full-scale test sections of SPCP on national highways (NH-2 and NH-33) in India. Slabs were constructed by introducing an initial vertical saw-cut of 3 to 5 mm wide and to a depth of 1/4th to 1/3rd of the thickness. The adopted construction practices through field demonstration and implication of SPCP for highways is the main thrust of the paper which helps the practitioners, designers for adopting such projects in the future.
Thriving in Graduate School as an International Student: How to Combat the Hidden Costs and Barriers
Authors: Dominguez Melanie Sayuri , Kim Seo-young Silvia
Published: January 2022

International students face various hidden costs that pose potential barriers to thriving in graduate school. In this chapter, we lay out several types of hidden costs: (1) higher expenses and time needed for the international status, (2) adjusting to living in a new country and its cultural differences, and (3) biases and racism. We emphasize that the success and happiness of international students depend on the department and the committee’s understanding of these hidden costs. We highlight strategies that international students can take as well as point-by-point advice for the supporters of international students.
Hambatan Pembelajaran Daring Dalam Membangun Karakter Siswa Sekolah Dasar Di Tengah Pandemi
Authors: Aulia Azzahra Hanum
Published: January 2022

Pandemi Covid-19 mengharuskan sekolah melakukan pembelajaran daring di rumah sesuai dengan arahan Mendikbud melalui Surat Edaran No. 4 Tahun 2020. Penelitian ini bertujuan untuk mengetahui hambatan serta bagaimana membangun karakter siswa melalui pembelajaran daring. Penelitian ini menggunakan metode library research dengan teknik pengumpulan data dengan cara studi kepustakaan atau menelusuri sumber yang relevan dengan penelitian. Hasil penelitian ini diharapkan dapat memberikan sumbangsih kepada pemerintah, guru dan orang tua agar memberikan solusi dan perannya dalam pembelajaran daring.
Evaluasi Pelaksanaan Edukasi Kesiapan Belajar Mandiri (EKBM) Pada Mahasiswa Pembelajar Jarak Jauh Di Universitas Terbuka
Authors: Purwantiningsih Ary
Published: January 2022

Penelitian ini merupakan penelitian kualitatif tentang evaluasi pelaksanaan Edukasi Kesiapan Belajar Mandiri pada mahasiswa pembelajar jarak jauh di UT.  Penelitian ini bertujuan untuk mengetahui:1. pelaksanaan EKBM di UPBJJ-UT, 2. faktor-faktor yang mempengaruhi pelaksanaan Edukasi Kesiapan Belajar Mandiri. 3. Kendala yang ditemui dalam pelaksanaan Edukasi Kesiapan Belajar Mandiri dan solusi yang harus dilakukan untuk mengatasi kendala tersebut, 4. Persepsi tentang dampak yang dirasakan oleh mahasiswa terhadap pelaksanaan Edukasi Kesiapan Belajar Mandiri. Teknik pengumpulan data menggunakan Forum Group Discussion (FGD) dengan mahasiswa dan petugas UPBJJ-UT. Hasil penelitian menunjukkan bahwa pelaksanaan EKBM pada umumnya berjalan dengan lancar walaupun ada beberapa faktor yang mempengaruhi pelaksanaan EKBM yaitu dari sudut instruktur sendiri, motivasi yang rendah, kedisiplinan, waktu, lingkungan, kebiasaan dan usia. Akan tetapi semua itu bisa diatasi.Persepsi mahasiswa tentang dampak pelaksanaan EKBM sangat bagus. Pelatihan EKBM perlu untuk dipertahankan karena mahasiswa sangat terbantu dalam mempelajari modul, mereka menjadi tahu cara belajar yang lebih baik.
Tracer Study Lulusan Program Studi Ilmu Hukum Universitas Terbuka
Authors: Apriandhini Megafury , Wahyuni Purwaningdyah Murti , Mutiara Dewi , Isfarin Nadia Nurani , Chairunnisa Madiha Dzakiyyah
Published: January 2022

Program Studi Ilmu Hukum di Universitas Terbuka memberikan peluang kepada siapapun, di manapun, dan kapanpun untuk menemempuh pendidikan tinggi sebagai sarana meningkatkan kompetensi diri dalam bidang hukum. Kurikulum dirancang dan diperbarui sesuai dengan kebutuhan mahasiswa selama studi. Untuk mengukur ketercapaian kompetensi lulusan dalam dunia kerja perlu dilakukan penelurusan melalui tracer studi. Hal ini menjadi tantangan tersendiri karena beragamnya lulusan yang tersebar di seluruh wilayah Indonesia. Dengan metode penelusuran melalui penyebaran kuesioner yang disebar melalui email, aplikasi whatsapp, dan melalui hubungan telepon dilakukan untuk mencapai sampling sebesar 25% dari keseluruhan lulusan. Prodi Ilmu Hukum baru mulai meluluskan pada tahun 2017, hingga 2019 sudah tercatat terdapat 1.402 lulusan yang terjaring dalam tracer study. Berdasarkan hasil yang diperoleh dari penelitian ini, lulusan Prodi Ilmu Hukum bekerja pada bidang hukum dengan presentase lebih dari 90%. Dari keseluruhan lulusan mendapatkan manfaat dengan gelar sarjana hukum, yaitu mendapatkan pekerjaan di bidang hukum atau mendapatkan manfaat atas gelarnya di instansi tempat dia bekerja sebelumnya
IDENTIFIKASI GEJALA PERUBAHAN IKLIM DI KOTA BANDAR LAMPUNG BERDASARKAN DATA IKLIM MAKRO TAHUN 1998-2020
Authors: Pratiwi Fennidya Nur , Asbi Adnin Musadri , Kurnianingsih Nela Agustin
Published: January 2022

Perubahan iklim saat ini merupakan hal penting yang dapat mempengaruhi kehidupan masyarakat dan pembangunan di masa yang akan datang. Untuk itu setiap stakeholder perlu mempersiapkan berbagai strategi program dalam menghadapi fenomena perubahan iklim guna mengurangi dampak yang akan ditimbulkan. Dalam hal penentuan program tersebut, maka penting bagi stakeholder untuk mengetahui bagaimana kondisi iklim pada wilayah yang mereka naungi. Penelitian ini bertujuan untuk mengindentifikasi gejala perubahan iklim yang terjadi di Kota Bandar Lampung berdasarkan dua indikator yaitu: Pola Perubahan Suhu Udara; Pola Perubahan Curah Hujan; serta sejarah kejadian yang berkaitan dengan perubahan iklim. Penelitian ini dilakukan dengan menggunakan pendekatan kualitatif dengan metode regresi linier berganda dan pendekatan kualitatif dengan metode deskriptif naratif. Hasil penelitian ini menunjukkan bahwa Kota Bandar Lampung dalam kurun waktu ± 23 tahun terakhir mengalami gejala dari perubahan iklim berupa perubahan pola curah hujan dan suhu udara serta dampak-dampak dari perubahan iklim seperti fenomena banjir rob.
БИОДЕМОГРАФИЧЕСКИЕ АСПЕКТЫ АДАПТАЦИИ КЕРЧЕНСКОЙ ДИАСПОРЫ ИТАЛЬЯНЦЕВ
Authors: Дзини С. , Спицына Н.Х. , Хохлов Н.В.
Published: January 2022

После краткого введения об истории возникновения и формирования диаспоры «итальянцев Крыма», в статье описаны результаты комплексного социального и биодемографического анализа, проведенного среди современных представителей изучаемой группы, на основании разработанной нами программы анкетирования.
Представленные данные, собранные в ходе экспедиций в Крым и в Италию в 2016–2019 гг., обнародуются впервые. Современные итальянцы Крыма являются потомками итальянских мигрантов, прибывших в черноморско-азовский регион, в частности на Крымский полуостров c Апеннинского полуострова, разными миграционными потоками, с конца XVIII века и до начала XX века.
К ВОПРОСУ ОБ ИНТЕРПРЕТАЦИИ ЗУБНЫХ НАХОДОК В ЯЙСКОМ НЕОЛИТИЧЕСКОМ МОГИЛЬНИКЕ (КЕМЕРОВСКАЯ ОБЛАСТЬ)
Authors: Аксянова Г.П.
Published: January 2022

Биологические находки из Яйского неолитического могильника, раскопанного В.И. Матющенко в 1955–1956 гг., не описаны подробно и не введены в научный оборот до настоящего времени. Они представлены зубами животных и несколькими палеоантропологическими находками – фрагментами посткраниального скелета, обломком левой верхней челюсти с несколькими зубами, изолированным нижним моляром, предположительно М3. Зубы животных разные по своей морфологии, некоторые с просверленным корнем. Это позволило автору раскопок интерпретировать их как ожерелье или подвески на погребальном костюме. Зубы человека, вероятно, принадлежавшие женщине в возрасте 25-35лет, в элементах данного погребального костюма не зафиксированы. В настоящей работе впервые дано морфологическое описание этих древних зубных находок человека из южнотаежной зоны Западной Сибири, предпринята попытка межгруппового сопоставления с разновременными материалами.
АНТРОПОЛОГИЧЕСКИЙ АНАЛИЗ ПОГРЕБЕНИЙ ЭПОХИ БРОНЗЫ ИЗ КУРГАНА № 1 МОГИЛЬНИКА «БОГОМОЛЬНЫЕ ПЕСКИ»
Authors: Васильев С.В. , Боруцкая С.Б. , Васильев Д.В.
Published: January 2022

В данной работе мы вводим в научный оборот результаты изучения палеоантропологического материала из Нижнего Поволжья из Курганной группы «Богомольные пески», оставленной населением эпохи бронзы. Данный курганный могильник располагался в Астраханской области в Енотаевском районе. В статье приводятся итоги изотопного анализа костного материала, а также результаты исследования посткраниальных скелетов. Изотопный анализ показал, что основой рациона у жителей эпохи бронзы территории современной Астраханской области были мясо птицы и хищных рыб. Кроме того, изотопный анализ обнаружил, что у детей мясная пища занимала большее место в диете, чем у взрослых мужчин. Морфологический анализ посткраниального скелета выявил относительную удлинённость плечевой кости. Реконструированная прижизненная длина тела мужчин оказалась выше средней.
Early Growth Response 1 Suppresses Macrophage Phagocytosis by Inhibiting NRF2 Activation Through Upregulation of Autophagy During Pseudomonas aeruginosa Infection
Authors: Pang Zheng , Xu Yan , Zhu Qingjun
Published: January 2022

Pseudomonas aeruginosa is an opportunistic pathogen that causes life-threatening infections in cystic fibrosis patients and immunocompromised individuals. A tightly regulated immune response possessed by healthy individuals can effectively control P. aeruginosa infections, whereas the patients with dysregulated immune response are susceptible to this bacterial pathogen. Early growth response 1 (Egr-1) is a zinc-finger transcription factor involved in regulation of various cellular functions, including immune responses. We previously identified that Egr-1 was deleterious to host in a mouse model of acute P. aeruginosa pneumonia by promoting systemic inflammation and impairing bacterial clearance in lung, which associated with reduced phagocytosis and bactericidal ability of leucocytes, including macrophages and neutrophils. However, the molecular mechanisms underlying the Egr-1-suppressed phagocytosis of P. aeruginosa are incompletely understood. Herein, we investigated whether the Egr-1-regulated autophagy play a role in macrophage phagocytosis during P. aeruginosa infection by overexpression or knockdown of Egr-1. We found that overexpression of Egr-1 inhibited the phagocytic activity of macrophages, and the autophagy activator rapamycin and inhibitor chloroquine could reverse the effects of Egr-1 knockdown and Egr-1 overexpression on phagocytosis of P. aeruginosa, respectively. Furthermore, the Egr-1-overexpressing macrophages displayed upregulated expression of autophagy-related proteins LC3A, LC3B and Atg5, and decreased levels of p62 in macrophages. Further studies revealed that the macrophages with Egr-1 knockdown displayed enhanced activation of transcription factor NRF2 and expression of scavenger receptors MACRO and MSR1. Altogether, these findings suggest that Egr-1 suppresses the phagocytosis of P. aeruginosa by macrophages through upregulation of autophagy and inhibition of NRF2 signaling.
Recipe Recommendation With Hierarchical Graph Attention Network
Authors: Tian Yijun , Zhang Chuxu , Metoyer Ronald , Chawla Nitesh V.
Published: January 2022

Recipe recommendation systems play an important role in helping people find recipes that are of their interest and fit their eating habits. Unlike what has been developed for recommending recipes using content-based or collaborative filtering approaches, the relational information among users, recipes, and food items is less explored. In this paper, we leverage the relational information into recipe recommendation and propose a graph learning approach to solve it. In particular, we proposeHGAT, a novel hierarchical graph attention network for recipe recommendation. The proposed model can capture user history behavior, recipe content, and relational information through several neural network modules, including type-specific transformation, node-level attention, and relation-level attention. We further introduce a ranking-based objective function to optimize the model. Thorough experiments demonstrate thatHGAToutperforms numerous baseline methods.
Deciphering the Epigenetic Code of Stem Cells Derived From Dental Tissues
Authors: Li Ye , Zhao Xitong , Sun Meng , Pei Dandan , Li Ang
Published: January 2022

Stem cells derived from dental tissues (DSCs) exhibit multipotent regenerative potential in pioneering tissue engineering regimens. The multipotency of DSCs is critically regulated by an intricate range of factors, of which the epigenetic influence is considered vital. To gain a better understanding of how epigenetic alterations are involved in the DSC fate determination, the present review overviews the current knowledge relating to DSC epigenetic modifications, paying special attention to the landscape of epigenetic modifying agents as well as the related signaling pathways in DSC regulation. In addition, insights into the future opportunities of epigenetic targeted therapies mediated by DSCs are discussed to hold promise for the novel therapeutic interventions in future translational medicine.
Using the Residual Network Module to Correct the Sub-Seasonal High Temperature Forecast
Authors: Jin Wei , Zhang Wei , Hu Jie , Weng Bin , Huang Tianqiang , Chen Jiazhen
Published: January 2022

The high temperature forecast of the sub-season is a severe challenge. Currently, the residual structure has achieved good results in the field of computer vision attributed to the excellent feature extraction ability. However, it has not been introduced in the domain of sub-seasonal forecasting. Here, we develop multi-module daily deterministic and probabilistic forecast models by the residual structure and finally establish a complete set of sub-seasonal high temperature forecasting system in the eastern part of China. The experimental results indicate that our method is effective and outperforms the European hindcast results in all aspects: absolute error, anomaly correlation coefficient, and other indicators are optimized by 8–50%, and the equitable threat score is improved by up to 400%. We conclude that the residual network has a sharper insight into the high temperature in sub-seasonal high temperature forecasting compared to traditional methods and convolutional networks, thus enabling more effective early warnings of extreme high temperature weather.
The Role of Aldosterone in OSA and OSA-Related Hypertension
Authors: Wang Yi , Li Chuan Xiang , Lin Ying Ni , Zhang Li Yue , Li Shi Qi , Zhang Liu , Yan Ya Ru , Lu Fang Ying , Li Ning , Li Qing Yun
Published: January 2022

Obstructive sleep apnea (OSA) is regarded as an independent risk factor for hypertension. The possible mechanism includes oxidative stress, endothelial injury, sympathetic excitement, renin–angiotensin–aldosterone system activation, etc. Clinical studies have found that there is a high coexistence of OSA and primary aldosteronism in patients with hypertension and that elevated aldosterone levels are independently associated with OSA severity in resistant hypertension. The underlying mechanism is that aldosterone excess can exacerbate OSA through increasing overnight fluid shift and affecting the mass and function of upper airway muscles during the sleep period. Thus, a bidirectional influence between OSA and aldosterone exists and contributes to hypertension in OSA patients, especially resistant hypertension.
Comprehensive Analysis of Hub Genes Associated With Competing Endogenous RNA Networks in Stroke Using Bioinformatics Analysis
Authors: Chen Xiuqi , Wu Danhong
Published: January 2022

Background: Acute ischemic stroke (AIS) is the second leading cause of death and the third leading cause of disability worldwide. Long noncoding RNAs (lncRNAs) are promising biomarkers for the early diagnosis of AIS and closely participate in the mechanism of stroke onset. However, studies focusing on lncRNAs functioning as microRNA (miRNA) sponges to regulate the mRNA expression are rare and superficial.

Methods: In this study, we systematically analyzed the expression profiles of lncRNA, mRNA (GSE58294), and miRNA (GSE110993) from the GEO database. Gene ontology (GO) analysis was performed to reveal the functions of differentially expressed genes (DEGs), and we used weighted gene co-expression network analysis (WGCNA) to investigate the relationships between clinical features and expression profiles and the co-expression of miRNA and lncRNA. Finally, we constructed a lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) network with selected DEGs using bioinformatics methods and obtained ROC curves to assess the diagnostic efficacy of differentially expressed lncRNAs (DElncRNAs) and differentially expressed mRNAs (DEmRNAs) in our network. The GSE22255 dataset was used to confirm the diagnostic value of candidate genes.

Results: In total, 199 DElncRNAs, 2068 DEmRNAs, and 96 differentially expressed miRNAs were detected. The GO analysis revealed that DEmRNAs primarily participate in neutrophil activation, neutrophil degranulation, vacuolar transport, and lysosomal transport. WGCNA screened out 16 lncRNAs and 195 mRNAs from DEGs, and only eight DElncRNAs maintained an area under the curve higher than 0.9. By investigating the relationships between lncRNAs and mRNAs, a ceRNA network containing three lncRNAs, three miRNAs, and seven mRNAs was constructed. GSE22255 confirmed that RP1-193H18.2 is more advantageous for diagnosing stroke, whereas no mRNA showed realistic diagnostic efficacy.

Conclusion: The ceRNA network may broaden our understanding of AIS pathology, and the candidate lncRNA from the ceRNA network is assumed to be a promising therapeutic target and diagnostic biomarker for AIS.
Single-Cell Ribonucleic Acid Sequencing Clarifies Cold Tolerance Mechanisms in the Pacific White Shrimp (Litopenaeus Vannamei)
Authors: Zhu Weilin , Yang Chunling , Chen Xiuli , Liu Qingyun , Li Qiangyong , Peng Min , Wang Huanling , Chen Xiaohan , Yang Qiong , Liao Zhenping , Li Min , Pan Chuanyan , Feng Pengfei , Zeng Digang , Zhao Yongzhen
Published: January 2022

To characterize the cold tolerance mechanism of the Pacific white shrimp (Litopenaeus vannamei), we performed single-cell RNA sequencing (scRNA-seq) of ∼5185 hepatopancreas cells from cold-tolerant (Lv-T) and common (Lv-C) L. vannamei at preferred and low temperatures (28°C and 10°C, respectively). The cells fell into 10 clusters and 4 cell types: embryonic, resorptive, blister-like, and fibrillar. We identified differentially expressed genes between Lv-T and Lv-C, which were mainly associated with the terms “immune system,” “cytoskeleton,” “antioxidant system,” “digestive enzyme,” and “detoxification,” as well as the pathways “metabolic pathways of oxidative phosphorylation,” “metabolism of xenobiotics by cytochrome P450,” “chemical carcinogenesis,” “drug metabolism-cytochrome P450,” and “fatty acid metabolism.” Reconstruction of fibrillar cell trajectories showed that, under low temperature stress, hepatopancreas cells had two distinct fates, cell fate 1 and cell fate 2. Cell fate 1 was mainly involved in signal transduction and sensory organ development. Cell fate 2 was mainly involved in metabolic processes. This study preliminarily clarifies the molecular mechanisms underlying cold tolerance in L. vannamei, which will be useful for the breeding of shrimp with greater cold tolerance.
Toripalimab: the First Domestic Anti-Tumor PD-1 Antibody in China
Authors: Zhang Lin , Hao Bo , Geng Zhihua , Geng Qing
Published: January 2022

Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab is able to bind to PD-1 and block the interaction with its ligands. The binding of toripalimab to PD-1 is mainly attributed to the heavy chain of the former and the FG loop of the latter. Toripalimab received a conditional approval in China for the treatment of melanoma (second-line) in December, 2018. It has also received approvals to treat nasopharyngeal carcinoma (first-line and third-line) and urothelial carcinoma (second-line) in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Toripalimab has exhibited primary anti-tumor effects in tumors such as melanoma, lung cancer, digestive tract tumors, hepatobiliary and pancreatic tumors, neuroendocrine neoplasms, nasopharyngeal carcinoma and urothelial carcinoma. It showed a satisfactory anti-tumor effect and long-term survival benefits in Chinese melanoma patients, while the combination of axitinib with toripalimab exhibited an impressive result in metastatic mucosal melanoma. As a checkpoint inhibitor, toripalimab was generally well-tolerated in the enrolled patients. Due to different study populations, comparisons could not be made directly between toripalimab and other drugs in most cases. Nevertheless, the introduction of toripalimab may offer a valuable choice for decision-making in the treatment of tumors in the future.
Secretory Leukocyte Protease Inhibitor Is Present in Circulating and Tissue-Recruited Human Eosinophils and Regulates Their Migratory Function
Authors: Osiecka Oktawia , Skrzeczynska-Moncznik Joanna , Morytko Agnieszka , Mazur Angelika , Majewski Pawel , Bilska Bernadetta , Kapinska-Mrowiecka Monika , Kosalka-Wegiel Joanna , Pastuszczak Maciej , Pyza Elzbieta , Cichy Joanna
Published: January 2022

Eosinophils and secretory leukocyte protease inhibitor (SLPI) are both associated with Th2 immune responses and allergic diseases, but whether the fact that they are both implicated in these conditions is pathophysiologically related remains unknown. Here we demonstrate that human eosinophils derived from normal individuals are one of the major sources of SLPI among circulating leukocytes. SLPI was found to be stored in the crystalline core of eosinophil granules, and its dislocation/rearrangement in the crystalline core likely resulted in changes in immunostaining for SLPI in these cells. High levels of SLPI were also detected in blood eosinophils from patients with allergy-associated diseases marked by eosinophilia. These include individuals with eosinophilic granulomatosis with polyangiitis (EGPA) and atopic dermatitis (AD), who were also found to have elevated SLPI levels in their plasma. In addition to the circulating eosinophils, diseased skin of AD patients also contained SLPI-positive eosinophils. Exogenous, recombinant SLPI increased numbers of migratory eosinophils and supported their chemotactic response to CCL11, one of the key chemokines that regulate eosinophil migratory cues. Together, these findings suggest a role for SLPI in controlling Th2 pathophysiologic processes via its impact on and/or from eosinophils.
GSK-3α/β Activity Negatively Regulates MMP-1/9 Expression to Suppress Mycobacterium tuberculosis Infection
Authors: Zhou Xinying , Lie Linmiao , Liang Yao , Xu Hui , Zhu Bo , Huang Yingqi , Zhang Lijie , Zhang Zelin , Li Qianna , Wang Qi , Han Zhenyu , Huang Yulan , Liu Honglin , Hu Shengfeng , Zhou Chaoying , Wen Qian , Ma Li
Published: January 2022

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is the deadliest infectious disease and a global health problem. Macrophages (Mφs) and neutrophils that can phagocytose Mtb represent the first line of immune response to infection. Glycogen synthase kinase-3α/β (GSK-3α/β) represents a regulatory switch in host immune responses. However, the efficacy and molecular mechanisms of how GSK-3α/β interacts with Mtb infection in Mφs remain undefined. Here, we demonstrated that Mtb infection downregulated GSK-3α/β activity and promoted matrix metalloproteinase-1 (MMP-1) and MMP-9 expressions in Mφs derived from acute monocytic human leukemia THP-1 cells (THP-1-Mφs). We confirmed the upregulation of MMP-9 expression in tissues of TB patients compared with patients of chronic inflammation (CI). In THP-1-Mφs and C57BL/6 mice, GSK-3α/β inhibitor SB216763 significantly increased MMP-1/9 production and facilitated Mtb load, while MMP inhibitors blocked MMP-1/9 expression and Mtb infection. Consistently, GSK-3α/β silencing significantly increased MMP-1/9 expression and Mtb infection, while overexpression of GSK-3α/β and constitutive activated GSK-3α/β mutants significantly reduced MMP-1/9 expression and Mtb infection in THP-1-Mφs. MMP-1/9 silencing reduced Mtb infection, while overexpression of MMP-1/9 promoted Mtb infection in THP-1-Mφs. We further found that GSK-3α/β inhibition increased Mtb infection and MMP-1/9 expression was blocked by ERK1/2 inhibitor. Additionally, we showed that protein kinase C-δ (PKC-δ) and mammalian target of rapamycin (mTOR) reduced GSK-3α/β activity and promoted MMP-1/9 production in Mtb-infected THP-1-Mφs. In conclusion, this study suggests that PKC-δ-mTOR axis suppresses GSK-3α/β activation with acceleration of MMP-1/9 expression through phospho-ERK1/2. These results reveal a novel immune escape mechanism of Mtb and a novel crosstalk between these critical signaling pathways in anti-TB immunity.
Autoimmune Epilepsy - Novel Multidisciplinary Analysis, Discoveries and Insights
Authors: Levite Mia , Goldberg Hadassa
Published: January 2022

Epilepsy affects ~50 million people. In ~30% of patients the etiology is unknown, and ~30% are unresponsive to anti-epileptic drugs. Intractable epilepsy often leads to multiple seizures daily or weekly, lasting for years, and accompanied by cognitive, behavioral, and psychiatric problems. This multidisciplinary scientific (not clinical) ‘Perspective’ article discusses Autoimmune Epilepsy from immunological, neurological and basic-science angles. The article includes summaries and novel discoveries, ideas, insights and recommendations. We summarize the characteristic features of the respective antigens, and the pathological activityin vitroand in animal models of autoimmune antibodies to: Glutamate/AMPA-GluR3, Glutamate/NMDA-NR1, Glutamate/NMDA-NR2, GAD-65, GABA-R, GLY-R, VGKC, LGI1, CASPR2, and β2 GP1, found in subpopulations of epilepsy patients. Glutamate receptor antibodies: AMPA-GluR3Bpeptide antibodies, seem so far as the most exclusive and pathogenic autoimmune antibodies in Autoimmune Epilepsy. They kill neural cells by three mechanisms: excitotoxicity, Reactive-Oxygen-Species, and complement-fixation, and induce and/or facilitate brain damage, seizures, and behavioral impairments. In this article we raise and discuss many more topics and new insights related to Autoimmune Epilepsy. 1. Few autoimmune antibodies tilt the balance between excitatory Glutamate and inhibitory GABA, thereby promoting neuropathology and epilepsy; 2. Many autoantigens are synaptic, and have extracellular domains. These features increase the likelihood of autoimmunity against them, and the ease with which autoimmune antibodies can reach and harm these self-proteins. 3. Several autoantigens have ‘frenetic character’- undergoing dynamic changes that can increase their antigenicity; 4. The mRNAs of the autoantigens are widely expressed in multiple organs outside the brain. If translated by default to proteins, broad spectrum detrimental autoimmunity is expected; 5. The autoimmunity can precede seizures, cause them, and be detrimental whether primary or epiphenomenon; 6. Some autoimmune antibodies induce, and associate with, cognitive, behavioral and psychiatric impairments; 7. There are evidences for epitope spreading in Autoimmune Epilepsy; 8. T cells have different ‘faces’ in the brain, and in Autoimmune Epilepsy: Normal T cells are needed for the healthy brain. Normal T cells are damaged by autoimmune antibodies to Glutamate/AMPA GluR3, which they express, and maybe by additional autoantibodies to: Dopamine-R, GABA-R, Ach-R, Serotonin-R, and Adrenergic-R, present in various neurological diseases (summarized herein), since T cells express all these Neurotransmitter receptors. However, autoimmune and/or cytotoxic T cells damage the brain; 9. The HLA molecules are important for normal brain function. The HLA haplotype can confer susceptibility or protection from Autoimmune Epilepsy; 10. There are several therapeutic strategies for Autoimmune Epilepsy.
DNA Based Vaccine Expressing SARS-CoV-2 Spike-CD40L Fusion Protein Confers Protection Against Challenge in a Syrian Hamster Model
Authors: Tamming Levi A. , Duque Diana , Tran Anh , Zhang Wanyue , Pfeifle Annabelle , Laryea Emmanuel , Wu Jianguo , Raman Sathya N. Thulasi , Gravel Caroline , Russell Marsha S. , Hashem Anwar M. , Alsulaiman Reem M. , Alhabbab Rowa Y. , Gao Jun , Safronetz David , Cao Jingxin , Wang Lisheng , Chen Wangxue , Johnston Michael J. W. , Sauve Simon , Rosu-Myles Michael , Li Xuguang
Published: January 2022

SARS-CoV-2 infections present a tremendous threat to public health. Safe and efficacious vaccines are the most effective means in preventing the infections. A variety of vaccines have demonstrated excellent efficacy and safety around the globe. Yet, development of alternative forms of vaccines remains beneficial, particularly those with simpler production processes, less stringent storage conditions, and the capability of being used in heterologous prime/boost regimens which have shown improved efficacy against many diseases. Here we reported a novel DNA vaccine comprised of the SARS-CoV-2 spike protein fused with CD40 ligand (CD40L) serving as both a targeting ligand and molecular adjuvant. A single intramuscular injection in Syrian hamsters induced significant neutralizing antibodies 3-weeks after vaccination, with a boost substantially improving immune responses. Moreover, the vaccine also reduced weight loss and suppressed viral replication in the lungs and nasal turbinates of challenged animals. Finally, the incorporation of CD40L into the DNA vaccine was shown to reduce lung pathology more effectively than the DNA vaccine devoid of CD40L. These results collectively indicate that this DNA vaccine candidate could be further explored because of its efficacy and known safety profile.
Cytohesin-2/ARNO: A Novel Bridge Between Cell Migration and Immunoregulation in Synovial Fibroblasts
Authors: Wang Yilin , Çil Çağlar , Harnett Margaret M. , Pineda Miguel A.
Published: January 2022

The guanine nucleotide exchange factor cytohesin-2 (ARNO) is a major activator of the small GTPase ARF6 that has been shown to play an important role(s) in cell adhesion, migration and cytoskeleton reorganization in various cell types and models of disease. Interestingly, dysregulated cell migration, in tandem with hyper-inflammatory responses, is one of the hallmarks associated with activated synovial fibroblasts (SFs) during chronic inflammatory joint diseases, like rheumatoid arthritis. The role of ARNO in this process has previously been unexplored but we hypothesized that the pro-inflammatory milieu of inflamed joints locally induces activation of ARNO-mediated pathways in SFs, promoting an invasive cell phenotype that ultimately leads to bone and cartilage damage. Thus, we used small interference RNA to investigate the impact of ARNO on the pathological migration and inflammatory responses of murine SFs, revealing a fully functional ARNO-ARF6 pathway which can be rapidly activated by IL-1β. Such signalling promotes cell migration and formation of focal adhesions. Unexpectedly, ARNO was also shown to modulate SF-inflammatory responses, dictating their precise cytokine and chemokine expression profile. Our results uncover a novel role for ARNO in SF-dependent inflammation, that potentially links pathogenic migration with initiation of local joint inflammation, offering new approaches for targeting the fibroblast compartment in chronic arthritis and joint disease.
Anti-Inflammatory Effects of Acupuncture at ST36 Point: A Literature Review in Animal Studies
Authors: Oh Ji-Eun , Kim Seung-Nam
Published: January 2022

So far, a number of acupuncture studies have shown anti-inflammatory effects of acupuncture treatment, mostly known at specific point ST36. However, there is no literature that oversaw the inflammation-regulatory effects of acupuncture in each tissue. Therefore, we investigated how acupuncture at specific acupoint ST36 regulates inflammation and its underlying mechanisms. We searched literatures on PubMed until July 2021 using the keywords “animal, acupuncture, ST36, inflammation, immune,” and 292 literatures were searched. We ultimately selected 69 studies to determine the anti-inflammatory actions of acupuncture at ST36 and classified the changes of inflammatory mediators according to target regions. Forty-three studies were included in body fluids, 27 studies in the digestive system, 17 studies in the nervous system, and 30 studies in other tissues or organs. In this review, we found that acupuncture at ST36 has clinical benefits in relieving inflammation through several mechanisms such as vagus nerve activation, toll-like receptor 4 (TLR4)/NF-κB signaling, macrophage polarization, mitogen-activated protein kinase (MAPK) signaling pathway, and cholinergic anti-inflammatory pathway. We expect that these data will inform further studies related to ST36 acupuncture on inflammation.
CAR-T Plus Radiotherapy: A Promising Combination for Immunosuppressive Tumors
Authors: Qin Vicky Mengfei , Haynes Nicole M. , D’Souza Criselle , Neeson Paul J. , Zhu Joe Jiang
Published: January 2022

Radiotherapy (RT) is the standard-of-care treatment for more than half of cancer patients with localized tumors and is also used as palliative care to facilitate symptom relief in metastatic cancers. In addition, RT can alter the immunosuppressive tumor microenvironment (TME) of solid tumors to augment the anti-tumor immune response of immune checkpoint blockade (ICB). The rationale of this combination therapy can also be extended to other forms of immunotherapy, such as chimeric antigen receptor T cell (CAR-T) therapy. Similar to ICB, the efficacy of CAR-T therapy is also significantly impacted by the immunosuppressive TME, leading to compromised T cell function and/or insufficient T cell infiltration. In this review, we will discuss some of the key barriers to the activity of CAR-T cells in the immunosuppressive TME and focus on how RT can be used to eliminate or bypass these barriers. We will present the challenges to achieving success with this therapeutic partnership. Looking forward, we will also provide strategies currently being investigated to ensure the success of this combination strategy in the clinic.
Systematic Evaluation of HLA-G 3’Untranslated Region Variants in Locally Advanced, Non-Metastatic Breast Cancer Patients: UTR-1, 2 or UTR-4 are Predictors for Therapy and Disease Outcome
Authors: Rebmann Vera , Schwich Esther , Michita Rafael Tomoya , Grüntkemeier Lisa , Bittner Ann-Kathrin , Rohn Hana , Horn Peter A. , Hoffmann Oliver , Kimmig Rainer , Kasimir-Bauer Sabine
Published: January 2022

Despite major improvements in diagnostics and therapy in early as well as in locally advanced breast cancer (LABC), metastatic relapse occurs in about 20% of patients, often explained by early micro-metastatic spread into bone marrow by disseminated tumor cells (DTC). Although neoadjuvant chemotherapy (NACT) has been a successful tool to improve overall survival (OS), there is growing evidence that various environmental factors like the non-classical human leukocyte antigen-G (HLA-G) promotes cancer invasiveness and metastatic progression. HLA-G expression is associated with regulatory elements targeting certain single-nucleotide polymorphisms (SNP) in the HLA-G 3’ untranslated region (UTR), which arrange as haplotypes. Here, we systematically evaluated the impact of HLA-G 3’UTR polymorphisms on disease status, on the presence of DTC, on soluble HLA-G levels, and on therapy and disease outcome in non-metastatic LABC patients. Although haplotype frequencies were similar in patients (n = 142) and controls (n = 204), univariate analysis revealed that the UTR-7 haplotype was related to patients with low tumor burden, whereas UTR-4 was associated with tumor sizes >T1. Furthermore, UTR-4 was associated with the presence of DTC, but UTR-3 and UTR-7 were related to absence of DTC. Additionally, increased levels of soluble HLA-G molecules were found in patients carrying UTR-7. Regarding therapy and disease outcome, univariate and multivariate analysis highlighted UTR-1 or UTR-2 as a prognostic parameter indicative for a beneficial course of disease in terms of complete response towards NACT or progression-free survival (PFS). At variance, UTR-4 was an independent risk factor for a reduced OS besides already known parameters. Taken into account the most common HLA-G 3’UTR haplotypes (UTR-1–UTR-7, UTR-18), deduction of the UTR-1/2/4 haplotypes to specific SNPs revealed that the +3003C variant, unique for UTR-4, seemed to favor a detrimental disease outcome, while the +3187G and +3196G variants, unique for UTR-1 or UTR-2, were prognostic parameters for a beneficial course of disease. In conclusion, these data suggest that the HLA-G 3’UTR variants +3003C, +3187G, and +3196G are promising candidates for the prediction of therapy and disease outcome in LABC patients.
Effect of the Addition of 4 wt% Zr to BCC Solid Solution Ti52V12Cr36 at Melting/Milling on Hydrogen Sorption Properties
Authors: Kamble Amol , Sharma Pratibha , Huot Jacques
Published: January 2022

The addition of 4 wt% Zr to Ti52V12Cr36 alloy was carried out in two different ways: arc-melting or ball-milling. The cast alloy showed rapid hydrogen absorption up to 3.6 wt% of hydrogen capacity within 15 min. Ball milling this sample worsened the kinetics, and no hydrogen absorption was registered when milling was carried out for 30 or 60 min. When zirconium is added by ball-milling, the kinetic is slower than that when addition is by arc-melting. This is due to the fact that when added by milling, zirconium does not form a ternary phase with Ti, V, and Cr but instead is just dispersed on the particles’ surface.
Oral Health-Related Quality of Life in Patients With Chronic Respiratory Diseases—Results of a Systematic Review
Authors: Li Simin , Ning Wanchen , Wang Wei , Ziebolz Dirk , Acharya Aneesha , Schmalz Gerhard , Zhao Jianjiang , Huang Shaohong , Xiao Hui
Published: January 2022

Background: This systematic review evaluates the oral health-related quality of life (OHRQoL) of patients with chronic respiratory diseases.

Methods: A systematic literature search was performed based on the PubMed, Medline, Web of Science, and Scopus, using the search terms: “oral health-related quality of life” and “respiratory disease” or “lung” and “oral health-related quality of life.” Full-text articles published until June 30, 2021 and reporting any OHRQoL measurement in children or adults with a chronic respiratory disease or condition were included and analyzed qualitatively.

Results: A total of seven out of 44 studies were included, of which four studies examined adults and three studies investigated children. The respective diseases were chronic obstructive pulmonary disease (COPD) (n = 2), sleep apnea (n = 2), severe asthma (n = 1), cystic fibrosis (n = 1), and lung transplantation (n = 1). Four studies confirmed a worse OHRQoL in the respiratory diseased group compared to healthy controls. The overall OHRQoL was reduced in the included studies. Oral health, health-related quality of life, and disease-related parameters were rarely examined with regard to OHRQoL.

Conclusion: Patients with chronic respiratory diseases show a reduced OHRQoL. Oral health should be fostered in these individuals to support their OHRQoL.