bluuebunny/crossref_metadata_2025 huggingface dataset:
Rancang Bangun Media Pembelajaran Obat Tradisional Untuk Penyakit Kulit Berbasis Android
Authors:   Sekolah Tinggi Teknologi Garut, Latifah Ayu , Supriatna Asep Deddy , Hawaari Kanbar
Published: May 2021

Kesehatan merupakan hal yang penting bagi semua manusia karena tanpa kesehatan yang baik, maka manusia akan sulit dalam melaksanakan aktivitasnya sehari-hari. Sehat secara fisik yaitu terbebas dari berbagai penyakit, salah satunya adalah penyakit kulit. Informasi atau tingkat pengetahuan masyarakat mengenai obat tradisional masih minim karena terbatas hanya mengenai jamu karena itu supaya informasi mengenai tingkat pengetahuan masyarakat tentang obat tradisional meningkat, maka di buatlah informasi yang dikemas menggunakan media pembelajaran. Tujuan penelitian ini adalah merancang media pembelajaran berbasis android dengan fitur-fitur yang dapat menarik perhatian masyarakat mengenai informasi obat tradisional untuk penyakit kulit. Metode pengembangan sistem yang digunakan dalam pembuatan aplikasi ini adalah Multimedia Development Life Cycle. Adapun tahapan yang dilakukan pada metode ini adalah konsep, perancangan, pengumpulan data, pembuatan, pengujian, dan distribusi. Hasil dari penelitian ini berupa aplikasi media pembelajaran berbasis android dengan materi Obat Tradisional Untuk Penyakit Kulit yang berisi fitur materi, kuis, game, tentang, backsound dan video, sehingga masyarakat dapat lebih tertarik dalam mempelajari konten yang disajikan serta lebih mudah memahami dan mengetahui informasi mengenai obat tradisional untuk penyakit kulit.
Kajian Adiksi Internet dan Adiksi Media Sosial dari Sisi Filsafat Sains
Authors:   Sekolah Tinggi Teknologi Garut, Chandra Ade , Latifah Ayu , Pratama Hasta , Maherdy Okyza , Imbar Radiant Victor , Mahayana Dimitri
Published: May 2021

Perkembangan internet sangat mempengaruhi seluruh aspek kehidupan manusia dan sebagian pengguna internet adalah generasi muda. Dengan pengguna internet yang semakin banyak maka masalah adiksi internet dan sosial media menjadi hal yang diangkat oleh Dr. Kimberly Young. Penelitian ini akan meneliti adiksi internet dan sosial media yang akan dianalisis dengan metode deskriptif dan inferensial menggunakan analisis regresi logistik biner. Apakah usia sekolah, jenis pekerjaan dan waktu akses website mempengaruhi kecenderungan seseorang mengalami adiksi internet dan sosial media. Berdasarkan hasil uji statistik dapat disimpulkan bahwa variabel usia sekolah, jenis pekerjaan dan waktu akses website mempengaruhi kecenderungan seseorang mengalami adiksi internet. Sedangkan variabel jenis kelamin dan domisili tidak mempengaruhi kecenderungan seseorang mengalami adiksi internet. Kajian ini membuktikan bahwa adiksi pada internet maupun media sosial itu nyata di Indonesia dan dapat digolongkan sebagai science, bukan pseudo-science. Oleh karenanya perlu adanya perhatian khusus terhadap kasus ini, karena dampak yang ditimbulkan selain memiliki pengaruh buruk pada kesehatan secara fisik, juga dapat menimbulkan gangguan secara psikologis.
Perancangan Media Informasi Penginapan Griya Santolo Garut Selatan dengan Teknologi Augmented Reality
Authors:   Sekolah Tinggi Teknologi Garut, Rahayu Raden Erwin Gunadhi , Lesmana Sandi
Published: May 2021

Pada saat ini media informasi yang disebarkan untuk memperkenalkan penginapan griya santolo garut selatan hanya sebatas dari brosur yang disebarkan ke berbagai tempat sehingga infromasi yang disebarkan terbatas karena wisatawan yang mengetahui hanya wisatawan yang memperoleh brosur saja. Tujuan dalam penelitian ini adalah membuat media informasi penginapan Griya Santolo Garut Selatan berbasis android dengan menrapkan teknologi Augmented Reality. Metodologi yang digunakan dalam membuat media informasi penginapan Griya Santolo menggunakan metodologi Multimedia Development Life Cycle (MDLC) yang terdiri dari 6 (enam) tahapan, diantaranya tahapan concept, design, material collecting, assembly, testing dan tahapan distribution, akan tetapi tahapan yang dilakukan berdasarkan metodologi MDLC dalam penelitian ini dibatasi sampai tahapan testing. Sedangkan yang menjadi pemodelan dalam penelitian ini berupa tipe – tipe penginapan Griya Santolo. Manfaat yang dihasilkan dari penelitian ini adalah media informasi yang dibuat dapat dijadikan sebagai salah satu inovasi untuk mengenalkan penginapan Griya Santolo serta bermanfaat bagi pengelola penginapan untuk perkembangan inovasi guna mengenalkan penginapan menjadi lebih luas lagi. Hasil dari penelitian ini berupa aplikasi media infromasi penginapan Griya Santolo berbasis android dengan teknologi Augmented Reality yang memvisualisaikan tipe penginapan Conifera, tipe penginapan Azalea dan tipe penginapan Magnolia dalam bentuk 3 (tiga) dimensi.
Rancang Bangun Sistem Informasi Geografis Hasil Pertanian di Kabupaten Garut
Authors:   Sekolah Tinggi Teknologi Garut, Rahayu Raden Erwin Gunadhi , Fauzi Anwar
Published: May 2021

Pertanian merupakan kegiatan manusia untuk mengelola sumber daya alam. Pertanian sangat berperan penting pada kestabilan kehidupan manusia sehingga perlu dipastikan pasokan dan permintaan seimbang, hal tersebut diistilahkan sebagai ketahanan pangan terutama komoditas padi yang menjadi makanan pokok indonesia. Pada praktiknya untuk menjaga kestabilan dibutuhkan data yang bersifat real time yang di petakan secara visual di mana Dinas Pertanian selaku pemillik otoritas dapat mengakses data terbaru dari komoditas padi yang dilaporkan oleh penyuluh di lapangan. Tujuan dilakukannya penelitian ini yaitu untuk melakukan pemetaan geografis wilayah hasil pertanian padi dan mengetahui daerah mana saja yang menghasilkan hasil yang baik di Kabupaten Garut. Manfaatnya diharapkan dapat mengetahui mengenai komoditas hasil pertanian padi yang menghasilkan hasil yang baik di Kabupaten Garut. Pembangunan sistem dilakukan menggunakan metodologi Rational Unified Process dan menggunakan permodelan Unified Modelling Language. Dengan dilakukannya penelitian ini, hasil yang didapat berupa sistem yang dapat mengetahui daerah mana yang menghasilkan produki padi yang baik dan yang tidak. Dari penelitian ini berkontribusi kepada pengetahuan berupa diterapkannya sistem informasi geografis sebagai media informasi mengenai daerah hasil pertanian yang dilaporkan oleh penyuluh dilapangan.
Pembuatan Aplikasi Ensiklopedia Tanaman Bunga dengan Menggunakan QR Code Berbasis Android di Taman Bunga Nusantara Cianjur
Authors:   Sekolah Tinggi Teknologi Garut, Supriatna Ade , Nafisa Hasna Izzatun
Published: May 2021

Taman Bunga Nusantara adalah sebuah taman bunga yang menggelorakan kembali kecintaan masyarakat terhadap kekayaan flora khususnya bunga dan tanaman hias dalam bentuk suatu objek wisata agro dengan fasilitas pendukung yang tertata dalam rangka memberikan misi rekreatif dan edukatif bagi para pengunjung. QR merupakan singkatan dari Quick Response atau respon cepat untuk menyampaikan informasi dengan cepat dan mendapatkan respon yang cepat pula. Aplikasi Ensiklopedia ini dibuat menggunakan metode pengembangan perangkat lunak prototyping. Hasil dari penelitian ini berupa aplikasi ensiklopedia digital yang bertujuan memberikan informasi mengenai tanaman Bunga yang terdapat pada Taman Bunga Nusantara Cianjur menggunakan sistem QR Code berbasis Android.
Comparison of Upper Extremity Physical Fitness Levels in Wheelchair Archery and Basketball Athletes
Authors: Erten Ayşe Büşra , Aras Bayram Gülay , Algun Candan
Published: May 2021

Purpose: The aim of this study was to investigate the relationship between upper extremity physical fitness levels of wheelchair archery and wheelchair basketball athletes. Methods: Ten wheelchair basketball players and ten wheelchair archers, who met the inclusion criteria were included in the study. Athletes were divided into two groups according to their sports branch. Hand grip strength, shoulder flexibility, reaction time, trunk balance and upper extremity muscle strength were measured among the upper extremity physical fitness parameters. Measurements were repeated separately for both upper extremities. In addition, the demographic data of the individuals were recorded through the questionnaire. Results: There was no statistically significant difference between the groups in terms of age, height, weight and body mass index (p>0.05). The duration of disability and the year of doing sports were significantly higher in basketball athletes, while weekly training hours were significantly higher in archery athletes (p<0.05). When the groups were compared, there was a statistically significant difference in right hand grip strength, trunk balance and all upper extremity muscle strength parameters in favor of wheelchair basketball athletes (p<0.05). There was no statistically significant difference in left hand grip strength, shoulder flexibility and reaction time of all upper extremities between the two groups (p>0.05). Conclusion: According to results, it was thought that these differences between two different sports groups are due to the different nature of the two sports branches and the fact that individuals cannot be distributed homogenously between groups according to the types of disabilities.
Pengaruh Covid-19 Terhadap Proses Pembelajaran Daring di Yayasan Pendidikan Cawan Bethel
Authors: Tambunan Witarsa , Tampubolon Hotner , Sinaga Dameria
Published: May 2021

Kegiatan Pengabdian Kepada Masyarakat (PKM) yang diadakan oleh Dosen Program Study Manajemen Pendidikan Pascasarjana di Yayasan Pendidikan Cawan mensosialisasikan alternatif pembelajaran penggunaan daring pada masa pandemic covid 19. Tujuan penelitian ini untuk 1).Membuktikan Ketidak siapan Sekolah Melaksanakan Pembelajaran Daring, 2). Membantu Keterbatasan Sarana Dan Prasarana di Yayasan Pendidikan Cawan, 3). Meningkatkan  penguasaan Tekonologi Tinggi guru di Yayasan Pendidikan Cawan, 4). Membangun Jaringan Internet Kurang Memadai di Yayasan Pendidikan Cawan, 5). Meningkatkan  Gadget yang dimiliki siswa di Yayasan Pendidikan Cawan. Penelitian ini menggunakan metode kualitatif sebab akibat (causalitatif) dengan pendekatan Pohon Masalah , Pohon Sasaran dan Pohon Alternatif . Hasilnya : 1). Ternyata Pandemic covid -19 memaksa guru-guru di Yayasan Pendidikan Cawan untuk dapat menggunakan teknologi dalam proses pembelajaran, 2.)Ternyata Kemampuan guru dalam menggunakan tekonologi pada proses pembelajaran merupakan salah satu indikator kesiapan sekolah dalam melaksanakan pembelajaran daring, 3). Ternyata Inovasi dan kreativitas dalam menggunakan media teknologi sebagai media pembelajaran menjadi hal yang mutlak diperlukan di era globalisasi, khususnya di masa pandemic saat ini, 4).Ternyata Pemberdayaan guru melalui berbagai pelatihan penggunaan teknologi, informasi dan computer yang ada dapat membantu guru untuk meningkatkan kemampuan dasarnya sehingga dapat menggunakan teknologi dalam pembelajaran.

Kata kunci : Pembelajaran Daring, Pandemic Covid 19, Pemberdayaan Guru.
In silico Design of Linear DNA for Robust Cell-Free Gene Expression
Authors: Chen Xinjie , Lu Yuan
Published: May 2021

Cell-free gene expression systems with linear DNA expression templates (LDETs) have been widely applied in artificial cells, biochips, and high-throughput screening. However, due to the degradation caused by native nucleases in cell extracts, the transcription with linear DNA templates is weak, thereby resulting in low protein expression level, which greatly limits the development of cell-free systems using linear DNA templates. In this study, the protective sequences for stabilizing linear DNA and the transcribed mRNAs were rationally designed according to nucleases’ action mechanism, whose effectiveness was evaluated through computer simulation and cell-free gene expression. The cell-free experiment results indicated that, with the combined protection of designed sequence and GamS protein, the protein expression of LDET-based cell-free systems could reach the same level as plasmid-based cell-free systems. This study would potentially promote the development of the LDET-based cell-free gene expression system for broader applications.
Phenotypic Robustness of Epidermal Stem Cell Number in C. elegans Is Modulated by the Activity of the Conserved N-acetyltransferase nath-10/NAT10
Authors: Hintze Mark , Katsanos Dimitris , Shahrezaei Vahid , Barkoulas Michalis
Published: May 2021

Individual cells and organisms experience perturbations from internal and external sources, yet manage to buffer these to produce consistent phenotypes, a property known as robustness. While phenotypic robustness has often been examined in unicellular organisms, it has not been sufficiently studied in multicellular animals. Here, we investigate phenotypic robustness in Caenorhabditis elegans seam cells. Seam cells are stem cell-like epithelial cells along the lateral edges of the animal, which go through asymmetric and symmetric divisions contributing cells to the hypodermis and neurons, while replenishing the stem cell reservoir. The terminal number of seam cells is almost invariant in the wild-type population, allowing the investigation of how developmental precision is achieved. We report here that a loss-of-function mutation in the highly conserved N-acetyltransferase nath-10/NAT10 increases seam cell number variance in the isogenic population. RNA-seq analysis revealed increased levels of mRNA transcript variability in nath-10 mutant populations, which may have an impact on the phenotypic variability observed. Furthermore, we found disruption of Wnt signaling upon perturbing nath-10 function, as evidenced by changes in POP-1/TCF nuclear distribution and ectopic activation of its GATA transcription factor target egl-18. These results highlight that NATH-10/NAT-10 can influence phenotypic variability partly through modulation of the Wnt signaling pathway.
LncRNA Landscape of Coronary Atherosclerosis Reveals Differentially Expressed LncRNAs in Proliferation and Migration of Coronary Artery Smooth Muscle Cells
Authors: Zhou Yaqing , Zhang Sheng , Ji Wenfeng , Gan Xiongkang , Hua Lei , Hou Can , Chen Jiaxin , Wang Yanjun , He Shu , Zhou Hanxiao , Jia Enzhi
Published: May 2021

We aimed to investigate differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in atherosclerosis and validate the expression of lncRNAs and co-expressed target genes in proliferation and migration models of human coronary artery smooth muscle cells (HCASMCs). Ten coronary artery specimens from a subject who died from a heart attack were employed. The pathological analysis was analyzed by hematoxylin and eosin (H&E) staining, and the lncRNAs and mRNAs were identified by RNA sequencing. Bioinformatic analyses were performed to predict possible mechanisms. The proliferation and migration of HCASMCs were induced with oxidized low-density lipoprotein (ox-LDL). Differentially expressed lncRNAs and mRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). In this study, 68 lncRNAs and 222 mRNAs were identified differentially expressed in atherosclerosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the Fanconi anemia pathway may be involved in atherosclerosis. GON4L was found to be the co-localized target gene of LNC_000439, and 14 genes had high correlations with the expression of seven lncRNAs. In addition, nine lncRNA–miRNA–mRNA networks were constructed, and 53 co-expressed gene modules were detected with weighted gene co-expression network analysis (WGCNA). LNC_000684, LNC_001046, LNC_001333, LNC_001538, and LNC_002115 were downregulated, while LNC_002936 was upregulated in proliferation and migration models of HCASMCs. In total, six co-expressed mRNAs were upregulated in HCASMCs. This study suggests that the differentially expressed lncRNAs identified by RNA sequencing and validated in smooth muscle cells may be a target for regulating HCASMC proliferation and migration in atherosclerosis, which will provide a new diagnostic basis and therapeutic target for the treatment of cardiovascular diseases.
Evaluating the Effectiveness of Personalized Medicine With Software
Authors: Kapelner Adam , Bleich Justin , Levine Alina , Cohen Zachary D. , DeRubeis Robert J. , Berk Richard
Published: May 2021

We present methodological advances in understanding the effectiveness of personalized medicine models and supply easy-to-use open-source software. Personalized medicine involves the systematic use of individual patient characteristics to determine which treatment option is most likely to result in a better average outcome for the patient. Why is personalized medicine not done more in practice? One of many reasons is because practitioners do not have any easy way to holistically evaluate whether their personalization procedure does better than the standard of care, termed improvement. Our software, “Personalized Treatment Evaluator” (the R package PTE), provides inference for improvement out-of-sample in many clinical scenarios. We also extend current methodology by allowing evaluation of improvement in the case where the endpoint is binary or survival. In the software, the practitioner inputs 1) data from a single-stage randomized trial with one continuous, incidence or survival endpoint and 2) an educated guess of a functional form of a model for the endpoint constructed from domain knowledge. The bootstrap is then employed on data unseen during model fitting to provide confidence intervals for the improvement for the average future patient (assuming future patients are similar to the patients in the trial). One may also test against a null scenario where the hypothesized personalization are not more useful than a standard of care. We demonstrate our method’s promise on simulated data as well as on data from a randomized comparative trial investigating two treatments for depression.
A Landscape-Level Assessment of Restoration Resource Allocation for the Eastern Monarch Butterfly
Authors: Solis-Sosa Rodrigo , Mooers Arne Ø. , Larrivée Maxim , Cox Sean , Semeniuk Christina A. D.
Published: May 2021

The Monarch butterfly eastern population (Danaus plexippus) is in decline primarily due to habitat loss. Current habitat restoration programs focus on re-establishing milkweed, the primary food resource for Monarch caterpillars, in the central United States of America. However, individual components of the Monarch life cycle function as part of an integrated whole. Here we develop the MOBU-SDyM, a migration-wide systems dynamics model of the Monarch butterfly migratory cycle to explore alternative management strategies’ impacts. Our model offers several advances over previous efforts, considering complex variables such as dynamic temperature-dependent developmental times, dynamic habitat availability, and weather-related mortality across the entire range. We first explored whether the predominant focus of milkweed restoration in the mid-range of the Monarch’s migration could be overestimating the Monarch’s actual habitat requirements. Second, we examined the robustness of using the recommended 1.2–1.6 billion milkweed stems as a policy objective when accounting for factors such as droughts, changes in temperature, and the stems’ effective usability by the Monarchs. Third, we used the model to estimate the number and distribution of stems across the northern, central, and southern regions of the breeding range needed to reach a self-sustainable long-term Monarch population of six overwintering hectares. Our analysis revealed that concentrating milkweed growth in the central region increases the size of the overwintering colonies more so than equivalent growth in the south region, with growth in the northern region having a negligible effect. However, even though simulating an increase in milkweed stems in the south did not play a key role in increasing the size of the overwintering colonies, it plays a paramount role in keeping the population above a critically small size. Abiotic factors considerably influenced the actual number of stems needed, but, in general, our estimates of required stems were 43–91% larger than the number of stems currently set as a restoration target: our optimal allocation efforts were 7.35, 92, and 0.15% to the south, central, and northern regions, respectively. Systems dynamics’ analytical and computational strengths provided us with new avenues to investigate the Monarch’s migration as a complex biological system and to contribute to more robust restoration policies for this unique species.
Novel Anti-Cytokine Strategies for Prevention and Treatment of Respiratory Allergic Diseases
Authors: Gubernatorova Ekaterina O. , Namakanova Olga A. , Gorshkova Ekaterina. A. , Medvedovskaya Alexandra D. , Nedospasov Sergei A. , Drutskaya Marina S.
Published: May 2021

Asthma is a heterogeneous inflammatory disease characterized by airflow obstruction, wheezing, eosinophilia and neutrophilia of the airways. Identification of distinct inflammatory patterns characterizing asthma endotypes led to the development of novel therapeutic approaches. Cytokine or cytokine receptor targeting by therapeutic antibodies, such as anti-IL-4 and anti-IL-5, is now approved for severe asthma treatment. However, the complexity of cytokine networks in asthma should not be underestimated. Inhibition of one pro-inflammatory cytokine may lead to perturbed expression of another pro-inflammatory cytokine. Without understanding of the underlying mechanisms and defining the molecular predictors it may be difficult to control cytokine release that accompanies certain disease manifestations. Accumulating evidence suggests that in some cases a combined pharmacological inhibition of pathogenic cytokines, such as simultaneous blockade of IL-4 and IL-13 signaling, or blockade of upstream cytokines, such as TSLP, are more effective than single cytokine targeting. IL-6 and TNF are the important inflammatory mediators in the pathogenesis of asthma. Preliminary data suggests that combined pharmacological inhibition of TNF and IL-6 during asthma may be more efficient as compared to individual neutralization of these cytokines. Here we summarize recent findings in the field of anti-cytokine therapy of asthma and discuss immunological mechanisms by which simultaneous targeting of multiple cytokines as opposed to targeting of a single cytokine may improve disease outcomes.
CD40 Activity on Mesenchymal Cells Negatively Regulates OX40L to Maintain Bone Marrow Immune Homeostasis Under Stress Conditions
Authors: Bassani Barbara , Tripodo Claudio , Portararo Paola , Gulino Alessandro , Botti Laura , Chiodoni Claudia , Jachetti Elena , Bolli Niccolò , Ciciarello Marilena , Joehrens Korinna , Anagnostopoulos Ioannis , Na Il-Kang , Curti Antonio , Colombo Mario P. , Sangaletti Sabina
Published: May 2021

Background

Within the bone marrow (BM), mature T cells are maintained under homeostatic conditions to facilitate proper hematopoietic development. This homeostasis depends upon a peculiar elevated frequency of regulatory T cells (Tregs) and immune regulatory activities from BM-mesenchymal stem cells (BM-MSCs). In response to BM transplantation (BMT), the conditioning regimen exposes the BM to a dramatic induction of inflammatory cytokines and causes an unbalanced T-effector (Teff) and Treg ratio. This imbalance negatively impacts hematopoiesis, particularly in regard to B-cell lymphopoiesis that requires an intact cross-talk between BM-MSCs and Tregs. The mechanisms underlying the ability of BM-MSCs to restore Treg homeostasis and proper B-cell development are currently unknown.

Methods

We studied the role of host radio-resistant cell-derived CD40 in restoring Teff/Treg homeostasis and proper B-cell development in a murine model of BMT. We characterized the host cellular source of CD40 and performed radiation chimera analyses by transplanting WT or Cd40-KO with WT BM in the presence of T-reg and co-infusing WT or - Cd40-KO BM-MSCs. Residual host and donor T cell expansion and activation (cytokine production) and also the expression of Treg fitness markers and conversion to Th17 were analyzed. The presence of Cd40+ BM-MSCs was analyzed in a human setting in correlation with the frequency of B-cell precursors in patients who underwent HSCT and variably developed acute graft-versus-host (aGVDH) disease.

Results

CD40 expression is nearly undetectable in the BM, yet a Cd40-KO recipient of WT donor chimera exhibited impaired B-cell lymphopoiesis and Treg development. Lethal irradiation promotes CD40 and OX40L expression in radio-resistant BM-MSCs through the induction of pro-inflammatory cytokines. OX40L favors Teff expansion and activation at the expense of Tregs; however, the expression of CD40 dampens OX40L expression and restores Treg homeostasis, thus facilitating proper B-cell development. Indeed, in contrast to dendritic cells in secondary lymphoid organs that require CD40 triggers to express OX40L, BM-MSCs require CD40 to inhibit OX40L expression.

Conclusions

CD40+ BM-MSCs are immune regulatory elements within BM. Loss of CD40 results in uncontrolled T cell activation due to a reduced number of Tregs, and B-cell development is consequently impaired. GVHD provides an example of how a loss of CD40+ BM-MSCs and a reduction in B-cell precursors may occur in a human setting.
Oncolytic Adenovirus Coding for a Variant Interleukin 2 (vIL-2) Cytokine Re-Programs the Tumor Microenvironment and Confers Enhanced Tumor Control
Authors: Quixabeira Dafne C. A. , Zafar Sadia , Santos Joao M. , Cervera-Carrascon Victor , Havunen Riikka , Kudling Tatiana V. , Basnet Saru , Anttila Marjukka , Kanerva Anna , Hemminki Akseli
Published: May 2021

The notion of developing variants of the classic interleukin 2 (IL-2) cytokine has emerged from the limitations observed with the systemic use of human IL-2 in the clinic: severe adverse events accompanied by low therapeutic response rate in treated patients. Modifications made in the IL-2 receptor-binding structure leads to preferential binding of IL-2 variant cytokine to receptors on effector anti-tumor lymphocytes over T regulatory (TReg) cells. Because of their inherent immunogenicity, oncolytic adenoviruses are useful for expression of immunomodulatory molecules in tumors, for induction of a pro-inflammatory state in the tumor microenvironment. In the present study, we constructed an adenovirus coding for an IL-2 variant (vIL-2) protein, Ad5/3-E2F-d24-vIL2. Functionality of the new virus was testedin vitro, and anti-tumor efficacy and mechanism of action studies were performed in immunocompetent hamsters bearing pancreatic tumors. Ad5/3-E2F-d24-vIL2 treatment elicited efficient anti-tumor response, with 62.5% monotherapy complete response. Moreover, it promoted substantial repression of genes associated with myeloid cells mediated immunosuppression (CD11b, ARG1, CD206). This was seen in conjunction with upregulation of genes associated with tumor-infiltrating lymphocyte (TIL) cytotoxicity (CD3G, SAP, PRF1, GZMMandGZMK). In summary, Ad5/3-E2F-d24-vIL2 demonstrates therapeutic potential by counteracting immunosuppression and in efficiently coordinating lymphocytes mediated anti-tumor response in immunosuppressive tumors. Thus, Ad5/3-E2F-d24-vIL2 is a promising candidate for translation into clinical trials in human immunosuppressive solid tumors.
Antigenic Evolution on a Global Scale Reveals the Potential Natural Selection of Severe Acute Respiratory Syndrome-Coronavirus 2 by Pre-existing Cross-Reactive T-Cell Immunity
Authors: Zhang Chengdong , Jin Xuanxuan , Chen Xianyang , Qiu Li , Leng Qibin , Qiu Tianyi
Published: May 2021

The mutation pattern of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has changed constantly during worldwide community transmission of this virus. However, the reasons for the changes in mutation patterns are still unclear. Accordingly, in this study, we present a comprehensive analysis of over 300 million peptides derived from 13,432 SARS-CoV-2 strains harboring 4,420 amino acid mutations to analyze the potential selective pressure of the host immune system and reveal the driver of mutations in circulating SARS-CoV-2 isolates. The results showed that the nonstructural protein ORF1ab and the structural protein Spike were most susceptible to mutations. Furthermore, mutations in cross-reactive T-cell epitopes between SARS-CoV-2 and seasonal human coronavirus may help SARS-CoV-2 to escape cellular immunity under long-term and large-scale community transmission. Additionally, through homology modeling and protein docking, mutations in Spike protein may enhance the ability of SARS-CoV-2 to invade host cells and escape antibody-mediated B-cell immunity. Our research provided insights into the potential mutation patterns of SARS-CoV-2 under natural selection, improved our understanding of the evolution of the virus, and established important guidance for potential vaccine design.
Anisotropy and Current Control of Magnetization in SrRuO3/SrTiO3 Heterostructures for Spin-Memristors
Authors: Goossens A. S. , Leiviskä M. A. T. , Banerjee T.
Published: May 2021

Spintronics-based nonvolatile components in neuromorphic circuits offer the possibility of realizing novel functionalities at low power. Current-controlled electrical switching of magnetization is actively researched in this context. Complex oxide heterostructures with perpendicular magnetic anisotropy (PMA), consisting of SrRuO3 (SRO) grown on SrTiO3 (STO) are strong material contenders. Utilizing the crystal orientation, magnetic anisotropy in such simple heterostructures can be tuned to either exhibit a perfect or slightly tilted PMA. Here, we investigate current induced magnetization modulation in such tailored ferromagnetic layers with a material with strong spin-orbit coupling (Pt), exploiting the spin Hall effect. We find significant differences in the magnetic anisotropy between the SRO/STO heterostructures, as manifested in the first and second harmonic magnetoresistance measurements. Current-induced magnetization switching can be realized with spin-orbit torques, but for systems with perfect PMA this switching is probabilistic as a result of the high symmetry. Slight tilting of the PMA can break this symmetry and allow the realization of deterministic switching. Control over the magnetic anisotropy of our heterostructures therefore provides control over the manner of switching. Based on our findings, we propose a three-terminal spintronic memristor, with a magnetic tunnel junction design, that shows several resistive states controlled by electric charge. Non-volatile states can be written through SOT by applying an in-plane current, and read out as a tunnel current by applying a small out-of-plane current. Depending on the anisotropy of the SRO layer, the writing mechanism is either deterministic or probabilistic allowing for different functionalities to emerge. We envisage that the probabilistic MTJs could be used as synapses while the deterministic devices can emulate neurons.
Iron Regulates the Warburg Effect and Ferroptosis in Colorectal Cancer
Authors: Yuan Yin , Ni Shuo , Zhuge Aoxiang , Li Bo , Li Lanjuan
Published: May 2021

Iron promotes the proliferation of cancer cells, but it also contributes to cell death. Here we explored whether iron could promote the Warburg effect of colorectal cancer (CRC) cells and suppress sensitivity to ferroptosis by inducing reactive oxygen species (ROS) and regulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, cell proliferation abilities were measured by CCK-8, EdU incorporation, and colony formation assays. Seahorse XF96 respirometry assays were used to detect the Warburg effect and the level of ROS was assess by DCFH-DA fluorescent probes. Results showed that iron exposure promoted the Warburg effect of CRC cells by inducing ROS and activating NRF2 both in vivo and in vitro. In addition, iron exposure also induced ferroptosis in CRC cells, but at the same time its inhibitory proteins SLC7A11 and GPX4 were also upregulated, indicating an enhanced resistance to ferroptosis. Our results revealed that iron can effectively promote tumorigenesis. Meanwhile, iron elimination or a low-iron diet might be valid therapeutic approaches for CRC.
D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats
Authors: Kato Risako , Zhang Edlyn R. , Mallari Olivia G. , Moody Olivia A. , Vincent Kathleen F. , Melonakos Eric D. , Siegmann Morgan J. , Nehs Christa J. , Houle Timothy T. , Akeju Oluwaseun , Solt Ken
Published: May 2021

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.
Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study
Authors: Chen Zhao-Yang , Zhu Yang-Hui , Zhou Ling-Yan , Shi Wei-Qiao , Qin Zhou , Wu Bin , Yan Yu , Pei Yu-Wen , Chao Ning-Ning , Zhang Rui , Wang Mi-Ye , Su Ze-Hao , Lu Xiao-Jun , He Zhi-Yao , Xu Ting
Published: May 2021

The aim of this study was to investigate the correlation between genetic polymorphisms of azathioprine-metabolizing enzymes and adverse reactions of myelosuppression. To this end, a retrospective analysis was performed on 1,419 Chinese patients involving 40 different diseases and 3 genes: ITPA (94C>A), TPMT*3 (T>C), and NUDT15 (415C>T). Strict inclusion and exclusion criteria were established to collect the relative cases, and the correlation between azathioprine and myelosuppression was evaluated by adverse drug reaction criteria. The mutation rates of the three genes were 29.32, 3.73, and 21.92% and grades I to IV myelosuppression occurred in 54 (9.28%) of the 582 patients who took azathioprine. The highest proportion of myelosuppression was observed in 5 of the 6 (83.33%) patients carrying the NUDT15 (415C>T) TT genotype and 12 of the 102 (11.76%) patients carrying the NUDT15 (415C>T) CT genotype. Only the NUDT15 (415C>T) polymorphism was found to be associated with the adverse effects of azathioprine-induced myelosuppression (odds ratio [OR], 51.818; 95% CI, 5.280–508.556; p = 0.001), which suggested that the NUDT15 (415C>T) polymorphism could be an influencing factor of azathioprine-induced myelosuppression in the Chinese population. Epistatic interactions between ITPA (94C>A) and NUDT15 (415C>T) affect the occurrence of myelosuppression. Thus, it is recommended that the genotype of NUDT15 (415C>T) and ITPA (94C>A) be checked before administration, and azathioprine should be avoided in patients carrying a homozygous NUDT15 (415C>T) mutation. This study is the first to investigate the association between genetic polymorphisms of these three azathioprine-metabolizing enzymes and myelosuppression in a large number of cases with a diverse range of diseases.
Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments
Authors: Alghamri Mahmoud S. , McClellan Brandon L. , Hartlage Carson S. , Haase Santiago , Faisal Syed Mohd , Thalla Rohit , Dabaja Ali , Banerjee Kaushik , Carney Stephen V. , Mujeeb Anzar A. , Olin Michael R. , Moon James J. , Schwendeman Anna , Lowenstein Pedro R. , Castro Maria G.
Published: May 2021

Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15  months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.
Preventing Failures by Dataset Shift Detection in Safety-Critical Graph Applications
Authors: Song Hoseung , Thiagarajan Jayaraman J. , Kailkhura Bhavya
Published: May 2021

Dataset shift refers to the problem where the input data distribution may change over time (e.g., between training and test stages). Since this can be a critical bottleneck in several safety-critical applications such as healthcare, drug-discovery, etc., dataset shift detection has become an important research issue in machine learning. Though several existing efforts have focused on image/video data, applications with graph-structured data have not received sufficient attention. Therefore, in this paper, we investigate the problem of detecting shifts in graph structured data through the lens of statistical hypothesis testing. Specifically, we propose a practical two-sample test based approach for shift detection in large-scale graph structured data. Our approach is very flexible in that it is suitable for both undirected and directed graphs, and eliminates the need for equal sample sizes. Using empirical studies, we demonstrate the effectiveness of the proposed test in detecting dataset shifts. We also corroborate these findings using real-world datasets, characterized by directed graphs and a large number of nodes.
Investigating the Influence of Structure and Heterogeneity in Waste Rock Piles on Mass Loading Rates—A Reactive Transport Modeling Study
Authors: Raymond Katherine E. , Seigneur Nicolas , Su Danyang , Mayer K. Ulrich
Published: May 2021

Placement methods and material availability during waste rock pile (WRP) construction may create significant heterogeneities in physical and geochemical parameters (such as grain size, permeability, mineralogy, and reactivity) and influence the internal pile structure. Due to the enormous scale of WRPs, it is difficult to capture the influence of heterogeneities on mine drainage composition and evolution. Although laboratory- or field-scale experimental studies have provided much insight, it is often challenging to translate these results to full scale WRPs. This study uses a numerical modeling approach to investigate the influence of physical and chemical heterogeneities, structure, and scale on the release of acid rock drainage (ARD) through 2D reactive transport simulations. Specifically, the sensitivity of drainage quality to parameters including grain size distribution, sulfide mineral weathering rates, abundance and distribution of primary minerals, and pile structure as a function of construction methods are investigated. The geochemical model includes sulfide oxidation, pH buffering by calcite dissolution, and ferrihydrite and gypsum as secondary phases. Simulation results indicate that the implications of heterogeneity and construction method are scale-dependent; when grain size distribution trends observed in a pile's core are applied to the entirety of a pile, results between push- and end-dumping methods vary substantially—however, predicted drainage for different construction methods become more similar when features such as traffic surfaces, structural variation, and multiple benches are also considered. For all scales and construction methods investigated, simulated results demonstrate that pile heterogeneity and structure decrease peak mass loading rates 2 to 3-fold, but cause prolonged ARD release compared to the homogeneous case. These findings have implications for the economics of planning water treatment facilities for life of mine and closure operations.
How Turbulent is the Magnetically Closed Corona?
Authors: Klimchuk James A. , Antiochos Spiro K.
Published: May 2021

We argue that the magnetically closed corona evolves primarily quasi-statically, punctuated by many localized bursts of activity associated with magnetic reconnection at a myriad of small current sheets. The sheets form by various processes that do not involve a traditional turbulent cascade whereby energy flows losslessly through a continuum of spatial scales starting from the large scale of the photospheric driving. If such an inertial range is a defining characteristic of turbulence, then the magnetically closed corona is not a turbulent system. It nonetheless has a complex structure that bears no direct relationship to the pattern of driving.
The Evolution of Phenolic Compounds in Vitis vinifera L. Red Berries during Ripening: Analysis and Role on Wine Sensory—A Review
Authors: Allegro Gianluca , Pastore Chiara , Valentini Gabriele , Filippetti Ilaria
Published: May 2021

The study of phenolic maturity in Vitis vinifera L. requires a multidisciplinary approach to understand how the evolution of berry flavonoids and cell wall material influence the colour and the textures of red wine. This is a challenging issue which involves researchers of viticulture and enology, and the results of their work are of particular interest for the producers of high-quality red wines. This review reports the current knowledge regarding phenolic maturity, describing the sensorial traits of the different compounds, the evolution of berry flavonoids and the methodologies used to evaluate their characteristics. Finally, the role of cell wall material in influencing the extractability of anthocyanins and proanthocyanidins was shown. By means of a critical review of the results, it can be hypothesised that prolonged ripening improved colour characteristics and mouthfeel properties, thanks to the higher amounts of extractable skin flavonoids associated with lower amounts of seed proanthocyanidins, and to the increased affinity of the cell wall material for the proanthocyanidins most involved in the perception of unpleasant astringency.
The Influence of Breed, Sex, Origin and Housing Conditions on Undesirable Behaviors in Ancient Dog Breeds
Authors: Wójcik Anna , Powierża Kinga
Published: May 2021

Abnormal repetitive behaviors often pose problems for dog owners. Such behaviors are considered undesirable if they pose a nuisance or a danger to humans. Ancient dog breeds are intelligent, sociable, active, boisterous and need regular outdoor exercise, but are also independent and reluctant to follow commands. This study aimed to identify factors (breed, sex, origin, housing conditions) and situations that contribute to undesirable behaviors, such as aggression towards humans and other dogs/animals, separation anxiety, excessive vocalization, and oral and locomotion behaviors in Akita, Alaskan Malamute, Basenji, Samoyed and Siberian husky. Undesirable behaviors in dogs were analyzed based on the results of 897 questionnaires. Breed influenced aggressive behavior towards other dogs/animals, aggression towards humans, undesirable oral and locomotion behaviors, and excessive vocalization. Aggressive behaviors were more prevalent in females than in males. Housing conditions were linked with aggression towards other dogs/animals, aggression at mealtime, and excessive vocalization. Undesirable behaviors were most frequently reported in Akitas, Siberian huskies and Samoyeds, and they were more prevalent in males than in females and dogs living indoors with or without access to a backyard. Aggressive behaviors towards other dogs and animals, excessive vocalization and undesirable motor activities posed the greatest problems in ancient dog breeds.
Comparing Behavioural Problems in Imported Street Dogs and Domestically Reared Danish Dogs—The Views of Dog Owners and Veterinarians
Authors: Munkeboe Natascha , Lohse-Lind Amalie , Sandøe Peter , Forkman Björn , Nielsen Søren Saxmose
Published: May 2021

Street dogs are common in southern and eastern parts of Europe. They are often adopted by people living in North European countries, including Denmark. However, these dogs may experience difficulties adjusting to their new life as companion animals, and this may in turn lead to behavioural problems and complications for owners. The objective of this study was therefore to investigate whether former street (FS) dogs display a higher degree of behavioural problems than dogs reared in Denmark (RD). Two questionnaires were developed. One was distributed to Danish dog owners and resulted in 3020 useful answers. FS dogs were found to display 9 of the 45 listed behaviours more often than RD dogs. All of these behaviours were related to fear, aggression and stress. The second questionnaire was distributed to Danish veterinarians working in small animal practices and resulted in 173 useful answers. The most commonly reported behavioural problems were fear of humans, stress and problems when the dog was left at home alone. The extent of the behavioural problems reported by the veterinarians was much greater than that reported by the dog owners which, at least partly, may be due to fear-induced reactions of the dogs when handled at the veterinary clinic.