bluuebunny/crossref_metadata_2025 huggingface dataset:
КОІНТЕГРАЦІЙНИЙ АНАЛІЗ ЗВ’ЯЗКУ ІНФЛЯЦІЇ З КРИПТОВАЛЮТОЮ BITCOIN
Authors: СКЛЯРЕНКО Олена , ЩЕРБАТИХ Денис , КОТВИЦЬКА Наталія , ШАРОВА Світлана
Published: December 2024

Емпіричне дослідження потенційної ролі криптовалюти як інструменту хеджування інфляції набуває все більшої актуальності на тлі нещодавньої глобальної економічної невизначеності та інфляційного тиску. У цьому дослідженні вивчається довгостроковий зв'язок між цінами на Bitcoin та інфляцією за допомогою коінтеграційного аналізу, використовуючи щомісячні дані з січня 2015 року по червень 2023 року. Використовуючи коінтеграційні тести Енгла-Гренджера та Йохансена в рамках методу ковзного вікна, ми оцінюємо стабільність та еволюцію цього взаємозв'язку з плином часу.Результати свідчать про складний і мінливий у часі зв'язок між криптовалютою Bitcoin та інфляцією. Тест Йохансена виявив коінтеграцію у 25% ковзних інтервалів, тоді як тест Енгла-Гренджера знайшов докази лише у 3,6% інтервалів, що свідчить про те, що будь-який довгостроковий рівноважний зв'язок є радше епізодичним, ніж стабільним. Помітний структурний злам спостерігається близько 2021 року, що збігається зі значними змінами як на ринках криптовалют, так і в глобальних економічних умовах.Отримані результати ставлять під сумнів наратив про Bitcoin як надійний інструмент хеджування інфляції, вказуючи на те, що його зв'язок з інфляцією є менш стабільним, ніж у традиційних активів для хеджування. Період після 2021 року демонструє особливо високу волатильність цього взаємозв'язку, незважаючи на більш широке інституційне впровадження та увагу до нього з боку широкого загалу. Результати дослідження свідчать про те, що хоча Bitcoin може пропонувати властивості хеджування інфляції протягом певних періодів, ці властивості не є достатньо послідовними, щоб покладатися на них для систематичного захисту від інфляції.
PENINGKATAN LITERASI DIGITAL DAN MOTIVASI GURU SEKOLAH DASAR MELALUI PENGEMBANGAN MEDIA BELAJAR MANDIRI BERBASIS TPACK DENGAN CANVA
Authors: Astuti Yenni Masni , Dike Daniel , Fatawi Izzul
Published: December 2024

ABSTRAKPenelitian ini untuk meningkatkan literasi digital dan motivasi guru sekolah dasar melalui pengembangan media belajar mandiri berbasis TPACK dengan Canva. Penelitian menggunakan metode Research and Development (RnD) dengan model pengembangan ADDIE. Penelitian dilakukan di Gugus 2 Pandan dengan 3 sekolah yaitu SDN 9 Merarai, SDN 10 SP 1 Pandan, dan SDN 11 SP 2 Pandan dengan jumlah 30 guru. Hasil Penelitian ini adalah menurut ahli media, ahli materi dan praktisi media Canva dapat kategori valid. Uji keefektivan media Canva analisis literasi digital dan motivasi guru sebelum dan sesudah melibatkan 30 orang guru. Hasil angket sebelum pelatihan memiliki hasil “cukup baik”. Sikap terhadap teknologi dan persepsi manfaat dengan hasil “baik”. Setelah pelatihan keterampilan teknis  dan penggunaan Canva memiliki hasil sangat baik. Sikap terhadap teknologi dan persepsi manfaat memiliki hasil sangat baik. Berdasarkan uji efektifitas disimpulkan bahwa media belajar mandiri berbasis TPACK dengan Canva sangat efektivif terhadap literasi digital dan motivasi guru.Kata Kunci: Literasi Digital, Motivasi, Media Belajar Mandiri, TPACK, CanvaABSTRACTThis research is to increase digital literacy and motivation of elementary school teachers through the development of TPACK-based independent learning media with Canva. The research uses the Research and Development (RnD) method with the ADDIE development model. The research was conducted in Cluster 2 Pandan with 3 schools, namely SDN 9 Merarai, SDN 10 SP 1 Pandan, and SDN 11 SP 2 Pandan with a total of 30 teachers. The results of this research are that according to media experts, material experts and media practitioners, Canva can be categorized as valid. Test the effectiveness of Canva media analysis of digital literacy and teacher motivation before and after involving 30 teachers. The results of the questionnaire before the training were "fairly good". Attitudes towards technology and perceived benefits with “good” results. After technical skills training and use of Canva had excellent results. Attitudes towards technology and perceived benefits have very good results. Based on the effectiveness test, it was concluded that TPACK-based independent learning media with Canva was very effective for digital literacy and teacher motivation.Keywords: Digital Literacy, Motivation, Independent Learning Media, TPACK, Canva
PENGARUH BUDAYA ORGANISASI TERHADAP KUALITAS PELAYANAN PUBLIK DI KANTOR KEPALA DESA BANTARJATI KECAMATAN KERTAJATI KABUPATEN MAJALENGKA
Authors: Herdiana Deni , Kurnia Nugraha Detri
Published: December 2024

Penelitian ini dilatarbelakangi oleh adanya suatu permasalahan terkait kualitas pelayanan publik yang disebabkan oleh budaya organisasi. Perumusan masalah pada penelitian ini ditujukan untuk mengetahui bagaimana budaya organisasi, kualitas pelayanan publik dan seberapa besar pengaruh budaya organisasi terhadap kualitas pelayanan publik di Kantor Kepala Desa Bantarjati.
Data penelitian ini terdiri dari data primer dan sekunder yang diperoleh melalui penelitian langsung di lapangan. Populasi pada penelitian ini terdiri dari 57 orang dan diambil sebagai sampel sebanyak 50 orang, dengan nilai presisi 95%. Sedangkan teknik analisis data pada penelitian ini, yaitu menggunakan metode kuantitatif dengan pendekatan deskriptif-kuantitatif.
Hasil penelitian ini menunjukkan bahwa budaya organisasi dan kualitas pelayanan publik secara deskriptif nilainya tergolong baik. Sedangkan secara kauntitatif hasil penelitian ini menunjukkan bahwa terdapat pengaruh positif yang kuat dari budaya organisasi terhadap kualitas pelayanan publik, yang apabila dipersentasikan nilainya adalah 57,5% dan sisanya 42,5% dipengaruhi oleh faktor lain di luar variabel budaya organisasi.
Secara garis besarnya kesimpulan pada penelitian ini adalah bahwa penerapan budaya organisasi yang baik secara empiris akan berdampak positif terhadap kualitas pelayan publik di Kantor Desa Bantarjati Kecamatan Kertajati Kabupaten Majalengka.
Pengaruh Kompetensi Kerja Karyawan dan Komitmen Kerja Terhadap Kinerja
Authors: Fauzi Haris , Kurnadi Engkun , Nuraeni Neni Sri
Published: December 2024

Penelitian ini berawal dari ditemukannya permasalahan pada kinerja karyawan. Masalah yang terlihat dalam penelitian ini adalah kinerja karyawan yang diakibatkan oleh kompetensi kerja dan komitmen kerja, dimana karyawan tidak memiliki keterampilan kerja yang baik serta di tambah dengan rasa loyalitas pegawai yang rendah saat bekerja. Penelitian ini bertujuan untuk mengetahui pengaruh kompetensi kerja dan komitmen kerja terhadap kinerja karyawan.
 Metode yang digunakan dalam penelitian ini adalah analisis deskriptif dan verifikatif. Populasi dalam penelitian ini adalah karyawan PT. Persada Selaras Indonesia yang berjumlah 93 orang, dengan sampel seluruh karyawan PT. Persada Selaras Indonesia sebanyak 93 orang. Teknik sampling yang digunakan yaitu sampling jenuh. Teknik pengumpulan datanya berupa observasi, wawancara, dan penyebaran kuesioner. Adapun alat analisis yang digunakan dalam penelitian ini yaitu dengan melakukan uji asumsi klasik, regresi linier berganda, koefisien determinasi, uji kelayakan model dan uji hipotesis secara parsial (uji t).
 Hasil dari penelitian ini menunjukan bahwa kompetensi kerja dan komitmen kerja berpengaruh positif dan signifikan terhadap kinerja karyawan pada karyawan PT. Persada Selaras Indonesia.
Pengaruh Variabel Makroekonomi Dan Ketidakpastian Global Terhadap Neraca Perdagangan Indonesia Tahun 2013-2023
Authors: Ulwiyah Badi'atul , Meliza
Published: December 2024

Neraca perdagangan merupakan salah satu ukuran yang mencerminkan sejauh mana keseimbangan perekonomian suatu negara dengan dunia luar. Penelitian ini bertujuan untuk mengevaluasi dampak variabel makroekonomi dan ketidakpastian global terhadap neraca perdagangan Indonesia tahun 2013 hingga 2023 dengan menggunakan pendekatan kuantitatif ARDL. Temuan menunjukkan bahwa nilai tukar, inflasi, dan ketidakpastian global berpengaruh signifikan terhadap neraca perdagangan dalam jangka pendek, namun tidak memiliki dampak yang sama dalam jangka panjang. Secara spesifik nilai tukar mempunyai dampak positif yang signifikan, inflasi juga mempunyai dampak positif yang signifikan, sedangkan ketidakpastian global mempunyai dampak negatif yang signifikan. Namun suku bunga dan PDB tidak memberikan pengaruh yang signifikan terhadap neraca perdagangan Indonesia baik dalam jangka pendek maupun jangka panjang. Penelitian ini memberikan wawasan berharga bagi kebijakan ekonomi dan perdagangan Indonesia untuk mengatasi tantangan global dan meningkatkan neraca perdagangan negara.
Evaluating the Growth of Village Revenue by Enhancing Village-Owned Enterprises (BUMDes) Through the Application of Good Corporate Governance
Authors: Adriyana Rika , Affa Ahmad Syaiful , Surendra  , Pramestu Meidiastika Widya
Published: December 2024

Badan Usaha Milik Desa (BUMDes) adalah badan usaha yang seluruh atau sebagian besar modalnya dimiliki Desa melalui penyertaan secara langsung yang berasal dari kekayaan desa yang dipisahkan guna mengelola aset, jasa pelayanan dan usaha lainnya. BUMDes atau badan usaha milik desa menjadi sebuah terobosan bagi setiap desa untuk terus berinovasi dalam meningkatkan pendapatan asli desa (PADes). Penelitian ini bertujuan untuk mendeksripsikan optimalisasi pengelolaan BUMDes dengan menerapkan prinsip good governance yaitu kooperatif, partisipatif, emansipatif, akuntabel, transparan dan sustainibility. Berdasarkan survey di lapangan, menyebar kuesioner dan wawancara terhadap beberapa pengelola BUMDes, maka hasil menunjukkan bahwa BUMDes sudah mengimplementasikan aspek good governance dengan baik. Namun ada aspek yang belum dilakukan secara optimal yaitu akuntabilitas dalam pembuatan laporan keuangan yang belum sesuai dengan standar akuntansi
Manajemen Pentahelix Dalam Pencegahan Dan Penaggulangan Terorisme Di Desa Kananga Kabupaten Bima
Authors: Fuad Muhammad , Umar  , Najamudin
Published: December 2024

Terorisme merupakan kejahatan yang kini banyak dibahas di media cetak dan elektronik, terutama di Indonesia, yang terdampak serius sejak Bom Bali I tahun 2002. Hingga kini, aksi terorisme terus terjadi dalam berbagai bentuk, melibatkan individu dan kelompok. Penelitian ini bertujuan untuk menganalisis penerapan konsep pentahelix dalam upaya pencegahan dan penanggulangan terorisme di Desa Kananga, Kabupaten Bima, serta mengidentifikasi tantangan yang dihadapi. Penelitian ini menggunakan metode kualitatif dengan pendekatan studi kasus, melibatkan informan yang mewakili lima elemen pentahelix: pemerintah (Danramil, Kapolsek, Kepala Desa), akademisi (tokoh pendidikan), bisnis (pengelola bisnis lokal), komunitas (tokoh masyarakat), dan media (pengelola media lokal). Informan dipilih dengan purposive sampling, dan data dikumpulkan melalui wawancara, observasi, serta dokumentasi. Hasil penelitian menunjukkan bahwa penerapan konsep pentahelix melalui pendekatan berbasis budaya, pendidikan, dan kebersamaan efektif dalam menjaga harmoni sosial serta mencegah masyarakat terpapar radikalisme. Namun, kendala utama yang dihadapi meliputi kurangnya koordinasi antar-lembaga, terbatasnya akses ke komunitas yang rentan, serta persepsi negatif sebagian masyarakat terhadap upaya ini. Penelitian menyimpulkan bahwa konsep pentahelix mampu menciptakan sinergi positif antara pemerintah, akademisi, bisnis, komunitas, dan media, namun tantangan dalam koordinasi dan persepsi perlu diatasi untuk memaksimalkan efektivitas dalam pencegahan terorisme
Intelligence and power as scientific leadership factors in the digital world: present discussions
Authors:   The State Academic Universi-ty for the Humanities, Trufanova Elena O. ,   Yaroslav-the-Wise Novgorod State University, Yakovleva Aleksandra F. ,   The State Academic Universi-ty for the Humanities,   Lomonosov Moscow State University
Published: December 2024

The review of the new book by the famous philosophers of science Alexandr P. Alekseev and Irina Yu. Alekseeva “The Fate of Intelli-gence and the Mission of Reason: Philosophy Facing the Challenges of the Digitalization Era” (Moscow, 2021) includes the analysis of several generalizations and conclusions note-worthy from the viewpoint of modern understanding of scientific leadership in the knowledge society. The review notes that the book focuses on the concept of intelligence, which is understood by its authors as the val-ue of human life, which requires protection against the dangers of the digital environ-ment. An important place in the book is oc-cupied by a historical and philosophical overview of the research of artificial intelligence, systematizing the developments of Russian scientists of the first half and middle of the 20th century, such as S. Korsakov, D. Pospelov and V. Pushkin, A. Lyapunov, S. Yanovskaya, as well as philosophers A. Bogdanov, L. Ba-zhenov, and E. Ilyenkov. The review empha-sizes the modern philosophical understanding of the reason and its correlation with the in-tellect in the conditions of its technologiza-tion. The authors of the review conclude that through the problem of intellectual sovereignty of modern society, formulated in the book, it is possible to analyze the interaction between science and government in the context of new challenges of digitalization: when the government uses technology as an evalua-tion criterion for any activity, for example, scientific, and when the development of the technologies themselves have the power to determine the future of entire industries in many ways.
The arguments of dissenters: how has network protest affected social order?
Authors:   Lomonosov Moscow State University, Pogozhina Natalya N.
Published: December 2024

The article is a reflection on the network form of protest in the realities of the modern world and bases on a critical consideration of a number of provisions presented in the monograph “New Social Movements in the Network Era: Articles, Interviews, Expert Opin-ion” edited by K. K. Momdzhyan and R. E. Ba-rash. The author follows the optics of the book, identifying the key lines of influence of protest communication on the systemic or-ganization of modern society. She also notes the need to assess the role of new media in shaping the agenda and expanding the field of protest discourse. The article examines the mechanisms for generating protest on the network and representing radical protest ac-tivism in mass culture. The specifics of Russian protest are given. The demonstration of a number of theoretical positions regarding the social base and the shaping elements of the “new social movements,” which are the “starting point” of the new type of protest communication, allows us to conclude that network protest movements can act in the fu-ture as a separate communicative subsystem only if a number of functional barriers are overcome. These barriers include: gaps in connection with new forms of inequality in-cluding digital and algorithmic, as well as the need to find other “growth points” for con-stant self-circulation due to the lack of organi-zational and interactive potential, taking into account the heterarchicity and polycentricity of protest network communication.
The normative nature of legal communication
Authors:   Saratov State Law Academy, Erokhin Vladimir S. , Erokhina Natalia V. ,   Saratov State Law Academy
Published: December 2024

The purpose of the study is to determine the unity of legal, logical and rhetorical norms of legal communication. The article discusses the basic concepts, such as: normativity, legal norms, rhetorical norms, logical norms, and legal communication. To achieve this goal, it is necessary to solve a number of tasks: (1) in the most general form to determine the essence of communication as a social phe-nomenon, its rational and normative nature; (2) to determine the content of legal commu-nication as a type of communication; (3) to define the normative nature of legal commu-nication as a unity of legal, logical and rhetor-ical norms. In their research, the authors use a logical method that allows for a meaningful analysis of legal, logical and rhetorical norms of legal communication, as well as a critical method that allows them to comprehend their relationship and influence on the achievement of the results of legal communi-cation. The obtained results have shown that the normative nature of legal communication is expressed in the unity of legal, logical and rhetorical norms of information transmission, allowing to achieve a legally justified, logically accurate and rhetorically acceptable position, which the speaker seeks to convey. The rele-vance of the work is provided by the follow-ing. Communication in society is associated with difficulties, and sometimes the impossi-bility of transmitting information. For this rea-son, the analysis of the communication pro-cess from the viewpoint of social normativity makes it possible to discover ways of effective information exchange between individuals as subjects of social relations. The study of the normative nature of legal communication is also relevant to identify the causes of the pos-sible occurrence of negative socio-legal con-sequences of ineffective broadcasting of legal-ly and politically significant information. The identification of legal, logical and rhetorical requirements for legal communication is im-portant for the analysis and establishment of the legality, truth and acceptability of the transmitted information, which in turn con-tributes to its acceptance by the subjects of communication interaction. The research novelty of the work lies in a comprehensive approach to the study of the normative na-ture of legal communication, which includes logical, legal and rhetorical principles of its implementation. It is argued that the norma-tivity of legal communication is associated with the fulfillment of a few things. These are the requirements of legal norms designed to form the legitimacy of the results of commu-nicative interaction, logical requirements that help to achieve accuracy and consistency of the results obtained, and rhetorical principles, the use of which leads to the acceptabil-ity of the results of communication for the subjects involved in it.
Objectivity and the method of social epistemology
Authors:   Institute of Philosophy, Russian Academy of Sciences, Argamakova Alexandra A.
Published: December 2024

Sociology as the research method for science, technology and knowledge reveals historicity, variability, relativity, contextuality along with the situatedness of scientific beliefs. The usu-al outcome of sociological and epistemologi-cal research would be the dependence of knowledge from various forms of collective subjectivity in contrast to neutral “objective reality”, as scientific realists believe, crystal-lized in rational worldviews. Not surprising if historically the project of social epistemology meets diverse and incompatible reactions on its main principle and program of sociological justification of knowledge. In the inner and outer contexts, social epistemology has been differently correlated with the questions of objectivity, scientific realism and relativism. Its method could be treated in a range of atti-tudes: skeptically as it follows from internal-ism and scientific rationalism; or neutrally as a kind of facticity researched by sociologists; or, on the contrary, as a reliable way for increas-ing objectivity and reflexivity of cognition. What we explore is the following question: scientific knowledge as well as any kind of knowledge must be objective (from a pur-pose-oriented setting of cognition), even if sociology shows its relativity and subjectivity. What is specified in the subsequent dilemma: how subjective and objective properties of knowledge can be combinated and how should social epistemology explain this? It must be said additionally that the method of social epistemology takes normative and de-scriptive forms, with different obligations. As a normative discipline, it must set the criteria for objectivity and somehow lead the scien-tists. As a descriptive discipline, it may tell what kinds of factors actually influence the practice, escaping from responsibility for what is happening. But even then social epistemol-ogy cannot avoid the reluctant explanations of what is objective and subjective, social and factual, collective and individual types of knowledge.
Influence of dihydropyridines on the recovery of sensory function after a caudal nerve crush in the rat
Authors: Kappelle A.C. , Biessels G. , Van Buren T. , Brakkee J.H. , Gispen W.H.
Published: December 2024

Nimodipine, a Ca2+ antagonist of the dihydropyridine type, is known to display a variety of neuropharmacological effects including facilitation of functional recovery following a crush of the sciatic nerve in the rat. In the present study, we investigated the effect of nimodipine, nifedipine (another Ca2+ antagonist with a lesser penetration in neural parenchyma) and Bay K 8644 (a Ca2+ agonist) treatment following a crush of the major caudal nerve. The caudal nerve crush model was used because this model provided the opportunity for longitudinal evaluation of nerve repair. Recovery of sensory function was tested by vocal reaction following local stimulation with a small electric current. The results suggest that nimodipine (20 mg/kg) both enhances the initial sprouting response and exerts an effect on the outgrowth rate of newly developed sprouts. Neither nifedipine (20 mg/kg) nor Bay K 8644 (0.5 mg/kg) had any influence on the recovery of nerve function. Furthermore, it was demonstrated that nimodipine, nifedipine and Bay K 8644 had no influence on nerve conduction velocity of the non-injured sciatic nerve indicating that there was no general beneficial effect of these agents on the peripheral nerve.
Rehabilitation of Visuospatial Cognition and Visual Exploration in	Neglect: a Cross-over Study
Authors: Kerkhoff Georg
Published: December 2024

Right hemispheric brain damage is often accompanied by visual neglect of contralesional hemispace as well as profound visuospatial and visuoconstructive disorders. Despite some recent improvements in the treatment of neglect, few therapeutic approaches exist for disorders of visuospatial cognition and none has dealt with the question of how both disorders can be treated in combination. In the present cross-over rehabilitation study, thirteen neglect patients first received visual exploration training for six weeks followed by visuospatial training for four weeks. Eleven patients had a right-hemispheric lesion, 2 a left-hemispheric lesion. Ten subjects had parietal cortical lesions, 3 lesions were outside the parietal lobe. In the first treatment phase the patients received training, using computer controlled devices, intended to improve visual search and reading strategies. In the second phase of treatment, visual orientation discrimination was trained on a PC-monitor with verbal feedback by the therapist. Significant improvements were obtained after exploration training regarding the extent of visual search-field witbin the neglected hemifield, visual search performance in the whole visual field, reading time and reading errors but there was no change after visuospatial training for any of these measures. The reverse pattern was observed for visuospatial training: significant improvements were observed in line orientation judgements, clock perception, mental transposition of angles, horizontal writing and visuoconstructive abilities, but there was no change in any of these tests during exploration training. Feedback-based training of visual orientation discrimination revealed rapid (within 8-15 sessions) and stable improvements in this ability and a transfer to spatially related tasks. No significant correlations were obtained between training-related improvements and the time since brain damage for 9 of 10 tests, indicating that spontaneous recovery had no effect on the improvements during the two treatments. Likewise, no influence of age and gender on treatment progress was found. The phase-specific improvements in this study suggest that specific and differential treatment is necessary and effective for the treatment of visual exploration and visuospatial disorders in patients with visual neglect. Moreover, they indicate that feedback-based visual learning may prove an effective device in the neurorehabilitation of brain-damaged patients.
Differential Activation of MAPK and ICE/Ced-3 Protease in	Chemical-Induced Apoptosis
Authors: Kong Ah-Ng Tony , Yu Rong , Lei Wei , Mandlekar Sandhya , Tan Tse-Hua , Ucker David S.
Published: December 2024

Chemical-induced oxidative stress to a cell can signal many cellular responses which include proliferation, differentiation, hemeostasis, apoptosis or necrosis. To better understand the underlying molecular mechanisms after exposure to chemicals, we investigated the signal transduction pathways, in particular the mitogen-activated protein kinase (MAPK) pathway and the ICE/Ced-3 protease (caspase) pathway, activated by different agents. Butylated hydroxyanisol (BHA) and its metabolite, t-butyl-hydroquinone (tBHQ), both are well known phenolic antioxidants used in food preservatives, strongly activated c-Jun N-terminal kinase 1 (JNK1) and/or extracellular signal-regulated protein kinase 2 (ERK2) in a dose- and time-dependent fashion. Pretreatment with free radical scavengers N-acetyl-L-cysteine (NAC), glutathione (GSH), or vitamin E, inhibited ERK2 activation and, to a much lesser extent, JNK 1 activation by BHA and tBHQ, implicating the role of oxidative stress. Under conditions where JNK1 and ERK2 were activated, BHA also activated transcription factors nuclear factor kappa B (NF-?B), activated-protein-1 (AP-1), and anti-oxidant response element (ARE), leading to induction of genes such as c-jun, and c-fos. At relatively high concentrations, BHA and tBHQ stimulated proteolytic activity of ICE/Ced3 cysteine proteases, and caused apoptosis, which was blocked by pretreatment with NAC. Further increase in concentrations lead to rapid cell death predominantly occurred via necrosis. Some naturally occurring phytochemicals, such as phenylethyl isothiocyanate (PEITC), green tea polyphenols (GTP), and sulfarophane, which have been shown to be potent inducers of Phase II enzymes, also differentially regulated the activities of JNK, ERK, or CPP-32, in a time- and dose-dependent manner. Our data, together with the work of others, enable us to propose a model in which low concentrations of these chemicals (e.g., BHA, PEITC) activate MAPKs leading to induction of gene expression (e.g., c-jun, c-fos, GSI) which may protect the cells against toxic insults and enhance cell survival. At relatively high concentrations, these agents activated both MAPKS, and the ICE/Ced-3 caspase pathway, leading to apoptosis. The exact mechanisms by which MAPK and caspases are activated by these agents are currently unknown, but may involve oxidative modification of glutathione (GSH) and/or protein thiols, and/or generation of secondary messengers, ceramide and calcium, which further activate downstream events. Taken together, our results suggest that chemicals including phenolic antioxidants activate MAPK pathways which may lead to the induction of genes producing protection and survival mechanisms, as well as the ICE/Ced-3 protease pathway, leading to apoptosis. The balancing amongst these pathways may dictate the fate of the cells upon exposure to chemicals.
The Difference between Mechanisms of Kainate and Glutamate	Excitotoxicity In Vitro: Osmotic Lesion Versus Mitochondrial	Depolarization
Authors: Kiedrowski Lech
Published: December 2024

The hypothesis that a destabilization of mitochondrial function during neuronal exposure to excitatory amino acids may be involved in the mechanism of neuronal death was examined. The mitochondrial membrane potential (??m) and the cytoplasmic Ca2+ concentration ([Ca2+]c) were monitored simultaneously in single cultured rat cerebellar granule cells (CGCs) loaded with tetramethylrhodamine methyl ester (TMR) and fura-2; CGCs were depolarized with K+, or exposed to excitotoxic doses of glutamate or kainate, and viability of the same neurons was studied for 24-30 h. This approach made it possible to single out the neurons that died, and to describe the changes in ??m and [Ca2+]c that were characteristic for these neurons. Exposure to glutamate caused an increase in [Ca2+]c that was associated with a decrease in the mitochondrial TMR fluorescence, which indicates a decrease in ??m. The neurons that failed to restore ??m following glutamate withdrawal, also failed to restore low [Ca2+]c, and later died. Although a similar number of neurons died following kainate exposure as did after glutamate exposure, the kainate-elicited neuronal death resulted not from the collapse of ??m but from an excessive neuronal swelling, which led to rupture of the plasma membrane. Depolarzation with K+ was not neurotoxic and caused only a minor decrease in TMR fluorescence. These results indicate that in vitro glutamate and kainate destroy neurons by different mechanisms: glutamate by a failure to restore ??m following the exposure, and kainate by an osmotic lesion of the plasma membrane.
Lead Exposures Increases Oxidative Stress in Serum Deprived E14	Mesencephalic Cultures.
Authors: Scortegagna Marzia , Chikhale Elsbeth , Hanbauer Ingeborg
Published: December 2024

E14 mesencephalic cultures grown 6 days in Neurobasal Medium containing 10% horse serum consist of differentiated neurons and astroglia. In these cultures, glutathione and metallothionein-I/II are enriched in astrocytes and play an important role in heavy metal scavenging and oxidative stress response. A 24 h exposure to 25 µM Pb, in serum-containing medium, elevated the glutathione content by more than twofold and increased the metallothionein I/II-immunolabeled protein band. In contrast, exposure to 3 to 25 µM Pb is serum-free medium increased Pb uptake by cells 2 to 4-times above the levels found in 10% serum-containing medium, reduced the glutathione level and obliterated the metallothionein-I/II protein band. The rapid decrease of metallothionein-I/II and glutathione levels in serum-free medium implies that their regulation may depend on a serum factor operative in inducing immediate early genes. Exposure to 6 µM Pb in serum-free or in B27-supplemented medium increased the carbonyl content of several protein bands above control levels indicating that under conditions that curtail metallothionein induction Pb exposure causes increased oxidative stress.
Metallothionein, Neurotrophins and Selegiline in Providing	Neuroprotection in Parkinson's Disease
Authors: Ebadi M. , Ramana Kumari M.V. , Hiramatsu M. , Hao R. , Pfeiffer R.F. , Rojas P.
Published: December 2024

The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl-2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6-tetramethyl-4-piperidone as a "spin-trap" for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4-piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuro-protection in PD.
Aliphatic N-Methylpropargylamines as Potential Neurorescue	Agents
Authors: Yu P.H. , Zhang X. , Zuo D.M. , Lai C.T. , Tieu K. , Davis B.A. , Boulton A.A.
Published: December 2024

Several clinical investigations have indicated that R-deprenyl, a typical monoamine oxidas B inhibitor, delays the progression of Parkinson's and Alzheimer's disease. A number of aliphatic N-methylpropargylamines, such as R-2-hexyl-N-methylpropargylamines (R-2HxMP), have been found to be highly potent, irreversible, selective, MAO-B inhibitors both in vitro and in vivo. These aliphatic propargylamines do not affect noradrenaline of dopamine uptake and are chemically without an amphetamine moiety and therefore do not exhibit any amphetamine-like effects. They are capable of protecting mouse striatal dopamine neurons against MPTP-induced toxicity in the caudate, against MK-801-induced apoptosis in the retrosplenial cortex and against DSP-4-induced depletion of naradrenergic axons. They rescue hippocampal neurons in rodents following kainate-induced neuronal damage. They block the expression of heat shock protein (HSP70) and delayed c-Fos expression in hippocampal CA1 region as elicited by kainate. Confocal microscopy also revealed prevention of neuronal damage in hippocampal slices under hypoxia-hypoglycemia conditions. Aliphatic N-methylpropargylamines may be useful in the treatment of neurodegenerative disorders. The mechanism and site of action of the neurorescue effect of these propargylamines, however, remains to be established.
Prevention of Glutathione Depletion-Induced Apoptosis in Cultured	Human RPE Cells by Flupirtine
Authors: Wood J.P.M. , Pergande G. , Osborne N.N.
Published: December 2024

We have recently reported that the non-opiate analgesic, flupirtine, counteracts apoptosis in cultures of human retinal pigmented epithelial (RPE) cells induced by deprivation of serum, oxygen and glucose (experimental ischaemia). In the present study, human RPE cells grown on coverslips were treated with buthionine sulphoxamine (BSO), a compound that inhibits glutathione biosynthesis. BSO caused a dose-dependent reduction in culture density and an increase in the number of cell nuclei that were positively labelled by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) procedure. These data show that reduction of glutathione levels causes apoptosis in the RPE cultures. When flupirtine gluconate was co-incubated with BSO, it dose-dependently prevented the induction of apoptosis. The most effective concentration of flupitine found to inhibit cell death caused by BSO (1 µM - 1 mM) was 100 µM. The presence of serum (2% or 10%) in the culture medium did not have any effect on the outcome of apoptosis and overall cell death caused by BSO. Futhermore, melatonin, also known to reduce experimental ischaemia-induced overall cell death and apoptosis of cultured RPE cells had only a mild protective effect at 1 mM. The combined data suggest that flupirtine prevents apoptosis by increasing the cellular levels of reduced glutathione and/or protects the cells against the damaging effects of reactive oxygen species (ROS) that are produced subsequent to inhibition of glutathione production.
Oxidative Toxicity in Models of Neurodegeneration: Responses	to Melatonin
Authors: Reiter Russel J. , Garcia Joaquin J. , Pie Juan
Published: December 2024

In this brief review the antioxidative actions of melatonin are summarized and they are discussed relative to several models of oxidative neurotoxicity. Melatonin is a ubiquitously acting antioxidant. It has been shown to scavenge the hydroxyl radical, peroxyl radical, singlet oxygen and the peroxynitrite anion; secondarily, it also scavenges the superoxide anion radical. In addition, melatonin reportedly stimulates a number of antioxidative enzymes including glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase. On the other hand, melatonin inhibits the pro-oxidative enzyme nitric oxide synthase. Besides these actions which help to resist oxidative damage, melatonin prevents membrane rigidity, reduces polymorphonuclear cell infiltration into damaged tissue, limits the adhesion of leucocytes to endothelial cells, thereby increasing blood flow and reducing edema. Some or all of these actions may have been operative in the experimental models of oxidative neurotoxicity that were improved by melatonin treatment. In brief, melatonin has been found to protect the CNS from B-amyloid toxicity, experimental models of Parkinsonism, excitotoxicity, nitric oxide toxicity, aminolevulinic acid, lipopolysaccharide, hyperbaric hyperoxia, L-cysteine, cyanide and ischemia/reperfusion injury.
Effects of Exercise Following Lateral Fluid Percussion Brain	Injury in Rats
Authors: Hicks Ramona R. , Boggs Arden , Leider Denise , Kraemer Philip , Brown Russell , Scheff Stephen W. , Seroogy Kim B.
Published: December 2024

Previous studies have suggested that brain-derived neurotrophic factor (BDNF) is involved in memory and learning, and may be neuroprotective following various brain insults. Exercise has been found to increase BDNF mRNA levels in various brain regions, including specific subpopulations of hippocampal neurons. In the present study, we were interested in whether following traumatic brain injury, exercise could increase BDNF mRNA expression, attenuate neuropathology, and improve cognitive and neuromoter performance. We subjected adult male Sprague-Dawley rats to a fluid percussion brain injury, followed by either 18 days of treadmill exercise or handling. Spatial memory was evaluated in a Morris Water Maze (MWM) and motor function was evaluated with a battery of neuromotor tests. Neuropathology was evaluated by measuring the cortical lesion volume and the extent of neuronal loss in the hipocampus. Expression of BDNF mRNA in the hippocampus was assessed with in situ hybridization and densitometry. Hybridization signal for BDNF mRNA was significantly increased bilaterally in the exercise group in hippocampal regions CA1 and CA3 (p<0.05), but not in the granule cell layer of the dentate gyrus. No significant differences were observed between the groups in neuropathology, spatial memory, or motor performance. This study suggests that after traumatic brain injury, exercise elevates BDNF mRNA in specific regions of the hippocampus.
GM1-Ganglioside Suppresses Septodentate Sprouting and Enhances	Recovery from Entorhinal Cortex Lesions on DRL Perfomance and Locomotor	Behavior in Rats
Authors: Ramirez J.J. , MacDonald K. , Mañibo J. , Payne J. , Tuite C.
Published: December 2024

Administration of gangliosides accelerates recovery of function after entorhinal cortex lesions on open field activity and learned spatial alternation tasks. In the present study, we examined whether GM1 ganglioside might enhance recovery from bilateral entorhinal cortex lesions on a differential reinforcement of low-rate responding tak with a 20 sec delay (DRL-20) as well as on open field activity. Optical densitometry measurements were taken to assess sprouting by the acetylcholinesterase-containing septodentate pathway. Eighteen rats were assigned to sham/GM1, lesion/GM1, or lesion/saline conditions. After preoperative training and testing, the rats received surgery and were then tested post-operatively for thirty days. GM1 injections (20 mg/kg) were given beginning the day before surgery through day 5 postsurgery and then on alternating days. Relative to the lesion/saline group, rats in the lesion/GM1 group showed enhanced recovery on the DRL-20 and the open field tasks. The lesion/GM1 group had significantly less septodentate sprouting than the lesion group treated with saline. GM1 treatment may be facilitating recovery from bilateral entorhinal lesions by reducing the trauma of injury and denervation, reducing heterologous sprouting, or both.
Effects of Chronic GM1 Ganglioside Treatment on Cognitieve and	Motor Deficits in a Slowly Progressing Model of Parkinsonism in Non-Human	Primates
Authors: Pope-Coleman A. , Schneider J.S.
Published: December 2024

This study examined the effects of chronic GM1 ganglioside administration on the evolution of cognitive and motor deficits in monkeys exposed to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over an extended period of time. Monkeys were administered low doses of MPTP for 26 weeks. Once stable cognitive deficits and minimal motor deficits were observed, animals were randomized to saline (N = 2) or GM1 ganglioside (N = 3) treatment groups. Treatments were administered for 90 weeks concurrent with continued low dose MPTP administration. During the first phase of the study (treatment 1-31), GM1 administration ameliorated cognitive deficits and protected against further cognitive decline. Cognitieve deficits worsened in saline-treated animals during this period. In the second phase of the study (weeks 32-52) MPTP dose were increased to enhance the severity of the parkinsonism. GM1-treated animals had delayed onset of motor deficits and a continued preservation of cognitive function. Cognitive and motor function declined in the saline-treated group. In the final phase of the study (weeks 53-90), MPTP doses were lowered back to the levels used during the intial phase of study. GM1-treated animals had significant recovery of motor function, while motor and cognitive function continued to be severely impaired in the saline-treated group. These results suggest that chronic GM1 treatment could be useful in the long-term treatment of Parkinson's disease.
The effect of aging on the morphological nerve changes during	muscle reinnervation after nerve crush
Authors: Kawabuchi M. , Chongjian Z. , Islam A.T.M.S. , Hirata K. , Nada O.
Published: December 2024

The extent of the muscle endplate reinnervation that followed crush injury of the sciatic nerve was compared between young adult (4 and 5 months old) and aged (24 months old) animals. The time course of regeneration in the muscular nerve bundle, its ramification, and the nerve terminal was immunohistochemically estimated using an antibody against the neuron specific enolase (NSE), a neuronal marker. During early phases of regeneration (7, 21 and 28 days post-crush) in the young adult animal, there were tortuosity, vacuolation and/or unfasciculation in the nerve bundle and its ramification, along with immature nerve terminals and multiple innervation. Following a subsequent advancement in reinnervation to the denervated motor endplates, the adult type of single motor innervation was common on the day 56. The old muscles basically followed the course of reversible axotomy alike the young adult ones. The age difference accounted for as fol-lows: a reduced rate of reinnervation as indicated by a greater frequency of abnormal nerve bundles and immature nerve terminals at 28 days and 56 days post-crush, as well as unusual pathways or striking tortuosity represented by the NSE-labeled processes between day 7 and 56; late in the reinnervation period, abnormal regeneration characterized by damage of the nerve bundle, and poorly developed terminal architec-tures. These results suggest that despite the capability of the nerve from the old animals to extend its process, re-establishment of normal single motor innervation is reduced due to some age-related deficits, which may be related to the impaired Schwann cell-axon interactions.
Mechanisms of Cell Death in Cerebellar Disorders
Authors: Wüllner Ullrich , Evert Bernd , Klockgether Thomas
Published: December 2024

Recent advances in molecular genetic and cellular biology have provided new insights into the mechanisms leading to neuronal dysfunction and cell death in the disorders of the cerebellum. Trinucleotide repeat expansions have been identified as an important cause of inherited cerebellar ataxias and mechanisms involved in apoptotic cell death have become centerstage of scientific interest. In the present article, we review the recent findings in trinucleotide repeat disorders and address the possible link of glutamate neurotoxicity, impaired Ca2+ homeostasis and apoptosis.
Amyotrophic Lateral Sclerosis and Glutamate
Authors: Ludolph Albert C. , Meyer Thomas , Riepe Matthias W. , Volkel Helge
Published: December 2024

Amyotrophic lateral sclerosis is a progressive fatal disorder devastating the spinal cord and brain in humans. Excitotoxicity has been suggested to be involved in the pathogenesis of amyotrophic lateral sclerosis. This hypothesis has driven a wealth of basic research and stimulated development of neuroprotective therapies for chronic neurodegenerative disorders. As a result of these efforts, riluzole, an antiglutamatergic drug, has been established in the therapy of amyotrophic lateral sclerosis. A transgenic mouse showing features of amyotrophic lateral sclerosis has been subsequently engineered enabling studies of the disease in vivo. However, despite considerable progress, the etiology of amyotrophic lateral sclerosis remains obscure and the disturbances in excitatory neurotransmission should by no means be regarded as exclusive to the pathogenesis of the disease.
Glutamate Antagonists in Therapy of Stroke
Authors: Prass Konstantin , Dirnagl Ulrich
Published: December 2024

It is well established that excitotoxicity is a key mechanism of tissue destruction in focal cerebral ischemia (stroke). Very soon after onset of a critical perfusion deficit energy failure leads to neuronal depolarization and release of excitatory aminoacids, most notably glutamate. At the same time, energy dependent reuptake of excitatory amino acids is impede. Overstimulation of glutamate receptors (NMDA, AMPA/kainate, metabotropic) induces dramatically increased intracellular Ca2+ concentrations, release of K+ into the extracellular space, and cell swelling due to the passive movement of water with Na+ influx. The massively increased intracellular second messenger Ca2+ triggers numerous deleterious processes, including free radial formation and membrane degradation, mitochondrial dysfunction, inflammation, DNA-damage and apoptosis. A plethora of experimental studies have convincingly demonstrated the relevance of excitotoxicity in focal cerebral ischemia, and pointed to very effective experimental treatment strategies, many of which involve the blockade of glutamate receptors. Unfortunately, large clinical studies were so far unable to replicate the animal data in human stroke patients. This article, by reviewing excitotoxic damage of focal cerebral ischemia in the context of a complex pathophysiological cascade, aims at explaining this failure and stimulating further efforts in drug design and clinical evaluation to establish the first neuroprotective therapy of human stroke.