bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolving pronominal reference in local contexts: a referent selection task
Authors: Nuhbalaoglu Derya
Published: February 2021

Studies on global and local discourse have shown that sign languages indeed allow for occurrence of referentially unanchored pronominal index (ıx) signs referring to non-present antecedents to appear in ambiguous contexts. In local contexts, resolving the reference of these expressions has been suggested to either depend on a modality-specific anaphora resolution mechanism (localization) or on the next mention bias (first/second mention preference) influencing the salience of the referents. This paper presents a two-alternative forced choice referent selection task investigating the impact of a default localization pattern on the interpretation of referentially unanchored pronominal ix sign, in the local discourse with two competing antecedents. To do that, comparative response data was collected from right- and left-handed signers of German Sign Language (DGS) and Turkish Sign Language (TİD). Results provide evidence for second-mention or object preference for pronominal ix in both languages. In addition, the default localization pattern is identified only in restricted environments (i.e., with reciprocal verbs) to resolve pronominal reference. This modality-specific means is shown to be subject to variation across two unrelated sign languages under investigation.---Original in English.
Descrição da variação fonético-fonológica na letra manual “E” em Libras
Authors: Diniz Heloise Gripp
Published: February 2021

A expressão da Libras se dá majoritariamente pelas mãos, mas também envolve expressões faciais e corporais e o uso do espaço de sinalização. As produções manuais podem ser, de maneira geral, de dois tipos: sinais lexicais e datilolologia. Esta última se refere à soletração manual de palavras do português escrito por meio de configurações de mão, CM, que representam as letras do alfabeto. O uso da datilologia e a consequente formação de sinais datilológicos resulta do contato com a língua portuguesa. O presente artigo discute a variação fonético-fonológica na letra manual ‘E’, observada durante a soletração manual e a produção de sinais datilológicos. Nessas produções, percebeu-se a ocorrência de alguns processos fonológicos como a assimilação. Resultados preliminares sugerem os dois possíveis alofones para a letra manual “E”, cuja realização é influenciada pelo segmento vizinho da letra manual. Proponho que os dois alofones da letra manual “E” já identificados sejam representados por meio de símbolos [E●] e [E○], uma notação que futuramente poderá ser estendida para os possíveis alofones de outras letras manuais.
Exploring the effects of phrase-final lengthening in Italian Sign Language (LIS) noun phrases
Authors: Mantovan Lara
Published: February 2021

Phrase-final lengthening is a quite common prosodic phenomenon, previously accounted for in several spoken and signed languages. This study aims at investigating the prosodic cues produced in correspondence with the final boundary of noun phrases in Italian Sign Language (LIS), analyzing corpus data from both quantitative and qualitative perspectives. The quantitative analysis confirms that noun phrases in LIS are affected by phrase-final lengthening (i.e. in noun phrases including one nominal modifier, on average, postnominal modifiers are longer than prenominal ones) and reveals that the various modifier classes show different degrees of sensitivity to this phenomenon. Building on these results, the qualitative analysis explores in detail those modifier classes that show lengthening effects in the corpus: the main consequences in the phonological makeup of signs are insertion of movement repetition, prolonged path movement, final hold accompanied by head nod, and weak prop. The study also offers possible explanations for the fact that quantifiers, ordinals, and determinerlike pointing signs are less sensitive to lengthening effects in the phrase-final boundary, suggesting that particular morphosyntactic factors may come into play.---Original in English.
Pesquisas sobre línguas de sinais: uma contribuição à luz dos 25 anos de “Por uma gramática de línguas de sinais”
Authors: Costa Marília Uchôa Cavalcanti Lott de Moraes , Nevins Andrew , Silva Anderson Almeida da
Published: February 2021

Apresentação à Revista Linguíʃtica v.16, n.3.
Evaluación del comportamiento de vigas de concreto reforzadas y subreforzadas con varillas de PRFV
Authors:   Comisión de Estructuras del Colegio de Ingenieros Civiles de Chiapas. México., Sánchez Hernández Juan Alberto , Aguilar Carboney Jorge Alfredo , Jara Díaz Manuel ,   Facultad de Ingeniería. Universidad Autónoma de Chiapas. México,   Facultad de Ingeniería. Universidad Michoacana de San Nicolás de Hidalgo. México
Published: February 2021

Esta investigación evalúa el comportamiento y el diseño de vigas simplemente soportadas, hechas de concreto armado con barras de polímero reforzado con fibra de vidrio (GFRP-glass fiber reinforced polymer) sometidas a una carga simétrica. El propósito del trabajo es verificar las expresiones y consideraciones del código de diseño ACI 440 1R (2015) en las vigas de confinamiento (dalas) que generalmente se usan para huecos de puertas y ventanas en edificios residenciales. Para ello, se prueban experimentalmente en el laboratorio dos vigas de concreto armado con GFRP y cuantía mínima de acuerdo con el ACI440 1R, de sección 15x20 cm para determinar su capacidad y comportamiento mecánico. Como resultado, se encuentra que la resistencia obtenida hasta el fallo, tanto en corte como en flexión, fue mayor de lo esperado según la metodología de análisis. Los resultados de estas pruebas complementan el trabajo realizado por Sanchez Hernández (2019b).
ASEAN Inter Parliamentary Assembly: Development Trends and Significance for Russia
Authors:   IMEMO RAS, Russia, Moscow, Voda Kristina R.
Published: February 2021

The article analyzes the activities of the ASEAN Inter-Parliamentary Assembly (AIPA), evaluates its significance for regional integration, and identifies opportunities for parliamentary diplomacy of Russia. AIPA is not the ASEAN parliament with no legislative rights. For Russia, regular participation in the AIPA General Assembly as an observer aims to increase its presence and the country's political influence in Southeast Asia. However, the lack of international legal personality of the organization and the non-binding nature of its decisions reduce the effectiveness of the AIPA's work and diminishes its importance as a platform for the implementation of Russian parliamentary diplomacy.
Indonesia's Relations with the United States under Joko Widodo
Authors:   Moscow State Institute of International Relations, Maletin Nikolay P. , Khokhlova Natalia I. ,   MGIMO MFA of Russia
Published: February 2021

Relations between the two countries have experienced both ups and downs throughout the history of independent Indonesia. Naturally, a fair question arose as to what scenario would develop ties between the two states after Joko Widodo came to power in 2014. This problem, first of all, was the concern of the Indonesian public, because the United States is one of the key players in the global political arena. In this article, the authors examine the key moments in relations between the two countries that have occurred in recent years, and draw conclusions about the still remaining contradictions in their joint activities.
Regional Comprehensive Economic Partnership: Opportunities and Challenges for Thailand
Authors:   MGIMO University, Srisanit Witchanee
Published: February 2021

Multilateral economic cooperation in the framework of RCEP is one of Thailand's main goals for its integration into the global economy. Due to its geographical location in the center of Southeast Asia, which maintains its leading role in the region, especially in economic aspects, Thailand will be able to make use of its Eastern Economic Corridor (EEC) project to expand international trade with various partners in larger markets and attract foreign investment to the country through the Master Plan on ASEAN Connectivity (MPAC 2025), and the China’s Belt and Road Initiative (BRI) Within the framework of the cooperation, Thailand, however, will face not only numerous opportunities, but also challenges.
Fórmula hidrolisada na prevenção da doença alérgica em idade pediátrica: revisão baseada na evidência
Authors:   Médico de Família, Ornelas Luciana , Andrade Raquel ,   Médico de Família, Abreu Isabel ,   Médico de Família
Published: February 2021

Objetivo: Rever a evidência existente acerca da eficácia da suplementação com fórmulas hidrolisadas na prevenção de doença alérgica em crianças de termo. Fontes de dados: The Cochrane Database, MEDLINE/PubMed, National Guideline Clearinghouse, Guideline Finder e Canadian Medical Association. Métodos de revisão: Pesquisa de normas de orientação clínica, meta-análises, revisões sistemáticas e ensaios clínicos aleatorizados e controlados, entre janeiro de 2009 e janeiro de 2019, em inglês e limitado a estudos em humanos. A query de pesquisa incluiu os seguintes termos MeSH: Protein Hydrolysates; Hypersensitivity; Allergy and Immunology; Rhinitis; Allergic, Seasonal; Asthma. Para a atribuição dos níveis de evidência e forças de recomendação utilizou-se a Strenght Of Recomendation Taxonomy (SORT), da American Academy of Family Physicians. Resultados: Foram encontrados 23 artigos, dos quais três cumpriram os critérios de inclusão: duas meta-análises e um estudo de coorte. Apenas um dos estudos incluídos apresentou resultados estatisticamente significativos na redução da doença alérgica. Os restantes estudos não demonstraram evidência na redução da doença alérgica. Conclusões: Após a análise dos artigos concluiu-se que não existe evidência científica na utilização de suplementação com leite hidrolisado para a prevenção da doença alérgica (força de recomendação B). Considera-se que são necessários mais estudos, com qualidade superior, que validem a evidência encontrada e auxiliem na formulação de hipóteses.
Agradecimento a revisores de 2020
Authors:   Médico de Família, Maricoto Tiago
Published: February 2021

Agradecimento a revisores de 2020
Green New Deal als Quadratur des Kreises
Authors: Zeller Christian
Published: February 2021

Die Erderhitzung und das Überschreiten mehrerer planetaren Grenzen erfordern einen raschen und umfassenden Umbau der gesamten Produktion und eine Neuorientierung des Konsums. Unterschiedliche Vorschläge für einen Green New Deal antworten auf diese Herausforderung. Sie wollen den Kapitalismus mit institutionellen Reformen auf eine ökologisch nachhaltige Entwicklungsweise schieben. Ich argumentiere, dass diese Vorstöße den ökologischen Herausforderungen nicht genügen und ökonomisch unrealistisch sind.
Why is vertebral pneumaticity in sauropod dinosaurs so variable?
Authors: Taylor Mike , Wedel Mathew
Published: February 2021

The vertebrae of sauropod dinosaurs have distinctive and complex pneumatic features including fossae and foramina in the sides of their centra. These vary between individuals, serially within individuals, and even between the left and right sides of single vertebrae. This presents a conundrum because bone is usually the least variable material in the vertebrate body. Blood vessels, however, are much more labile, as can be seen in the varied occurrence of vascular foramina in the vertebrae not only of sauropods, but also of birds, crocodilians and mammals. Vascular variation arises in part from the ontogeny of vertebrae, which in their embryonic state are vascularised from within the neural canal: the hand-off from these vessels to others which penetrate from outside is not always completed. In birds, pneumatizing diverticula enter the vertebrae alongside blood vessels, in the vascular foramina that they form, before excavating the surrounding bone into larger pneumatic foramina. We propose that the same was true in sauropods, and that variation of vascularization directly caused variation of pneumatization. In most vertebrae, a single vascular foramen carries both artery and vein, but occasionally these vessels separate and each forms a separate foramen. This explains why in rare cases individual sauropod vertebrae have two pneumatic cavities on a single side: each arises from the vascular foramen formed by either artery or vein.
THE APPLICATION OF LOUD READING IN TEACHING PRONUNCIATION AT MTsN BANDA ACEH II IN TEACHING
Authors: Afna Mauloeddin
Published: February 2021

This study was conducted to investigate class activity in drilling pronunciation for English subject at junior high school level. It was conducted at MTsN Banda Aceh II, Aceh. To collect the data, the researcher used test, observation and interview. The students were taught by loud to improve students’ pronunciation in English. Several paragraphs were taken in charge of supporting loud reading drills.The drills took 45 minutes in one section. Test was used to identify the success of loud reading in teaching pronunciation. Observation, on the other hand, was designed to observe the school environment, teaching method, and students’ assessment. In addition, interview was carried out informally to the headmaster and teachers of MTsN Banda Aceh II. This study reveals that the mean is 80.2. This shows a positive use of the loud reading applied at the school. The study also exposes that this method is effective to help their reading ability and to maintain their pronunciation. Thus, the researcher concludes that loud reading has been effectively boosted the students’ pronunciation.
SUPERNATURALISM AND MYSTICISM IN WILLIAM SHAKESPEARE’S PLAY HAMLET
Authors: Nurmalasari Muharrani , Adha Ruly
Published: February 2021

William Shakespeare is the greatest dramatist in the world. He has produced a lot of literary works especially play or drama. Some of his plays still exist until now such as Julius Caesar, Hamlet, The Merchant of Venice, etc. Even, one of his plays Romeo and Juliet has been translated into several languages in the world. He produces two types of plays, namely comedy which usually talks about love and tragedy which talks about sadness. In tragedy plays, Shakespeare always puts supernatural and mystical elements such as in Julius Caesar, Macbeth, Hamlet, etc. The supernatural and mysticism elements are usually marked by the appearance of apparition, witch, fairy, etc, and the elements can determine the fate of main characters. This article tries to describe how Shakespeare puts supernatural and mystical elements in one of his tragedy plays Hamlet.
Características Clínicas, Epidemiológicas e Microscópicas do Câncer Bucal Diagnosticado na Universidade Federal de Alfenas
Authors: Carli Marina Lara de , Santos Sophia Loren , Pereira Alessandro Antônio Costa , Hanemann João Adolfo Costa
Published: February 2021

O presente trabalho teve por objetivo caracterizar e comparar as características clínicas e demográficas dos pacientes portadores de câncer bucal e avaliar os aspectos microscópicos de cada neoplasia, baseando-se na graduação histopatológica de malignidade. Foi realizado um levantamento de todas as neoplasias malignas diagnosticadas e arquivadas no Laboratório de Anatomia Patológica da Universidade Federal de Alfenas desde janeiro de 1998 até dezembro de 2006 e constatou-se um número de 49 tumores. Os resultados demonstraram que, dessas 49 lesões, 43 eram carcinomas espinocelulares, três eram neoplasias malignas de glândulas salivares e os demais eram carcinomas in situ, microinvasivos e verrucosos. Os tumores foram mais prevalentes em pacientes leucodermas, com idades entre 51 e 60 anos, e do gênero masculino. As lesões se localizavam com maior frequência em borda lateral de língua e se apresentavam na forma de úlceras infiltrativas. Constatou-se também que os tumores, em sua maioria, eram carcinomas espinocelulares bem diferenciados e apresentavam um índice de graduação histopatológica de malignidade entre 4 e 8. Concluiu-se que o câncer bucal ainda é uma lesão bastante prevalente e que tem uma predileção por pacientes leucodermas, acima de 50 anos de idade e do gênero masculino.
PENGENALAN BISNIS ONLINE KEPADA ANAK ANAK YAYASAN RUMAH HARAPAN DENGAN DEMONSTRATION METHOD
Authors: Mustomi Dede , Azizah Ayu , Puspasari Aprilia
Published: February 2021

Bisnis online telah menjadi bagian dari kegiatan ekonomi di masyarakat Indonesia. Hanya dengan bermodal perangkat gadget, siapaun bisa berbisnis online, tanpa perlu tempat seperti toko yang memerlukan biaya yang tidak sedikit. Kami mengadakan pelatihan bisnis online kepada anak anak Yayasan Rumah Harapan Karawang. Ada 20 peserta didik yang terlibat dalam pelatihan bisnis online. Kami menyediakan laptop, modul dan wifi dalam pelaksanaan pelatihan. Pelatihan diadakan selama dua hari. Tujuannya untuk memperkenalkan dunia bisnis online kepada para peserta didik. Pengabdian masyarakat ini berdampak positif untuk anak anak di Yayasan Rumah Harapan, mereka memiliki skill membuat akun email, akun media sosial dan pengetahuan tentang bisnis online, sehingga bisa menjadi bekal hidup mereka dikemudian hari.
TINGKAT PARTISIPASI MASYARAKAT PADA KEGIATAN REHAB RUMAH TIDAK LAYAK HUNI DI KOTA TANGERANG
Authors: Maulana Imron , Sunarti S
Published: February 2021

Kota Tangerang mencoba mengatasi masalah permukiman melalui program “Tangerang Berbenah” guna mempersiapkan kawasan hunian layak huni dengan lingkungan yang ramah dan sehat. Salah satu kegiatan dari program ini adalah rehab rumah tidak layak huni (RTLH) dengan menggunakan pendekatan partisipasi masyarakat, namun permasalahan partisipasi pada setiap daerah memiliki kecenderungan yang berbeda beda. Kegiatan rehab RTLH ini dilakukan di beberapa tempat yaitu Kelurahan Kedaung Baru dan Kelurahan Batu Ceper. Tujuan penelitian ini adalah untuk menganalisis tingkat partisipasi masyarakat pada kegiatan rehab RTLH. Metode penelitian yang digunakan adalah metode kuantitatif dengan teknik  analisis kuantitatif deskriptif dan tabulasi silang. Terdapat 40 responden yang kesemuanya adalah penerima manfaat bantuan rehab RTLH di Kota Tangerang pada tahun 2018. Hasil penelitian menunjukkan jika tingkat partisipasi masyarakat pada keseluruhan tahapan di Kota Tangerang tergolong tinggi atau rebellious dimana masyarakat mau bekerjasama secara kooperatif dengan stakeholder lainnya serta mereka mampu mengambil keputusan sendiri dalam menentukan kemauannya.
Chronic organ injuries in children with sickle cell disease
Authors: Allali Slimane , Taylor Melissa , Brice Joséphine , Montalembert Mariane de
Published: February 2021

Median life expectancy of patients with sickle cell disease has increased to up to 55 years but there are still frequent cases of premature death, mostly in patients with pre-existing organ failure such as pulmonary hypertension, kidney injury, and cerebral vasculopathy. Most organ injuries remain asymptomatic for a long time and can only be detected through early systematic screening. Protocols combining assessment of velocities on transcranial Doppler and regular transfusions in patients with abnormal velocities have been demonstrated to dramatically reduce the risk of stroke. In contrast, no consensus has been reached on systematic screening or therapy for silent cerebral infarcts. The prognostic significance of increased tricuspid regurgitant jet velocity on echocardiography has not yet been identified in children, whereas increased albuminuria is a good predictor of kidney injury. Finally, screening for hip and eye disorder is recommended; however, different countries adopt different screening strategies. Hydroxyurea is probably of potential benefit in preventing chronic organ damage but this requires further study in order to be fully demonstrated. Efficacy and safety of the other new drugs available are also under investigation.
Development and Validation of Valganciclovir and its Active Metabolite Ganciclovir Determination in Human Plasma by HPLC-MS/MS Method
Authors: Komarov T. N. , Shohin I. E. , Tokareva M. A. , Archakova O. A. , Bogdanova D. S. , Aleshina A. A. , Bagaeva N. S. , Davydanova V. V.
Published: February 2021

Introduction. Currently, physicochemical methods of quantification are actively used to determine the content of drugs in biological fluids. High-performance liquid chromatography with various detection methods is particularly widespread. One of the most difficult practical tasks is the chromatographic separation of so-called poorly retained compounds – drug substances poorly retained on the chromatographic column. Valganciclovir and Ganciclovir are among such substances. Aim. The aim of this study is to develop a method for valganciclovir and ganciclovir in human plasma by high performance liquid chromatography with tandem mass-spectrometry (HPLC-MS/MS) for pharmacokinetic studies.

Materials and methods. Determination of valganciclovir and ganciclovir in plasma by HPLC-MS/MS. The samples were processed by acetonitrile protein precipitation.

Results and discussion. This method was validated by next parameters: selectivity, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification, carry-over and stability.

Conclusion. The method of the determination of valganciclovir and ganciclovir in human plasma was developed and validated by HPLC-MS/MS. The linearity in plasma sample was achieved in the concentration range of 5.00–1000.00 ng/ml for valganciclovir and 50.00–10000.00 ng/ml for ganciclovir. Method could be applied to valganciclovir and ganciclovir determination in plasma for PK and BE studies.
PD-L1 as a Potential Target in Cancer Therapy (Review)
Authors: Andrusova N. N. , Kolganova M. A. , Aleshina A. V. , Shohin I. E.
Published: February 2021

Introduction. Cancer is one of the most serious and common diseases with a high level of mortality. Due to this reason the searching of new directions and methods of cancer treatment is becoming more and more important with each passing year. Significant advances in cancer immunotherapy have been reached over the past few decades. Moreover, an inhibition of the interaction between the programmed cell death receptor (PD-1) and its ligand (PD-L1), is sure to be perspective direction of the immuno-oncological therapy development.

Text. PD-1/PD-L1 interaction plays a pivotal role in negative regulation of immune system, that protects host’s cells and tissues from the excessive immune response. However, it is also used by tumor cells to avoid the host's immune system. The discovery of this mechanism led to the development of inhibiting PD-1 or PD-L1 agents that enhance anti-tumor immunity. Meanwhile, anti-PD-L1 agents provide less toxicity in comparison with anti-PD-1 agents. FDA currently approved Atesolizumab, Durvalumab, and Avelumab PD-L1 inhibitors for cancer treatment. These agents demonstrated effective response during the clinical trials, however, they are used for a limited number of oncological diseases. In addition, BMS-936559 is a promising agent that had passed the first stage of the clinical trials. Nevertheless, immunotherapy involving PD-L1 inhibitors is closely related to a vast number of severe side effects including immune-mediated effects caused by the inhibition of PD-L1 ligands located on healthy cells. In these terms, the development of new agents deprived of these disadvantages is the reason for further studies.

Conclusion. Immunotherapy in cancer uncovers new perspectives in treatment of refractory to standard therapies forms of cancer. And the development of new and improvement of existing PD-L1 blocking agents are of great importance in fighting against tumoral diseases.
Interpolymer Complexes Based on Carbopol® and Poly(2-ethyl-2-oxazoline) as Carriers for Buccal Delivery of Metformin
Authors: Viktorova A. S. , Elizarova E. S. , Romanova R. S. , Timergalieva V. R. , Khutoryanskiy V. V. , Moustafine R. I.
Published: February 2021

Introduction. Buccal drug delivery has a number of advantages over oral administration: ease of application, good blood supply to the buccal mucosa, drug can enter the systemic circulation directly, avoiding the "first pass effect through the liver", and are not exposed to the acidic environment of the gastric juice and the destructive action of digestive enzymes. The use of interpolymer complexes (IPCs) makes it possible not only to ensure adhesion to the mucosal membranes of the oral cavity, but also to achieve a prolonged release of drugs.

Aim. Development of carriers based on interpolymer complexes using Carbopol® 971 NF (C971) and poly(2-ethyl-2-oxazoline) (POZ) of different molecular weights for buccal delivery of metformin (MF).

Materials and methods. The study of IPC adhesion was carried out using a TA.XTplus texture analyzer (Stable Micro Systems, UK); mucin compacts with a diameter of 13 mm were used as a substrate; these were prepared by compressing porcine gastric mucin powder using a manual hydraulic press for IR spectroscopy (PerkinElmer, USA) at a pressure of 2.45 MPa. The study of the swelling capacity was carried out by placing polymer matrices in an artificial saliva medium, with constant thermostating at a temperature of 37.0 ± 0.5 °C for 5 hours. The study of the release of MF from the matrices based on IPC was carried out using a DFZ II apparatus (Erweka, Germany) according to the Flow Through Cell method (USP IV) with cells for tablets (22.6 mm) and adaptors for ointments, creams and gels in a medium simulating saliva. The concentration of MF in the samples from the dissolution tests was determined with UV-spectrophotometry (Lambda, PerkinElmer, USA) at 232.8 nm.

Results and discussion. In a comparative study of the mucoadhesive properties of polymer samples, IPC compacts showed a mucoadhesion capacity comparable to that of poly(2-ethyl-2-oxazoline); at the same time, compacts from physical mixtures (PM) and C971 are inferior in terms of the separation force to IPC samples, however, POZes dissolve in an artificial saliva medium, that is, they are not suitable as dosage forms for buccal delivery. For 5 hours of the experiment to assess the swelling capacity, the IPC matrices did not change significantly, which can ensure their comfortable use as carriers for buccal delivery. When evaluating the release of metformin from polymer matrices (with weight ratio MF/IPC 1: 0.5), the most complete release (more than 90 %) is observed from both IPC matrices compared to matrices of PM and individual polymers.

Conclusion. Polycomplex matrix systems based on C971-POZ (50 kDa) and C971-POZ (500 kDa) are suitable for buccal delivery of metformin.
Ophthalmic Drug Delivery Systems (Review)
Authors: Bakhrushina E. O. , Anurova M. N. , Demina N. B. , Lapik I. V. , Turaeva A. R. , Krasnuk I. I.
Published: February 2021

Introduction. Effective delivery of ophthalmic drugs is challenging. The eye has a number of protective systems and physiological barriers, which is why ophthalmic dosage forms have a low bioavailability, usually not exceeding 5 %. Topical drug administration is relatively easy to use and is most commonly prescribed by physicians for the treatment of ophthalmic diseases, especially the anterior segment of the eye. However, when using traditional delivery systems, a number of problems arise: patients' violation of the drug administration technique, and, as a consequence, a decrease in treatment compliance, restriction of drug delivery to the target eye tissues due to low epithelial permeability and rapid clearance after drug administration. Maintaining a constant therapeutic drug level is another challenge that traditional delivery systems often fail to cope with.

Text. The article discusses the types of ophthalmic delivery systems. Traditional ones are represented by such dosage forms as eye drops, ointments, gels. Modern ophthalmic dosage forms are represented by: eye films, contact lenses and eye implants. The characteristics, advantages and disadvantages of each type of delivery systems and their promising directions of development, as well as modern developments in this area are given.

Conclusion. Currently, most of the scientific research on the development of ophthalmic delivery systems is devoted to obtaining dosage forms capable of maintaining a constant concentration of the drug in the target tissue, providing the transport of active ingredients to them. This is achieved by using modern advances in nanotechnology and polymer chemistry. Receive liquid and soft dosage forms with micro-, nano- and micro-nano-carriers. Polymeric delivery systems such as films, lenses and implants are being actively developed and studied. The development of modern technological approaches opens up new possibilities for the treatment of a wide range of ophthalmic diseases by reducing the side effects often induced by the intrinsic toxicity of molecules, reducing the frequency of the administered dose and maintaining the pharmacological profile of the drug. Thus, the use of modern ophthalmic delivery systems can significantly limit the use of invasive treatments.
Use of Capillary Electrophoresis Method in Determination of Quantitative Content of Mangiferin in Grass of Species of Genus Hedysarum (Hedysarum Caucasicum M.Bieb., Hedysarum Grandiflorum Pall., Hedysarum Daghestanicum Rupr. ex Boiss) of flora of the North Caucasus
Authors: Imachueva D. R. , Serebryanaya F. K.
Published: February 2021

Introduction. The species of the genus Hedysarum L. of the Fabaceae family are of significant interest in connection with the accumulation of a group of biologically active substances with antibacterial and antiviral activity against DNA-containing viruses.

Aim. The purpose of the work is to develop a method for the quantitative determination of mangiferin in the aboveground part of species of the genus Hedysarum L., Hedysarum caucasicum M.Bieb., Hedysarum grandiflorum Pall., Hedysarum daghestanicum Rupr. ex. Boiss. collected in the North Caucasus by zonal capillary electrophoresis.

Materials and methods. The objects of the study were species of the genus Hedysarum L., namely Hedysarum caucasicum M.Bieb., Hedysarum grandiflorum Pall., Hedysarum daghestanicum Rupr. ex. Boiss. collected in the North Caucasus. Registration of electronic spectra was carried out on capillary electrophoresis "KAPEL'®-105m" (OJSC "Lumex-marketing", Russia) with quartz capillary Leff./Ltol. = 50/60 cm, ID = 75 μm. As a standard sample, mangiferin (substance-powder, mangiferin content ≥98 %, Sigma-Aldrich, Lot SLBP4044V) was used.

Results and discussion. As a result of comprehensive pharmacognostic studies of species of the kopecki genus growing in the North Caucasus under natural conditions, as well as under the conditions of introduction on the territory of the Botanical Garden of the Pyatigorsk Medical and Pharmaceutical Institute and the Mountain Botanical Garden of the Dagestan Federal Research Center of the Russian Academy of Sciences, we developed a method for the isolation and quantitative determination of mangiferin by capillary electrophoresis.

Conclusion. Studies show that the use of the zonal capillary electrophoresis method in the analysis of xanthones, including the determination of the quantitative content of mangiferin, is promising. The largest content of mangiferin (0.25 %) is distinguished by Hedysarum caucasicum M.Bieb., which confirms the assumption based on molecular genetic studies, since it is this species that belongs to the Obscura section, as well as the alpine penny used to produce mangiferin. Therefore, it is possible to provide this technique for analysis of mangiferin xanthone glycoside along with spectrophotometry and high performance liquid chromatography.
A ciência de alimentos na sua mesa: o uso da farinha do açafrão como ingrediente rico em antioxidantes para melhoria da saudabilidade em massas frescas integrais
Authors: Vilar Isabela , Wahanik Adriana L. , Pastore Glaucia Maria , Neri-Numa Iramaia Angélica , Felisberto Mária H. F. , Campelo Pedro H. , Clerici Maria Teresa Pedrosa Silva
Published: February 2021

Massa fresca com farinha de trigo integral (WWF) apresenta saudabilidade, mas o consumidor não está acostumado com seu consumo, devido à cor escura. Portanto, o uso de ingredientes regionais, que podem mudar de cor, pode ser uma opção para estimular seu uso e consumo diário. O objetivo deste estudo foi avaliar a capacidade tecnológica e antioxidante da massa fresca elaborada com 51% WWF (49% Farinha de Trigo Refinado - RWF) (Controle, M0) e a substituição parcial do RWF por farinha de cúrcuma (Curcuma longa) (TF) em 3, 6 ou 9% (respectivamente M1, M2 e M3). Os dados foram analisados por ANOVA e teste de Tukey (p-valor <0,05). As pastas com TF apresentaram coloração amarelada, maior tempo de cocção, firmeza e ganho de peso em relação ao M0. M2 apresentou aumento significativo de fenólicos totais (0,57 µg equivalente de ácido gálico / mg), ABTS (12,21 µmol equivalente de Trolox / mg) e DPPH (5,74 µg equivalente de Trolox / mg) em relação ao M0. A substituição do RWF em até 6% pelo TF nas massas com 51% do WWF foi benéfica para a mudança de cor e aumento das propriedades funcionais, além de aumentar o valor agregado desse tubérculo e promover seu consumo como ingrediente saudável e corante.
Presence or absence of microbiome modulates the response of mice organism to administered drug nabumetone
Authors: Jourová L , Lišková B , Lněničková K , Zemanová N , Anzenbacher P , Hermanová P , Hudcovic T , Kozáková H , Anzenbacherová E
Published: February 2021

The gut microbiota provides a wide range of beneficial functions for the host, and has an immense effect on the host’s health status. The presence of microbiome in the gut may often influence the effect of an orally administered drug. Molecular mechanisms of this process are however mostly unclear. We investigated how the effect of a nonsteroidal drug nabumetone on expression of drug metabolizing enzymes (DMEs) in mice intestine and liver is changed by the presence of microbiota, here, using the germ free (GF) and specific pathogen free (SPF) BALB/c mice. First, we have found in a preliminary experiment that in the GF mice there is a tendency to increase bioavailability of the active form of nabumetone, which we have found now to be possibly influenced by differences in expression of DMEs in the GF and SPF mice. Indeed, we have observed that the expression of the most of selected cytochromes P450 (CYPs) was significantly changed in the small intestine of GF mice compared to the SPF ones. Moreover, orally administered nabumetone itself altered the expression of some CYPs and above all, in different ways in the GF and SPF mice. In the GF mice, the expression of the DMEs (CYP1A) responsible for the formation of active form of the drug are significantly increased in the small intestine and liver after nabumetone application. These results highlight the importance of gut microbiome in processes involved in drug metabolism in the both gastrointestinal tract and in the liver with possible clinical relevance.
Integration of High Velocity Elastic Band for Hamstring Training in Pre-Season Routine of Football Players
Authors: Januševičius Donatas , Sniečkus Audrius , Mickevičius Mantas , Satkunskienė Danguolė , Muanjai Pornpimol , Kamandulis Sigitas
Published: February 2021

Background. A need for other methods of hamstring strengthening are thus warranted with the main aim of reducing the risk of injury during the subsequent intense athletic activities. The study aimed to examine changes in hamstring strength in response to high velocity elastic band training when incorporated into regular training routine of football players.

Methods. Research participants were professional top level football players (age 23.1 ± 5.7 years; weight 77.2 ± 7.7 kg, training experience 14.1 ± 5.8 years). In the pre-season, in addition to their routine training, the experimental group performed hamstring curls at maximal intensity while lying prone three times per week for five weeks, while control group continued their routine training. Concentric knee torque at 60°/s and 180°/s angular velocities, countermovement jump height, 30m sprint running performance from standing and flying start, and knee flexion-extension movement frequency were measured before and after the 5 weeks of training.

Results. Hamstring curl frequency during lying prone increase by 10.5 % (p < .05) in the experimental group and did not change in the control group. Peak torque for knee flexion and knee extension, jump height and sprint running performance did not change significantly in any group (p > .05).

Conclusion. High velocity elastic band training incorporated into regular pre-season routine is beneficial for football players to increase their knee extension-flexion maximal movement frequency with no evident effects on strength, jump and sprint running performance. Results might be related with concurrent training during preparatory training phase of the pre-season when several physical capacities are being developed simultaneously.

Keywords: high speed movements; peak torque; sprint performance; prevention of hamstring injuries; knee flexion strength.
Clathrin Heavy Chain 1 Plays Essential Roles During Oocyte Meiotic Spindle Formation and Early Embryonic Development in Sheep
Authors: Han Zhe , Hao Xin , Zhou Cheng-Jie , Wang Jun , Wen Xin , Wang Xing-Yue , Zhang De-Jian , Liang Cheng-Guang
Published: February 2021

As a major protein of the polyhedral coat of coated pits and vesicles, clathrin molecules have been shown to play a stabilization role for kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridges. Clathrin heavy chain 1 (CLTC), the basic subunit of the clathrin coat, plays vital roles in both spindle assembly and chromosome congression during somatic-cell mitosis. However, its function in oocyte meiotic maturation and early embryo development in mammals, especially in domesticated animals, has not been fully investigated. In this study, the expression profiles and functional roles of CLTC in sheep oocytes were investigated. Our results showed that the expression of CLTC was maintained at a high level from the germinal vesicle (GV) stage to metaphase II stage and that CLTC was distributed diffusely in the cytoplasm of cells at interphase, from the GV stage to the blastocyst stage. After GV breakdown (GVBD), CLTC co-localized with beta-tubulin during metaphase. Oocyte treatments with taxol, nocodazole, or cold did not affect CLTC expression levels but led to disorders of its distribution. Functional impairment of CLTC by specific morpholino injections in GV-stage oocytes led to disruptions in spindle assembly and chromosomal alignment, accompanied by impaired first polar body (PB1) emissions. In addition, knockdown of CLTC before parthenogenetic activation disrupted spindle formation and impaired early embryo development. Taken together, the results demonstrate that CLTC plays a vital role in sheep oocyte maturation via the regulation of spindle dynamics and an essential role during early embryo development.
Advances in the Relationship Between Regulator of Ribosome Synthesis 1 (RRS1) and Diseases
Authors: Hua Yanan , Song Jinlian , Peng Cuixiu , Wang Runze , Ma Zhongliang , Zhang Jinyu , Zhang Zheng , Li Ning , Hou Lin
Published: February 2021

A regulator of ribosome synthesis 1 (RRS1) was discovered in yeast and is mainly localized in the nucleolus and endoplasmic reticulum. It regulates ribosomal protein, RNA biosynthesis, and protein secretion and is closely involved in cellular senescence, cell cycle regulation, transcription, translation, oncogenic transformation etc., Mutations in the RRS1 gene are associated with the occurrence and development of Huntington’s disease and cancer, and overexpression of RRS1 promotes tumor growth and metastasis. In this review, the structure, function, and mechanisms of RRS1 in various diseases are discussed.
SIRT6 Maintains Redox Homeostasis to Promote Porcine Oocyte Maturation
Authors: Li Yu , Miao Yilong , Chen Jingyue , Xiong Bo
Published: February 2021

SIRT6, the sixth member of the sirtuin family proteins, has been characterized as a crucial regulator in multiple molecular pathways related to aging, including genome stability, DNA damage repair, telomere maintenance, and inflammation. However, the exact roles of SIRT6 during female germ cell development have not yet been fully determined. Here, we assessed the acquisition of meiotic competency of porcine oocytes by inhibition of SIRT6 activity. We observed that SIRT6 inhibition led to the oocyte meiotic defects by showing the impairment of polar body extrusion and cumulus cell expansion. Meanwhile, the compromised spindle/chromosome structure and actin dynamics were also present in SIRT6-inhibited oocytes. Moreover, SIRT6 inhibition resulted in the defective cytoplasmic maturation by displaying the disturbed distribution dynamics of cortical granules and their content ovastacin. Notably, we identified that transcript levels of genes related to oocyte meiosis, oxidative phosphorylation, and cellular senescence were remarkably altered in SIRT6-inhibited oocytes by transcriptome analysis and validated that the meiotic defects caused by SIRT6 inhibition might result from the excessive reactive oxygen species (ROS)-induced early apoptosis in oocytes. Taken together, our findings demonstrate that SIRT6 promotes the porcine oocyte meiotic maturation through maintaining the redox homeostasis.
Identification of Urine Metabolic Biomarkers for Vogt-Koyanagi-Harada Disease
Authors: Chang Rui , Zhu Ying , Xu Jing , Chen Lin , Su Guannan , Kijlstra Aize , Yang Peizeng
Published: February 2021

The diagnosis of Vogt-Koyanagi-Harada (VKH) disease is mainly based on a complex clinical manifestation while it lacks objective laboratory biomarkers. To explore the potential molecular biomarkers for diagnosis and disease activity in VKH, we performed an untargeted urine metabolomics analysis by ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). Through univariate and multivariate statistical analysis, we found 9 differential metabolites when comparing VKH patients with healthy controls, and 26 differential metabolites were identified when comparing active VKH patients with inactive VKH patients. Pathway enrichment analysis showed that glycine, serine and threonine metabolism, and arginine and proline metabolism were significantly altered in VKH versus healthy controls. Lysine degradation and biotin metabolism pathways were significantly altered in active VKH versus inactive VKH. Furthermore, the receiver operating characteristic (ROC) curve analysis revealed that the combination of acetylglycine and gamma-glutamylalanine could differentiate VKH from healthy controls with an area under the curve (AUC) of 0.808. A combination of ureidopropionic acid and 5′-phosphoribosyl-5-amino-4-imidazolecarboxamide (AICAR) had an excellent AUC of 0.958 for distinguishing active VKH from inactive VKH. In summary, this study identified abnormal metabolites in urine of patients with VKH disease. Further studies are needed to confirm whether these metabolites are specific for this disease.
Critical Functions of PP2A-Like Protein Phosphotases in Regulating Meiotic Progression
Authors: Lei Wen-Long , Qian Wei-Ping , Sun Qing-Yuan
Published: February 2021

Meiosis is essential to the continuity of life in sexually-reproducing organisms through the formation of haploid gametes. Unlike somatic cells, the germ cells undergo two successive rounds of meiotic divisions after a single cycle of DNA replication, resulting in the decrease in ploidy. In humans, errors in meiotic progression can cause infertility and birth defects. Post-translational modifications, such as phosphorylation, ubiquitylation and sumoylation have emerged as important regulatory events in meiosis. There are dynamic equilibrium of protein phosphorylation and protein dephosphorylation in meiotic cell cycle process, regulated by a conservative series of protein kinases and protein phosphatases. Among these protein phosphatases, PP2A, PP4, and PP6 constitute the PP2A-like subfamily within the serine/threonine protein phosphatase family. Herein, we review recent discoveries and explore the role of PP2A-like protein phosphatases during meiotic progression.
Human RecQ Helicases in DNA Double-Strand Break Repair
Authors: Lu Huiming , Davis Anthony J.
Published: February 2021

RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions, including DNA replication, transcription, DNA repair, and telomere maintenance. Humans have five RecQ helicases: RECQL1, Bloom syndrome protein (BLM), Werner syndrome helicase (WRN), RECQL4, and RECQL5. Defects in BLM and WRN cause autosomal disorders: Bloom syndrome (BS) and Werner syndrome (WS), respectively. Mutations in RECQL4 are associated with three genetic disorders, Rothmund–Thomson syndrome (RTS), Baller–Gerold syndrome (BGS), and RAPADILINO syndrome. Although no genetic disorders have been reported due to loss of RECQL1 or RECQL5, dysfunction of either gene is associated with tumorigenesis. Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. The importance of DSB repair is supported by the observations that defective DSB repair can cause chromosomal aberrations, genomic instability, senescence, or cell death, which ultimately can lead to premature aging, neurodegeneration, or tumorigenesis. In this review, we will introduce the human RecQ helicase family, describe in detail their roles in DSB repair, and provide relevance between the dysfunction of RecQ helicases and human diseases.
Molecular Behavior of HMGB1 in the Cochlea Following Noise Exposure and in vitro
Authors: Xiao Lili , Sun Yan , Liu Chengqi , Zheng Zhong , Shen Ying , Xia Liang , Yang Guang , Feng Yanmei
Published: February 2021

Noise-induced hearing loss (NIHL) is characterized by cellular damage to the inner ear, which is exacerbated by inflammation. High-mobility group box 1 (HMGB1), a representative damage-associated molecular pattern (DAMP), acts as a mediator of inflammation or an intercellular messenger according to its cellular localization. Blocking or regulating HMGB1 offers an attractive approach in ameliorating NIHL. However, the precise therapeutic intervention must be based on a deeper understanding of its dynamic molecular distribution and function in cochlear pathogenesis after acoustic trauma. Here, we have presented the spatiotemporal dynamics of the expression of HMGB1, exhibiting distribution variability in specific cochlear regions and cells following noise exposure. After gene manipulation, we further investigated the characteristics of cellular HMGB1 in HEI-OC1 cells. The higher cell viability observed in the HMGB1 knocked-down group after stimulation with H2O2 indicated the possible negative effect of HMGB1 on cellular lifespan. In conclusion, this study demonstrated that HMGB1 is involved in NIHL pathogenesis and its molecular biology has essential and subtle influences, preserving a translational potential for pharmacological intervention.
Recent Application of Zebrafish Models in Atherosclerosis Research
Authors: Tang Dandan , Geng Fang , Yu Chunxiao , Zhang Ruilin
Published: February 2021

Atherosclerotic cardiovascular disease is one of the leading causes of death worldwide. Establishing animal models of atherosclerosis is of great benefit for studying its complicated pathogenesis and screening and evaluating related drugs. Although researchers have generated a variety of models for atherosclerosis study in rabbits, mice and rats, the limitations of these models make it difficult to monitor the development of atherosclerosis, and these models are unsuitable for large scale screening of potential therapeutic targets. On the contrast, zebrafish can fulfill these purposes thanks to their fecundity, rapid development ex utero, embryonic transparency, and conserved lipid metabolism process. Thus, zebrafish have become a popular alternative animal model for atherosclerosis research. In this mini review, we summarize different zebrafish models used to study atherosclerosis, focusing on the latest applications of these models to the dynamic monitoring of atherosclerosis progression, mechanistic study of therapeutic intervention and drug screening, and assessment of the impacts of other risk factors.