bluuebunny/crossref_metadata_2025 huggingface dataset:
Interim measures as human rights protection instruments: to the problem statement
Authors: Mnatsakanian Siuzanna
Published: August 2021

Conceptual approaches to defining the nature and the scope of interim measures implementation as an instrument of human rights protection at international and national level are analyzed. The widespread use of interim measures as international standard of urgent respond to alleged violations of human rights has not led to the implementation of the legal institute concerned at the national level. Accordingly, this analysis aimed at defining the grounds of interim measures as human rights protection instrument application to be used by the state as an immediate response to human rights violations and possible violations.

European Court of Human Rights has a great practice of interim measures granting. Interim measures are granted by the Court only in clearly defined conditions, namely where there is a risk that serious violations of the Convention might occur. A high proportion of requests for interim measures are inappropriate and are therefore refused. Besides, interim measures are applied upon request of the applicant claiming about alleged violations of his or her human rights.

At the national level interim measures should/may be granted upon request of the applicant or by the duty-bearer’s initiative to prevent possible human rights violations. The grounds of interim measures granting should also be defined – the best international practice should be used taking into account the Ukrainian context. Another core issue analyzed is defining duty-bearers – subjects enforced to grant interim to prevent abuse in the sphere concerned.

It is obvious that court shall be the only authority to resolve the substantive case of alleged human rights violation. However, public and local authorities shall be enabled to grant interim measures to prevent the possible violations. With this, the scope and the sphere of its application at the national level shall be broader in comparison with the case law of the European Court of Human Rights.
İLERİ SİSTEMİK RİSK ALTINDA BULUNAN HASTALARDA AĞIZ VE DİŞ HASTALIKLARININ İNSİDANSININ İNCELENMESİ
Authors: ÇANAKÇİ Fatma Gülfeşan , ÇANAKÇİ Burhan Can
Published: August 2021

Bu çalışmanın amacı Trakya Üniversitesi, Diş Hekimliği Fakültesine başvuran hastalarda bulunan ağız ve diş hastalıklarının ileri sistemik sorunlara ve/veya hasara sebep olma ihtimali bulunan sistemik hastalıklara sahip hasta grupları içindeki sayılarının ve oranlarının değerlendirilmesidir. Trakya Üniversitesi, Diş Hekimliği Fakültesine başvuran rastgele 2000 hasta incelenmiştir. Tedaviye engel olmayan/tıbbi konsültasyon gerekliliği bulunmayan sistemik hastalıklar basit sistemik hastalıklar (SH) olarak, tedavi yapılması uygun olmayan veya tıbbi konsültasyona veya proflaksiye ihtiyaç duyulan sistemik hastalık varlığı ise riskli sistemik hastalık (RSH) olarak değerlendirilmiştir. Hastaların hastaların panaromik ve periapikal radyografları, anamnez formları ve tedavi planları incelenmiş, belirlenen dental problemlerin sayısı ve oranı tespit edilmiştir. Hastaların %39.5’inde SH, SH olan hastaların %31,2’inde ise RSH mevcuttur. RSH en sık ≥ 65 (%28.3) ve 41–62 (%17.5) yaş aralıklarında görülmüştür (P<0.05). En sık görülen RSH ileri kardiyak problemler (%12), geçirilmiş kanser, radyoterapi ve/veya kemoterapi hikayesi (%10.3), gebelik (%9.5) ve aktif kanser, radyoterapi ve/veya kemoterapi hikayesidir (%8, P<0.05). RSH sahip hastalarda en sık görülen dental problemler eksik diş/protetik tedavi gereksinimi (%26.9) ve lokalize periodontal hastalıklardır (%22.7, P<0.05). Detaylı sistemik anamnez ve konsültasyon dental tedaviler esnasında özellikle RSH’a sahip bireylerde yaşanacak sistemik komplikasyonlarda önemli ölçüde azalma sağlayacaktır. Ayrıca diş hekimlerinin olası sistemik komplikasyonlara karşı tıbbi eğitim alması önemlidir.
Evaluation of the tax benefit effectiveness for certain types of activities in Ukraine (part 2)
Authors:   SESE “The Academy of Financial Management”, SOKOLOVSKA Alla
Published: August 2021

The second part of the article considers the consequences of assessing tax benefits for cinematography and the space industry, which they enjoyed in 2014-2019. Since these types of activities, in addition to tax benefits, also received direct state support in the form of expenditures on targeted budget programs, the effectiveness of their aggregate state support was analyzed. It was found that for both activities it was quite effective. At the same time, of the four types of activity which were the subject of analysis, the largest state support during this period was provided to cinematography, the smallest – to the space industry, which indicates real state priorities. The analysis of state support for priority activities in Ukraine showed that the most common form of tax benefits provided to them, in contrast to EU countries, is exemption from VAT for transactions of supply of goods to the customs territory of Ukraine. However, the application of such a benefit (this exemption becomes a benefit only in the case of a long production cycle), firstly, requires the establishment of effective control at customs over the legality of its provision and accounting for the amount of the benefit and losses of budget revenues due to its provision, as well as the transfer of relevant information from the customs authorities to the State Tax Service for the purpose of taking them into account in general reports. Secondly, considering that this contradicts the requirements of Council Directive 2006/112/EC, its truly temporary application must be ensured. In general, according to the results of the study, it was concluded that the introduction of constant monitoring of the effectiveness of the use of tax benefits requires clarification of the list of benefits that are losses of budget revenues, and that do not lead to such losses; providing public access to the reports of the State Tax Service on the amounts of benefits that are losses of budget revenues; ensuring proper control over the legality of the application of tax benefits, the completeness and accuracy of their accounting, the fulfillment of the conditions for the provision and targeted use of funds released as a result of the application of tax incentives prescribed in the legislation; inclusion of information about tax expenditures in reports on the execution of state budget, preparation of annual reports on the fulfillment of the conditions for the provision of tax benefits defined in the Tax Code of Ukraine; in case of using temporary tax incentives, a mandatory audit of their effectiveness and efficiency as a prerequisite for extending the period of their use.
Methodological problems of BEPS analysis
Authors:   National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute”, IVANYTSKA Olga , KOSCHUK Tetiana ,   SESE “The Academy of Financial Management”
Published: August 2021

The article is devoted to the issues of the methodology of the analysis of the base erosion and profit shifting (BEPS) for the development of managerial approaches to counteracting these destructive phenomena in Ukraine. Eleven types of data sources identified by the OECD that can be used for BEPS analysis are determined. It is shown that most sources of information for the purposes of analyzing the scale and effects of BEPS have significant limitations: their absence or limited representativeness in some countries; regulatory restrictions on access to data; lack of most financial data to reflect the activities of multinational corporations (MNCs). The indicators that testify to BEPS or dangerous phenomena of financial abuse, which are reflected in reporting, are analyzed, namely: 1) disconnect between financial and real economic activities; 2) high profit rates of low-taxed affiliates of top global MNCs; 3) high profit rates of MNC affiliates in lower-tax locations; 4) MNCs vs. "comparable" non-MNC effective tax rate differentials; 5) profit shifting through intangibles; 6) profit shifting through interest. It is proved that for Ukraine the calculation of a number of indicators can be complicated due to the delay in the publication of official data; lack of appropriate statistical reporting. In general, indicators show that they provide limited information about financial transactions and cannot reliably relate any changes and their reflection to BEPS. Therefore, the implementation of measures to combat BEPS should be based not only on the results of calculations of OECD indicators, but also on other empirical studies that provide reliable information on the development of income transfer between countries.
And Once Again the Invisible Battle… Review of the book by A.I. Demchenko “Appassionata”
Authors:   Saratov State L.V. Sobinov Conservatory, Smirnova Natalia M.
Published: August 2021

Alexander I. Demchenko is well known to the musicological community and art lovers as the author of numerous books on various aspects of artistic creativity. His new monograph (Appassionata, Essays on Beethoven’s Music, Commemorating the 250th Anniversary of his Birth. Monograph. Moscow, 2021. 164 p.), addressed both to specialists and a broad circle of connoisseurs of the art of music, is focused entirely on analysis of the content-semantic essence of the artistic heritage of the great composer, to which all the cited facts of his life and consideration of the means of musical expression are subordinated. The core of the presentation is embodied in the works of Beethoven the basic essence of human existence (life activities, lyrical feelings, repose) and what determines the leading constants of Beethoven's attitude to the world (heroic moods, drama, epos).
Diversifikasi Nafkah di Pedesaan dalam Konteks Relasi Desa-Kota
Authors: Anik Susanti  , Nyimas Nadya Izana
Published: August 2021

Penelitian ini bertujuan untuk mendeskripsikan diversifikasi mata pencarian sebagai strategi yang dilakukan oleh penduduk pedesaan untuk mempertahankan dan meningkatkan taraf hidupnya. Isu ini penting untuk dikaji guna menggali berbagai alternatif cara dari permasalahan mendasar yang dilalui mereka. Ada empat masalah yang berkaitan dengan kehidupan sosial ekonomi di pedesaan, yaitu produktivitas tenaga kerja yang rendah, kepemilikan lahan yang semakin sempit seiring dengan banyaknya petani kecil, pendapatan rumah tangga yang relatif rendah dan upah buruh tani yang lebih rendah dibandingkan buruh bangunan dan industri. Akibatnya, pertanian subsisten memiliki prospek yang lemah dan tidak dapat diandalkan sebagai satu-satunya sumber mata pencarian penduduk pedesaan. Meskipun sektor pertanian tidak lagi digalakkan sebagai sumber pendapatan, sebagian penduduk pedesaan tetap bertani sambil melakukan berbagai kegiatan penunjang untuk memenuhi kebutuhan hidupnya. Bahkan, ada kecenderungan mereka memanfaatkan peluang yang ada untuk meningkatkan taraf hidupnya. Penduduk pedesaan sebenarnya memiliki berbagai tingkatan dalam mempertahankan eksistensi kehidupan dan meningkatkan taraf hidup rumah tangganya sesuai dengan keunikan tatanan sosial, ekonomi, ekologi dan budaya di suatu wilayah. Salah satunya yang menjadi fokus penelitian ini, yaitu diversifikasi mata pencarian rumah tangga di pedesaan dalam konteks hubungan desa dan kota. Kami berharap dapat menemukan formula yang dapat mendukung kemampuan penduduk pedesaan untuk mendiversifikasi mata pencarian mereka dalam menanggapi pembangunan perkotaan. Untuk mewujudkan tujuan tersebut, tim peneliti telah melakukan investigasi terhadap: (a) portofolio kegiatan mata pencarian masyarakat kecil pedesaan dalam rangka perjuangan untuk bertahan hidup dan peningkatan taraf hidup mereka dan (b) diversifikasi mata pencarian yang dilakukan oleh masyarakat kecil di konteks hubungan desa dan kota.
Online Learning in Social Adaptation Perspective
Authors: Daulay Pardamean , Umanailo M Chairul Basrun , Nursyifa Aulia
Published: August 2021

The trend of online learning is growing. Through the Circular of the Minister of Education and Culture Numbers 2 and 3 of 2020 requires that the entire teaching and learning process be carried out online. Not all elements of society can accept online learning patterns as a medium for transforming knowledge due to the availability of infrastructure to the characteristics of the community itself. This study aims to explain implementing online learning with the adaptation pattern proposed by Robert Merton. The research design used is a literature review. Articles are collected using the Science and Technology Index (Sinta) link, Garba Reference Digital (Garuda), Ministry of Religious Affairs Reference (Moraref), Indonesian Scientific Repository (Neliti) The Preprint Server of Indonesia (RINarxiv). The time range used is 2011-2021. Based on the results of the study and analysis of the articles collected, it was found that the pattern of adaptation carried out by educators and students is the antithesis of policies issued by the government. The pattern of adaptation carried out by the community is based on the resources and characteristics they have.
Media Sosial dan Kekerasan Berbasis Gender Online Selama Pandemi Covid-19
Authors: Hayati Nur
Published: August 2021

Dalam artikel ini akan dibahas tentang kekerasan berbasis gender online yang merupakan ancaman besar bagi masyarakat. Terutama sekarang ini, penggunaan internet untuk media sosial semakin marak dan pesat. Apalagi selama pandemi melanda Indonesia yang aktivitas masyarakatnya banyak dilakukan di rumah dengan melakukan work from home dan school from home, tidak menutup kemungkinan semakin besar pula terjadinya kekerasan berbasis gender online (KBGO) dalam media sosial. Berdasarkan data Komnas Perempuan dalam CATAHU 2021 tercatat bahwa pada 2020 kasus KBGO mengalami lonjakan, yaitu sekitar 940 yang pada 2019 tercatat 241 kasus. Dengan adanya kasus tersebut, untuk itulah penulis melakukan penelitian tentang media sosial dan kekerasan berbasis gender online selama pandemi covid-19. Tujuan dari artikel ini adalah agar kita semakin sadar bahwa KBGO terus mengintai masyarakat. Penelitian ini menggunakan metode penelitian studi literatur dengan mengumpulkan, mencatat, dan mengolah data dari berbagai bahan bacaan seperti buku, jurnal, dan sumber internet. Hasil penelitan menunjukkan bahwa KBGO paling banyak ditemukan pada platform media sosial Facebook, Instagram, dan WhatsApp. Bentuk KBGO yang ditemukan ini beragam, seperti pelecehan seksual online dengan kekerasan verbal, online grooming, dan ancaman dengan menyebarkan foto atau video asusila. Keburukan dari media sosial salah satunya menjadikan perilaku menyimpang atau pelaku KBGO. Media sosial yang seharusnya dapat dijadikan sebagi media membangun relasi dengan orang lain, malah menjadi tempat terjadinya KBGO. Oleh karenanya, media sosial dianggap tidak memiliki ruang aman bagi perempuan. Untuk mendapatkan perlindungan atas KBGO di media sosial, dibutuhkan payung hukum yang serius menangani kasus KBGO dan dapat membantu perempuan keluar dari jerat kasus KBGO.
Litigation Transformation in Law Enforcement Effort in Indonesia During the Covid-19 Pandemic
Authors: Dian Ratu Ayu Uswatun Khasanah  , Chairunnisa Madiha Dzakiyyah
Published: August 2021

The Covid 19 pandemic has accelerated digitization in all aspects of life. As an effort to deal with its spread, the legal realm has also undergone a transformation. The implementation of remote litigations during the Covid-19 pandemic has begun to take effect in line with the government's appeal for Physical/ Social distance. The litigations used the support of the internet network or known as e-litigation. It is nothing new in the world because previously developed countries, such as the United States, have used this method beforehand. The implementation of e-litigation in Indonesia is certainly different from other developed countries that are technologically ready. The implementation of e-litigation is a development of the previously implemented e-court program. This study examined the ins and outs of virtual litigations during the pandemic with all the regulations that assist them. The research used normative and empirical juridical methods that provide explanations so that it can be used as an evaluation of implementation during the pandemic period and towards the new normal era. The secondary data were taken from the primary materials from the regulations that apply during the pandemic and the new normal era. In addition, the secondary materials used were also from journals, books, and other literacy sources. The results of this paper can be used as a reference for further research on the transformation of law enforcement that puts forward the modernization of technology and information in fulfilling justice and social welfare.
ПАМЯТИ МАРИНЫ МИХАЙЛОВНЫ ГРОМЫКО
Authors: Чепелева Наталья Владимировна
Published: August 2021

Аннотация. Краткая памятная заметка включает в себя воспоминания прихожанки храма преподобномученицы Елизаветы о М. М. Громыко, также посещавшей этот храм по месту жительства. Автор останавливается на характеристике личных качеств М. М. Громыко, ее религиозности и участии в приходской жизни.
Abstract. A short memorandum includes the recollections of a parishioner of a church in Shcherbinka, Moscow region, about M. M. Gromyko, who also visited this temple at his place of residence. The author dwells on the characteristics of Gromyko’s personal qualities, her religiosity and participation in parish life together.
Effects of Microbial Consortia, Applied as Fertilizer Coating, on Soil and Rhizosphere Microbial Communities and Potato Yield
Authors: Overbeek William , Jeanne Thomas , Hogue Richard , Smith Donald L.
Published: August 2021

The use of biological inputs in crop production systems, as complements to synthetic inputs, is gaining popularity in the agricultural industry due to increasing consumer demand for more environmentally friendly agriculture. An approach to meeting this demand is the inoculation of field crops with beneficial microbes to promote plant growth and resistance to biotic and abiotic stresses. However, the scientific literature reports inconsistent results following applications of bio-inoculant to fields. The effects of inoculation with beneficial microbes on bulk soil and rhizospheric microbial communities is often overlooked as precise monitoring of soil microbial communities is difficult. The aim of this research was to use Illumina high throughput sequencing (HTS) to shed light on bulk soil and rhizospheric microbial community responses to two commercial microbial inoculants coated onto fertilizer granules, applied to potato fields. Bulk soil samples were collected 4 days before seeding (May 27th), 7 days after seeding (June 7th), at potato shoot emergence (June 21st) and at mid-flowering (July 26th). Rhizospheric soil was collected at the mid-flowering stage. The Illumina MiSeq HTS results indicated that the bulk soil microbial community composition, especially prokaryotes, changed significantly across potato growth stages. Microbial inoculation did not affect bulk soil or rhizospheric microbial communities sampled at the mid-flowering stage. However, a detailed analysis of the HTS results showed that bulk soil and rhizospheric microbial community richness and composition were different for the first treatment block compared to the other three blocks. The spatial heterogeneity of the soil microbial community between blocks of plots was associated with potato tuber yield changes, indicating links between crop productivity and soil microbial community composition. Understanding these links could help in production of high-quality microbial inoculants to promote potato productivity.
Nanofibrous Membrane Dressings Loaded With Sodium Hydrogen Sulfide/Endothelial Progenitor Cells Promote Wound Healing
Authors: Lian Jie , Ju Guanqun , Cai Xueyao , Cai Yuchen , Li Chun , Ma Sunxiang , Cao Yi
Published: August 2021

Hydrogen sulfide (H2S) has been identified as an important gasotransmitter. H2S donor can release H2S sustained and is used as wound dressing. Endothelial progenitor cells (EPCs), given their regenerative ability, have also been reported to enhance wound healing. However, effective drug carriers are missing for the clinical application of H2S and EPCs. In this study, we investigated a novel drug carrier nanofibrous membrane, which was prepared by blending the recombinant spider silk protein (rMaSp) and sodium hydrogen sulfide (NaHS) by electrospun. Our results show that the rMaSp/NaHS nanofibrous membrane is associated with high hemocompatibility and cytocompatibility and is capable of stably releasing H2S for a long period of time. We also tested the rMaSp/NaHS membrane loaded with EPCs in an in vivo cutaneous wound model. We showed that the rMaSp/NaHS/EPC system significantly enhances wound regeneration efficiency as compared to rMaSp membrane and rMaSp/NaHS membrane. This study provides key evidence supporting the clinical application of nanofibrous membrane in the field of skin tissue regeneration.
Diagnostic and Therapeutic Role of Extracellular Vesicles in Articular Cartilage Lesions and Degenerative Joint Diseases
Authors: Qiao Kai , Chen Qi , Cao Yiguo , Li Jie , Xu Gang , Liu Jiaqing , Cui Xiaolin , Tian Kang , Zhang Weiguo
Published: August 2021

Two leading contributors to the global disability are cartilage lesions and degenerative joint diseases, which are characterized by the progressive cartilage destruction. Current clinical treatments often fail due to variable outcomes and an unsatisfactory long-term repair. Cell-based therapies were once considered as an effective solution because of their anti-inflammatory and immunosuppression characteristics as well as their differentiation capacity to regenerate the damaged tissue. However, stem cell-based therapies have inherent limitations, such as a high tumorigenicity risk, a low retention, and an engraftment rate, as well as strict regulatory requirements, which result in an underwhelming therapeutic effect. Therefore, the non-stem cell-based therapy has gained its popularity in recent years. Extracellular vesicles (EVs), in particular, like the paracrine factors secreted by stem cells, have been proven to play a role in mediating the biological functions of target cells, and can achieve the therapeutic effect similar to stem cells in cartilage tissue engineering. Therefore, a comprehensive review of the therapeutic role of EVs in cartilage lesions and degenerative joint diseases can be discussed both in terms of time and favorability. In this review, we summarized the physiological environment of a joint and its pathological alteration after trauma and consequent changes in EVs, which are lacking in the current literature studies. In addition, we covered the potential working mechanism of EVs in the repair of the cartilage and the joint and also discussed the potential therapeutic applications of EVs in future clinical use.
Sevoflurane Inhibits Traumatic Brain Injury-Induced Neuron Apoptosis via EZH2-Downregulated KLF4/p38 Axis
Authors: Wang Zhongyu , Li Juan , Wang Anqi , Wang Zhaoyang , Wang Junmin , Yuan Jingjing , Wei Xin , Xing Fei , Zhang Wei , Xing Na
Published: August 2021

Traumatic brain injury (TBI) is characterized by physical damage to the brain tissues, ensuing transitory or permanent neurological dysfunction featured with neuronal loss and subsequent brain damage. Sevoflurane, a widely used halogenated anesthetic in clinical settings, has been reported to alleviate neuron apoptosis in TBI. Nevertheless, the underlying mechanism behind this alleviation remains unknown, and thus was the focus of the current study. First, Feeney models were established to induce TBI in rats. Subsequently, evaluation of the modified neurological severity scores, measurement of brain water content, Nissl staining, and TUNEL assay were employed to investigate the neuroprotective effects of sevoflurane. Immunofluorescence and Western blot analysis were further applied to detect the expression patterns of apoptosis-related proteins as well as the activation of the p38-mitogen-activated protein kinase (MAPK) signaling pathway within the lesioned cortex. Additionally, a stretch injury model comprising cultured neurons was established, followed by neuron-specific enolase staining and Sholl analysis. Mechanistic analyses were performed using dual-luciferase reporter gene and chromatin immunoprecipitation assays. The results demonstrated sevoflurane treatment brought about a decrease blood-brain barrier (BBB) permeability, brain water content, brain injury and neuron apoptosis, to improve neurological function. The neuroprotective action of sevoflurane could be attenuated by inactivation of the p38-MAPK signaling pathway. Mechanistically, sevoflurane exerted an inhibitory effect on neuron apoptosis by up-regulating enhancer of zeste homolog 2 (EZH2), which targeted Krüppel-like factor 4 (KLF4) and inhibited KLF4 transcription. Collectively, our findings indicate that sevoflurane suppresses neuron apoptosis induced by TBI through activation of the p38-MAPK signaling pathway via the EZH2/KLF4 axis, providing a novel mechanistic explanation for neuroprotection of sevoflurane in TBI.
Decreased Insulin Sensitivity in Telomerase-Immortalized Mesenchymal Stem Cells Affects Efficacy and Outcome of Adipogenic Differentiation in vitro
Authors: Kulebyakin Konstantin , Tyurin-Kuzmin Pyotr , Efimenko Anastasia , Voloshin Nikita , Kartoshkin Anton , Karagyaur Maxim , Grigorieva Olga , Novoseletskaya Ekaterina , Sysoeva Veronika , Makarevich Pavel , Tkachuk Vsevolod
Published: August 2021

Modern biomedical science still experiences a significant need for easy and reliable sources of human cells. They are used to investigate pathological processes underlying disease, conduct pharmacological studies, and eventually applied as a therapeutic product in regenerative medicine. For decades, the pool of adult mesenchymal stem/stromal cells (MSCs) remains a promising source of stem and progenitor cells. Their isolation is more feasible than most other stem cells from human donors, yet they have a fair share of drawbacks. They include significant variability between donors, loss of potency, and transformation during long-term culture, which may impact the efficacy and reproducibility of research. One possible solution is a derivation of immortalized MSCs lines which receive a broader use in many medical and biological studies. In the present work, we demonstrated that in the most widely spread commercially available hTERT-immortalized MSCs cell line ASC52telo, sensitivity to hormonal stimuli was reduced, affecting their differentiation efficacy. Furthermore, we found that immortalized MSCs have impaired insulin-dependent and cAMP-dependent signaling, which impairs their adipogenic, but not osteogenic or chondrogenic, potential under experimental conditions. Our findings indicate that hTERT-immortalized MSCs may present a suboptimal choice for studies involving modeling or investigation of hormonal sensitivity.
Aging Negatively Impacts DNA Repair and Bivalent Formation in the C. elegans Germ Line
Authors: Raices Marilina , Bowman Richard , Smolikove Sarit , Yanowitz Judith L.
Published: August 2021

Defects in crossover (CO) formation during meiosis are a leading cause of birth defects, embryonic lethality, and infertility. In a wide range of species, maternal aging increases aneuploidy and decreases oocyte quality. In C. elegans which produce oocytes throughout the first half of adulthood, aging both decreases oocytes quality and increases meiotic errors. Phenotypes of mutations in genes encoding double-strand break (DSB)-associated proteins get more severe with maternal age suggesting that early meiosis reflects a particularly sensitive node during reproductive aging in the worm. We observed that aging has a direct effect on the integrity of C. elegans meiotic CO formation, as observed by an increase of univalent chromosomes and fusions at diakinesis, with a considerable increase starting at 4 days. We also characterize the possible causes for the age-related changes in CO formation by analyzing both steady-state levels and kinetics of the ssDNA binding proteins RPA-1 and RAD-51. Profound reductions in numbers of both RPA-1 and RAD-51 foci suggests that both DSB formation and early meiotic repair are compromised in aging worms. Using laser microirradiation and γ-irradiation to induce exogenous damage, we show specifically that recruitment of these homologous recombination proteins is altered. Repair defects can be seen in two-and-one-half day-old adults making the loss of germline repair capacity among the earliest aging phenotypes in the worm.
Chromatin Conformation in Development and Disease
Authors: Boltsis Ilias , Grosveld Frank , Giraud Guillaume , Kolovos Petros
Published: August 2021

Chromatin domains and loops are important elements of chromatin structure and dynamics, but much remains to be learned about their exact biological role and nature. Topological associated domains and functional loops are key to gene expression and hold the answer to many questions regarding developmental decisions and diseases. Here, we discuss new findings, which have linked chromatin conformation with development, differentiation and diseases and hypothesized on various models while integrating all recent findings on how chromatin architecture affects gene expression during development, evolution and disease.
A Concise Synthetic Strategy Towards the Novel Calcium-dependent Lipopeptide Antibiotic, Malacidin A and Analogues
Authors: Kovalenko Nadiia , Howard Georgina K. , Swain Jonathan A. , Hermant Yann , Cameron Alan J. , Cook Gregory M. , Ferguson Scott A. , Stubbing Louise A. , Harris Paul W. R. , Brimble Margaret A.
Published: August 2021

Malacidin A is a novel calcium-dependent lipopeptide antibiotic with excellent activity against Gram-positive pathogens. Herein, a concise and robust synthetic route toward malacidin A is reported, employing 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis of a linear precursor, including late-stage incorporation of the lipid tail, followed by solution-phase cyclization. The versatility of this synthetic strategy was further demonstrated by synthesis of a diastereomeric variant of malacidin A and a small library of simplified analogues with variation of the lipid moiety.
The Importance of Spin State in Chiral Supramolecular Electronics
Authors: Garcia Ana M. , Martínez Gabriel , Ruiz-Carretero Amparo
Published: August 2021

The field of spintronics explores how magnetic fields can influence the properties of organic and inorganic materials by controlling their electron’s spins. In this sense, organic materials are very attractive since they have small spin-orbit coupling, allowing long-range spin-coherence over times and distances longer than in conventional metals or semiconductors. Usually, the small spin-orbit coupling means that organic materials cannot be used for spin injection, requiring ferromagnetic electrodes. However, chiral molecules have been demonstrated to behave as spin filters upon light illumination in the phenomenon described as chirality-induced spin selectivity (CISS) effect. This means that electrons of certain spin can go through chiral assemblies of molecules preferentially in one direction depending on their handedness. This is possible because the lack of inversion symmetry in chiral molecules couples with the electron’s spin and its linear momentum so the molecules transmit the one preferred spin. In this respect, chiral semiconductors have great potential in the field of organic electronics since when charge carriers are created, a preferred spin could be transmitted through a determined handedness structure. The exploration of the CISS effect in chiral supramolecular semiconductors could add greatly to the efforts made by the organic electronics community since charge recombination could be diminished and charge transport improved when the spins are preferentially guided in one specific direction. This review outlines the advances in supramolecular chiral semiconductors regarding their spin state and its influence on the final electronic properties.
Designed Artificial Protein Heterodimers With Coupled Functions Constructed Using Bio-Orthogonal Chemistry
Authors: Johnson Rachel L. , Blaber Hayley G. , Evans Tomas , Worthy Harley L. , Pope Jacob R. , Jones D. Dafydd
Published: August 2021

The formation of protein complexes is central to biology, with oligomeric proteins more prevalent than monomers. The coupling of functionally and even structurally distinct protein units can lead to new functional properties not accessible by monomeric proteins alone. While such complexes are driven by evolutionally needs in biology, the ability to link normally functionally and structurally disparate proteins can lead to new emergent properties for use in synthetic biology and the nanosciences. Here we demonstrate how two disparate proteins, the haem binding helical bundle protein cytochrome b562 and the β-barrel green fluorescent protein can be combined to form a heterodimer linked together by an unnatural triazole linkage. The complex was designed using computational docking approaches to predict compatible interfaces between the two proteins. Models of the complexes where then used to engineer residue coupling sites in each protein to link them together. Genetic code expansion was used to incorporate azide chemistry in cytochrome b562 and alkyne chemistry in GFP so that a permanent triazole covalent linkage can be made between the two proteins. Two linkage sites with respect to GFP were sampled. Spectral analysis of the new heterodimer revealed that haem binding and fluorescent protein chromophore properties were retained. Functional coupling was confirmed through changes in GFP absorbance and fluorescence, with linkage site determining the extent of communication between the two proteins. We have thus shown here that is possible to design and build heterodimeric proteins that couple structurally and functionally disparate proteins to form a new complex with new functional properties.
Association of Pulmonary Valve Morphology Differences With Outcomes in Tetralogy of Fallot Repair With Right Ventricular Outflow Tract Incision
Authors: Liu Jinyang , Jiang Xianchao , Peng Bo , Li Shoujun , Yan Jun , Wang Qiang , Liu Zhimin
Published: August 2021

Background: Current observational studies may not have large samples to investigate the relationship between pulmonary valve (PV) morphology differences and outcomes after complete repair for tetralogy of Fallot (TOF) by right ventricular outflow tract (RVOT) incision. This study aimed to assess the impact of PV morphology differences on outcomes after complete repair for TOF.

Methods: This is a retrospective cohort study. Consecutive patients who underwent TOF repair with RVOT incision at Fuwai Hospital from January 2012 to December 2017 were included and compared according to PV morphology differences (unicuspid or bicuspid was abnormal morphology, while the tricuspid valve was normal morphology). The primary outcome was defined as a composite of death, or reintervention, or significant annular peak gradient (APG), or significant pulmonary regurgitation (PR), whichever occurred first. Multivariable Cox model analysis was used to assess the relationships between PV morphology differences and outcomes. Subgroup analysis and Propensity-score analysis were performed as sensitivity analyses to assess the robustness of our results.

Results: The cohort included a total of 1,861 patients with primary diagnosis of TOF, with 1,688 undergoing CR-TOF with RVOT incision. The median age was 318 days [interquartile range (IQR): 223–534 days], a median weight of 8.9 kg (IQR: 7.6–10.5 kg) and 60.0% (1,011) were male. Complete follow-up data were available for 1,673 CR-TOF patients with a median follow-up duration of 49 months. Adjusted risks for the primary outcome and significant APG were lower for patients with normal PV morphology at follow up [adjusted hazard ratio (HR): 0.68; 95% CI: 0.46–0.98; adjusted HR: 0.22; 95% CI: 0.07–0.71, respectively]. The trend for the primary outcome during follow-up remained unchanged, even in subgroups and propensity score matching analyses.

Conclusions: In this analysis of data from a large TOF cohort, patients with normal tricuspid PVs were associated with a decreased risk of the primary outcome and a lower risk of significant APG, as compared with patients with abnormal unicuspid or bicuspid PVs.
Dynamic Changes of Metabolic Syndrome Alter the Risks of Cardiovascular Diseases and All-Cause Mortality: Evidence From a Prospective Cohort Study
Authors: He Di , Zhang Xuhui , Chen Shuohua , Dai Chen , Wu Qiong , Zhou Yaohan , Jin Ziqi , Wu Shouling , Zhu Yimin
Published: August 2021

Background: Metabolic syndrome (MetS) at baseline increases the risks of cardiovascular diseases (CVD) and all-cause mortality. However, MetS status is changeable during follow-up. The associations of dynamic changes of MetS with CVD and all-cause mortality remain unclear.

Methods: Thirty-one thousand four hundred eighty-one eligible subjects were included from the Kailuan cohort. Dynamic changes of MetS were divided into four patterns as MetS-free, MetS-developed, MetS-recovery and MetS-stable. The outcomes were CVD, all-cause mortality, and the subtypes of CVD as myocardial infarction (MI), stroke and heart failure. Multiple Cox regression models were used to calculate the adjusted hazard ratios (HRs) and confidence intervals (95% CIs).

Results: Altered risks of CVD, the subtypes of CVD, and all-cause mortality were observed among different dynamic patterns of MetS. Compared with the MetS-free group, MetS-developed group increased the risks of CVD (HR = 1.78, 95% CI = 1.51–2.11), MI (HR = 1.54, 95% CI = 1.01–2.34), stroke (HR = 1.78, 95% CI = 1.45–2.18), and heart failure (HR = 1.63, 95% CI = 1.11–2.39). MetS-recovery group decreased these risks with the HRs of 0.59 (95% CI = 0.48–0.72) for CVD, 0.62 (95% CI = 0.41–0.96) for MI, 0.59 (95% CI = 0.46–0.75) for stroke, and 0.56 (95% CI = 0.34–0.91) for heart failure compared with the MetS-stable group. However, the increased risk in the MetS-developed group and the decreased risk in the MetS-recovery group were not significant for all-cause mortality. When stratified by the onset age of MetS status change, early development of MetS (<50 years) had higher risks of CVD (HR = 2.20, 95% CI = 1.58–3.05), MI (HR = 2.35, 95% CI = 1.00–5.50), stroke (HR = 2.05, 95% CI = 1.38–3.05), heart failure (HR = 2.63, 95% CI = 1.15–6.04), and all-cause mortality (HR = 1.61, 95% CI = 1.13–2.30) than late development (≥50 years). Early recovery of MetS had lower risks with the HRs of 0.38 (95% CI = 0.24–0.59) for CVD, 0.43 (95% CI = 0.18–1.06) for MI, 0.37 (95% CI = 0.21–0.64) for stroke, 0.30 (95% CI = 0.09–1.04) for heart failure, and 0.68 (95% CI = 0.43–1.06) for all-cause mortality than late recovery.

Conclusion: Dynamic changes of MetS altered the risks of CVD and all-cause mortality, especially in individuals with an early onset age. These findings highlight the importance of dynamic changes of MetS and onset age on the prevention and control for CVD.
The Future of Exercise-Based Cardiac Rehabilitation for Patients With Heart Failure
Authors: Passantino Andrea , Dalla Vecchia Laura Adelaide , Corrà Ugo , Scalvini Simonetta , Pistono Massimo , Bussotti Maurizio , Gambarin Fabiana Isabella , Scrutinio Domenico , La Rovere Maria Teresa
Published: August 2021

Cardiac rehabilitation (CR) is a comprehensive program that includes exercise training, titration of medical therapy, lifestyle modification, educational support, and psychosocial assessment. All these components are safe and beneficial resulting in significant improvements in quality of life, functional capacity, mortality, and hospital readmission. Current guidelines support its use in a broad spectrum of cardiac disease. This review focuses on exercise-based CR for heart failure (HF) patients in whom CR is a recommended treatment. Exercise should be prescribed according to a personalized approach, optimizing, and tailoring the rehabilitative program to the patient's characteristics. Specific CR programs are dedicated to older patients, those with HF and preserved ejection fraction, and recipients of cardiac implantable electronic devices or left ventricular assistance device. Telemedicine may increase CR participation and overcome some of the barriers that limit its utilization.
FinDerS(+): Real-Time Earthquake Slip Profiles and Magnitudes Estimated from Backprojected Displacement with Consideration of Fault Source Maturity Gradient
Authors: Böse Maren , Hutchison Allie A. , Manighetti Isabelle , Li Jiawei , Massin Frédérick , Clinton John Francis
Published: August 2021

The Finite-Fault Rupture Detector (FinDer) algorithm computes rapid line-source rupture models from high-frequency seismic acceleration amplitudes (PGA). In this paper, we propose two extensions to FinDer, called FinDerS and FinDerS+, which have the advantage of taking into account a geological property of the source fault, its structural maturity, as well as its relation to the earthquake slip distribution. These two new algorithms calculate real-time earthquake slip profiles by backprojecting seismic and/or geodetic displacement amplitudes onto the FinDer line-source. This backprojection is based on a general empirical equation established in previous work that relates dynamic peak ground displacement (PGD) at the stations to on-fault coseismic slip. While FinDerS projects PGD onto the current FinDer line-source, FinDerS+ allows the rupture to grow beyond the current model extent to predict future rupture evolution. For an informed interpolation and smoothing of the estimated slip values, FinDerS and FinDerS+ both employ a generic empirical function that has been shown to relate the along-strike gradient of structural maturity of the ruptured fault, the earthquake slip distribution, and the rupture length. Therefore, while FinDer derives magnitudes from a relatively uncertain and general empirical rupture length-magnitude relations, FinDerS and FinDerS+ provide alternate and better informed magnitude estimates using the mean slip of the profiles derived from the integration of fault source maturity. The two new algorithms can incorporate both seismic strong-motion and geodetic displacement data. In order to recover PGD from strong-motion instruments, we double-integrate and high-pass filter (>0.075 Hz) the seismic acceleration records. Together, the three algorithms exploit the full spectrum of ground-motions, including high frequencies to derive a source fault model (FinDer) and low frequencies to determine the static offsets along this model (FinDerS and FinDerS+). We test the three algorithms for the 2019 MW7.1 Ridgecrest (California), 2016 MW7.0 Kumamoto (Japan), and 2008 MW7.9 Wenchuan (China) earthquakes. Conclusively, low-frequency PGD data and integration of the fault maturity gradient do not speed-up calculations for these events, but provide additional information on slip distribution and final rupture length, as well as alternative estimates of magnitudes that can be useful to check for consistency across the algorithm suite. The FinDer algorithms systematically outperform previously established real-time PGD-based magnitude estimates in terms of speed and accuracy. The resulting slip distributions can be useful for improved ground-motion prediction given the observed relationship between seismic radiation and fault maturity.
Paleodietary and Paleoclimatic Reconstruction of Hipparion Fauna at ∼9 Ma From the Xunhua Basin on the Northeastern Tibetan Plateau
Authors: Hu Fei , Song Bowen , Sun Yuanyuan , Huang Wei , Luo Mansheng , Ji Junliang , Lin Qixiang , Algeo Thomas J. , Zhang Kexin
Published: August 2021

Stable isotope analysis is pivotal for investigating the paleodiet and paleoecology of ancient mammals. Recently, a ∼9-Myr-old Hipparion fauna was discovered at an elevation of ∼2,200 m above sea level (a.s.l.) in the Xunhua Basin on the northeastern Tibetan Plateau. These fossils can provide key evidence for the ecosystem structure and regional paleoenvironmental reconstruction. Here we present carbon and oxygen isotopic compositions of 56 bulk and 85 serial tooth enamel samples from this fauna, which includes Hipparion platyodus Selve, Chilotherium sp. and Gazella gaudryi Schlosser. The enamel−δ13°C values display a wide range of variation (−11.4 to −5.0‰), with a mean value of −8.9 ± 1.0‰, indicating that the fauna consumed mainly C3 plants. However, the heaviest δ13C value of Hipparion (−5.0‰) suggests at least some consumption of C4 plants. Combined with pollen records, we infer that the Hipparion fauna in the Xunhua Basin was living in forest-grassland setting at ∼9 Ma. The reconstructed paleo-meteoric δ18O values of the Xunhua Basin at ∼9 Ma are lower than the mean annual δ18O of present-day precipitation in this region, suggesting a wetter climate or stronger monsoonal influence than today. Hipparion fauna in the Xunhua Basin yield significantly higher mean values of δ13C and δ18O than contemporary fossils in the Linxia Basin to the east, which is attributed to rapid uplift of the Jishi Shan, blocking water vapor transport by the East Asian Summer Monsoon and making the climate of the Xunhua Basin relatively drier.
RANKL-Induced Btn2a2 – A T Cell Immunomodulatory Molecule – During Osteoclast Differentiation Fine-Tunes Bone Resorption
Authors: Frech Michael , Schuster Gregor , Andes Fabian T. , Schett Georg , Zaiss Mario M. , Sarter Kerstin
Published: August 2021

Butyrophilins, which are members of the extended B7 family of immunoregulators structurally related to the B7 family, have diverse functions on immune cells as co-stimulatory and co-inhibitory molecules. Despite recent advances in the understanding on butyrophilins’ role on adaptive immune cells during infectious or autoimmune diseases, nothing is known about their role in bone homeostasis. Here, we analyzed the role of one specific butyrophilin, namely Btn2a2, as we have recently shown that Btn2a2 is expressed on the monocyte/macrophage lineage that also gives rise to bone degrading osteoclasts. We found that expression of Btn2a2 on monocytes and pre-osteoclasts is upregulated by the receptor activator of nuclear factor κ-B ligand (RANKL), an essential protein required for osteoclast formation. Interestingly, in Btn2a2-deficient osteoclasts, typical osteoclast marker genes (Nfatc1, cathepsin K, TRAP, and RANK) were downregulated following RANKL stimulation. In vitro osteoclast assays resulted in decreased TRAP positive osteoclast numbers in Btn2a2-deficient cells. However, Btn2a2-deficient osteoclasts revealed abnormal fusion processes shown by their increased size. In vivo steady state µCT and histological analysis of bone architecture in complete Btn2a2-deficient mice showed differences in bone parameters further highlighting the fine-tuning effect of BTN2a2. Moreover, in rheumatoid arthritis patients and experimental arthritis, we detected significantly decreased serum levels of the secreted soluble Btn2a2 protein. Taken together, we identified the involvement of the immunomodulatory molecule Btn2a2 in osteoclast differentiation with potential future implications in basic and translational osteoimmunology.