bluuebunny/crossref_metadata_2025 huggingface dataset:
Mewujudkan Desa BERSINAR (Bersih dari Narkoba) Melalui Pemberdayaan Masyarakat di Desa Masuru
Authors: Puluhulawa Rusdiyanto U , Nggilu Novendri M
Published: July 2022

Tujuan Program KKN Pengabdian ini adalah untuk mewujudkan desa yang bersih dari narkoba melalui pemberdayaan masyarakat dan peningkatan kesehatan bagi masyarakat di Desa Masuru. KKN Pengabdian ini melibatkan 15 orang Mahasiswa Peserta KKN. Metode yang digunakan adalah melalui pemberdayaan masyarakat dan aparat Desa Masuru, melalui program berupa Penyuluhan tentang Hukum Kesehatan dan pencegahan serta penanggulangan narkoba kepada masyarakat termasuk Kader Kesehatan, Karang Taruna dan aparat desa. Penyuluhan ini  melibatkan dinas dan stakeholder terkait, termasuk akademisi Fakultas Hukum guna menyebarluaskan akibat maupun sanksi yang akan diterima baik oleh pengguna maupun pengedar obat terlarang. Penyuluhan maupun sosialisasi ini bertujuan pula untuk meningkatkan pemahaman masyarakat dalam mencegah dan menanggulangi peredaran narkoba di wilayah tersebut. Olehnya, selain mengatasi permasalahan kesehatan masyarakat, juga bermanfaat bagi masyarakat dan pemerintah guna menyebarluaskan informasi mengenai bahaya dan penanggulangan obat terlarang di kalangan pemuda dan masyarakat luas di Desa Masuru Kecamatan Kwandang Kabupaten Gorontalo Utara, dalam rangka menuju wilayah bersinar. Hasil yang dicapai dalam KKN ini adalah pembentukan Agen Relawan, Agen Intelejen, Agen Pemulihan di Desa Masuru yang anggotanya terdiri dari masyarakat setempat, baik pemudan dan karang taruna juga tokoh masyarakat yang dipilih dan dipercaya masyarakat. Unit maupun personil inilah yang akan membantu pemerintah desa mensosialisasikan maupun mengontrol aktivitas masyarakat, termasuk melakukan pengawasan dan pengendalian bagi yang diduga terlibat dalam kegiatan mengkonsumsi maupun mengedarkan obat terlarang (narkoba). Kegiatan lainnya adalah Pendampingan terhadap Kader Kesehatan Desa dalam kegiatan pelayanan dan penyuluhan kesehatan, tidak saja terkait narkoba melainkan juga permasalahan kesehatan lainnya, melalui Bimtek BNN Kab. Gorontalo Utara dan Sosialisasi Anti Narkoba di Masyarakat Desa Masuru. Tujuannya adalah meningkatkan peran warga dalam menolong dirinya sendiri pada era pandemi maupun non pandemi, dalam konteks mewujudkan ketahanan desa dalam hal penyebarluasan ilmu pengetahuan dan teknologi informasi di bidang kesehatan pada masyarakat setempat.
Independence of central banks: index approach
Authors:   SHEE “Kyiv National Economic University named after Vadym Hetman”, KHOKHYCH Dmytro
Published: July 2022

Introduction. Central bank independence in developed economies and emerging countries requires justi?cation of its status and consolidation of responsibility for price stability in its mandate. The status of the central bank is important for impartial monetary policy decision-making. Problem Statement. Consolidation of the central bank’s mandate at the legislative level raises the problem of status quanti?cation, which means a way to quantify the status of macroeconomic policy bodies. This leads to the expansion of the powers of the central bank on the index approach basis , which demonstrates a lower level of its independence. Purpose. The inverse relationship between in?ation and the level of independence of the central bank encourages the search for alternative approaches in the context of quantifying its independence based on the index of constitutional independence, TOR index and index of political vulnerability of management. Methods. According to OECD countries, developed economies and emerging countries, the GMT index in most countries shows a fairly high ?gure. However, in practice there is a signi?cant di?erence between the formal and actual status of central banks, which a?ects the statistical signi?cance of the relationships obtained. Results. A study to quantify central bank independence based on an index approach has revealed a number of issues related to the interpretation of the central bank’s mandate, the density of the relationship between indices and in?ation rates, and the quanti?cation of legislation. In countries with weak institutions, asserting the link between in?ation and formal independence is quite complex, as opposed to the political and economic independence of the central bank. Conclusions. Addressing issues that lead to imbalances between the status of central banks and the consolidation of monetary objectives at the legislative level requires a clear de?nition of the powers and responsibilities of monetary authorities for the results of monetary policy towards achieving price stability.
Automatic international exchange of tax information: features of the preliminary conditions of implementation in Ukraine during the wartime
Authors:   Kyiv National Economic University named after Vadym Hetman, CHUKHRAIEVA Nataliia , OLIYNYK Yana ,   SESE “The Academy of Financial Management”
Published: July 2022

Introduction. The main trend in the international tax cooperation is to create institutional conditions to enhance the transparency of the ?nancial ?ows of multinational enterprises for tax administrations and to provide them with relevant information to assess and examine transfer pricing risks. The OECD provides governments with model legislation in the context of this issue, which brings to the fore the issue of its implementation to make the international exchange of tax information work automatically. Problem Statement. To determine the status of implementation of the OECD recommendations on substantial prerequisites for the automatic exchange of international tax information in Ukraine, in particular the peculiarities of their implementation in the martial law period. Purpose. To analyze approaches in the sphere of international exchange of information for tax purposes and to evaluate the status of implementation of substantial preconditions for the introduction of country by country reporting of the international group of companies. Methods. The comparative analysis of the national tax legislation and OECD recommendations regulating the aspects of creation of substantial preconditions for automatic international exchange of tax information was carried out. Results. The list is highlighted and the essence of essential preconditions for countries to obtain access to the international exchange of tax information is revealed. The level of implementation of the stages of introduction of country by country reporting of the international group of companies in Ukraine has been analyzed with the focus on the creation of the appropriate institutional conditions for the implementation of OECD recommendations. According to the results of the research, it has been proved that further steps of formation of the mentioned prerequisites in the country are regulation of con?dentiality aspects of tax information, which is the subject of international automatic exchange, which should correspond to the international approaches with an emphasis on the changes, caused by the introduction of martial law. Conclusions. Having joined the OECD Enhanced Cooperation Programme and committed to implementing the BEPS Action Plan, Ukraine is incorporated into the global tax regulatory framework. After the stage of drafting and approving legislative norms, creation of essential preconditions for obtaining and access to the international exchange of tax information, the next step is to ensure its confidentiality. In this process, it is important to protect the national interests and national security of Ukraine of income and property and prevention of tax evasion.
Electrostatic quantum dark energy in a seven-dimensional universe
Authors: Kesanasetty Sasidhar
Published: July 2022

This paper explains the dark energy and acceleration of the universe by quantizing the space in the hidden dimensions and provides the basis and background for the gravitational force through the curvature of space-time. Space-time is considered to be made of a four-dimensional elastic grid in a seven-dimensional universe in which matter also expands along with the universe. Each cube of the grid is considered a quantum of hidden three-dimensional space of Planck volume containing Planck charge, which makes the universe seven-dimensional. The dark energy is explained by the electrostatic repulsion between the Planck charges in each quantum of the hidden space. Mathematically, this electrostatic repulsion is related to the Hubble constant to explain the accelerated expansion due to dark energy and the increase in mass of matter.
Life in Context
Authors: Brindley Heather
Published: July 2022

Remarkably, there is no agreed definition of an Organism. Furthermore, the "characteristics of living things" is the name of a family of uncurated lists. Life in Context reports on the application of bioscientific information modelling techniques to the description of "living things". It addresses systems engineering modelling concerns, and demonstrates that "living" and "non-living" are "non-disjoint datatypes". The generalized patterns of the fully-personalized bio-state "Alive" relate to all domains of knowledge through keyword analysis and the concept of a "Complex System Object". The bio-state "Alive" may therefore be thought of as the Standard Model of Science. This work links back to the model of real-time choice described in "Maslow's Legacy" and "The Art of Choice". It forms part of the traceable derivation of the proposed Open Knowledge Reference Model (OKRM) described in "Outbound Insights" and related articles.
Землеробство в Уманському повіті за матеріалами київських губернських газет останньої чверті XIX – початку XX ст.
Authors: Kuznets Tetiana
Published: July 2022

Вивчення аграрної історії ХІХ – початку ХХ ст. продовжує залишатись актуальним з кількох причин. Однією з них є те, що переважна більшість населення українських земель цього періоду займалась землеробством і проживала у сільській місцевості. Тому сучасне осмислення історичного досвіду на різних етапах буття українського народу зумовлює необхідність комплексного вивчення землеробської галузі. А це диктує необхідність деталізації, застосування мікроісторичного підходу, залучення нових історичних джерел. Оперативна інформація про погодні умови, урожайність зернових культур, потреби хлібного ринку публікувалась на шпальтах періодичної преси. Такі відомості все ще мало затребувані дослідниками аграрної історії.

Мета: Систематизувати публікації київських губернських газет «Заря», «Киевское слово», «Киевлянин» про землеробство в Уманському повіті, який серед дванадцяти повітів Київської губернії був третім за величиною площі та мав багаті для сільського господарства ґрунти. На основі аналізу публікацій виявити фактори впливу на ефективність землеробства.

Наукова новизна полягає у тому, що у рамках мікроісторичного підходу здійснено комплексний аналіз зернової галузі у межах одного повіту в системі: природно-кліматичні умови – урожайність – кон’юнктура хлібного ринку – ціни на зерно. Висновки зроблені на основі 38 публікацій трьох губернських газет про Уманський повіт. Виявлені газетні матеріали введені до наукового обігу, що розширює джерельну базу аграрної історії України.

Методологія. У процесі підготовки статті використовувались методи: евристичний, хронологічної послідовності, системності. Завдячуючи цьому, вдалося виявити газетні публікації відповідної тематики, систематизувати їх у хронологічній послідовності та представити єдиною системою. Таким чином, виявлено тенденції впливу кількох чинників на стан землеробства у визначених територіальних рамках.

Висновки. Публікації київських губернських газет «Заря», «Киевское слово», «Киевлянин» 1881-1912 рр. про Уманський повіт дали можливість з’ясувати стан землеробства у комплексі чинників, які мали гальмівний і стимулюючий вплив на нього. Інформація про погодні умови, про урожайність, про ціни на ринку є зафіксованою реальністю без корекції органів статистики (земських, державних), що надає їй більшої долі об’єктивності. Систематизований у статті матеріал про погодні умови (безсніжні зими, засушливі весни, дощові жнива), про очікуваний урожай зернових культур і про реальну урожайність, про коливання цін на зерно та сезонні особливості хлібного ринку розширили уявлення про залежність ефективності землеробства від низки факторів. Виявлені урожайні та неврожайні роки, показана динаміка цін на основні зернові культури. Аргументовано твердження про те, що ціни на зерно визначала не урожайність зернових культур, а кон’юнктура хлібного ринку й отже: хоча землеробство і було заручником погодних умов, все ж на його ефективність визначальний вплив мав саме попит ринку.
«Бої за Грушевського»: доба Української революції у дискусіях діаспорних інтелектуалів повоєнного двадцятиліття
Authors: Telvak Vitalii , Sabinskyi Mykhailo
Published: July 2022

Мета дослідження полягає у з’ясуванні особливостей обговорення суспільно-політичної діяльності М. Грушевського в історіографії української діаспори. При цьому акцент зроблено на найменш знаному періоді закордонного грушевськознавства, коли студії над вивченням спадщини визначного інтелектуала здійснювали його молодші сучасники та колеги, котрим поталанило опинитися по інший бік «залізної» завіси. Також наголос зроблено на найяскравішій сторінці біографії Грушевського-політика – його головуванні у Центральній Раді, що й по сьогодні породжує чимало дискусій.

Наукова новизна статті полягає у всебічному дослідженні малознаної проблеми рецептивної грушевськіани – з’ясуванні особливостей інтерпретації суспільно-політичної діяльності М. Грушевського в роки революції українськими закордонними інтелектуалами у другій половині 1940-х – першій половині 1960-х рр.

Висновки. З’ясовано найбільш дискусійні проблеми грушевськознавчого дискурсу: стрімке полівіння політики голови Центральної Ради, його ставлення до власної армії, природа федералістських поглядів ученого тощо. Відтворено ідейний контекст історіографічних дискусій, що полягав у змагальності діаспорних інтелектуалів, які представляли республіканське та гетьманське партійні середовища, за утвердження в свідомості українців на вигнанні власної інтерпретації подій Української революції. На ці дискусії впливала поява нового фактичного матеріалу й оригінальних інтерпретативних моделей, що їх приносили мемуарні тексти сучасників М. Грушевського. Також і загальний поступ української гуманітаристики у вільному світі підштовхував до переосмислення класичних грушевськознавчих сюжетів. Завдячуючи цьому був сформований, приміром, цілком оригінальний погляд на федералістську модель визначного діяча. Загалом же, суспільно-політична грушевськіана досліджуваного двадцятиліття дала можливість поступово вийти на нові проблемно-тематичні обрії.
The External Exposome and Allergies: From the Perspective of the Epithelial Barrier Hypothesis
Authors: Celebi Sozener Zeynep , Özbey Yücel Ümüs , Altiner Seda , Ozdel Oztürk Betül , Cerci Pamir , Türk Murat , Gorgülü Akin Begüm , Akdis Mübeccel , Yilmaz Insu , Ozdemir Cevdet , Mungan Dilsad , Akdis Cezmi A.
Published: July 2022

Introduction

In the last decades, we have seen a rapid increase in the prevalence of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and food allergies. The environmental changes caused by industrialization, urbanization and modernization, including dramatic increases in air pollutants such as particulate matter (PM), diesel exhaust, nitrogen dioxide (NO2), ozone (O3), alarming effects of global warming, change and loss of biodiversity, affect both human health and the entire ecosystem.

Objective

In this review, we aimed to discuss the effects of the external exposome on epithelial barriers and its relationship with the development of allergic diseases by considering the changes in all stakeholders of the outer exposome together, in the light of the recently proposed epithelial barrier hypothesis.

Method

To reach current, prominent, and comprehensive studies on the subject, PubMed databases were searched. We included the more resounding articles with reliable and strong results.

Results

Exposure to altered environmental factors such as increased pollution, microplastics, nanoparticles, tobacco smoke, food emulsifiers, detergents, and household cleaners, and climate change, loss and change in microbial biodiversity, modifications in the consumption of dietary fatty acids, the use of emulsifiers, preservatives and the decrease in the antioxidant content of the widely consumed western diet may disrupt the epithelial barriers of the skin, respiratory and gastrointestinal tracts, making us more vulnerable to exogeneous allergens and microbes. Epithelial cell activation, microbial dysbiosis and bacterial translocation disrupt the immune balance and a chronic Th2 inflammation ensues.

Conclusion

Dramatic increases in air pollution, worrisome effects of global warming, dysbiosis, changing dietary habits and the complex interactions of all these factors affect the epithelial barriers and local and systemic inflammation. We want to draw attention to the emerging health effects of environmental changes and to motivate the public to influence government policies for the well-being of humans and the nature of the earth and the well-being of future generations.
Printability of Double Network Alginate-Based Hydrogel for 3D Bio-Printed Complex Structures
Authors: Greco Immacolata , Miskovic Vanja , Varon Carolina , Marraffa Chiara , Iorio Carlo S.
Published: July 2022

Three-dimensional (3D) bio-printing has recently emerged as a crucial technology in tissue engineering, yet there are still challenges in selecting materials to obtain good print quality. Therefore, it is essential to study the influence of the chosen material (i.e., bio-ink) and the printing parameters on the final result. The “printability” of a bio-ink indicates its suitability for bio-printing. Hydrogels are a great choice because of their biocompatibility, but their printability is crucial for exploiting their properties and ensuring high printing accuracy. However, the printing settings are seldom addressed when printing hydrogels. In this context, this study explored the printability of double network (DN) hydrogels, from printing lines (1D structures) to lattices (2D structures) and 3D tubular structures, with a focus on printing accuracy. The DN hydrogel has two entangled cross-linked networks and a balanced mechanical performance combining high strength, toughness, and biocompatibility. The combination of poly (ethylene glycol)-diacrylate (PEDGA) and sodium alginate (SA) enables the qualities mentioned earlier to be met, as well as the use of UV to prevent filament collapse under gravity. Critical correlations between the printability and settings, such as velocity and viscosity of the ink, were identified. PEGDA/alginate-based double network hydrogels were explored and prepared, and printing conditions were improved to achieve 3D complex architectures, such as tubular structures. The DN solution ink was found to be unsuitable for extrudability; hence, glycerol was added to enhance the process. Different glycerol concentrations and flow rates were investigated. The solution containing 25% glycerol and a flow rate of 2 mm/s yielded the best printing accuracy. Thanks to these parameters, a line width of 1 mm and an angle printing inaccuracy of less than 1° were achieved, indicating good shape accuracy. Once the optimal parameters were identified, a tubular structure was achieved with a high printing accuracy. This study demonstrated a 3D printing hydrogel structure using a commercial 3D bio-printer (REGEMAT 3D BIO V1) by synchronizing all parameters, serving as a reference for future more complex 3D structures.
Efficient Production of 2,5-Diketo-D-gluconic Acid by Reducing Browning Levels During Gluconobacter oxydans ATCC 9937 Fermentation
Authors: Li Guang , Shan Xiaoyu , Zeng Weizhu , Yu Shiqin , Zhang Guoqiang , Chen Jian , Zhou Jingwen
Published: July 2022

D-Glucose directly generates 2-keto-L-gulonic acid (2-KLG, precursor of vitamin C) through the 2,5-diketo-D-gluconic acid (2,5-DKG) pathway. 2,5-DKG is the main rate-limiting factor of the reaction, and there are few relevant studies on it. In this study, a more accurate quantitative method of 2,5-DKG was developed and used to screen G. oxydans ATCC9937 as the chassis strain for the production of 2,5-DKG. Combining the metabolite profile analysis and knockout and overexpression of production strain, the non-enzymatic browning of 2,5-DKG was identified as the main factor leading to low yield of the target compound. By optimizing the fermentation process, the fermentation time was reduced to 48 h, and 2,5-DKG production peaked at 50.9 g/L, which was 139.02% higher than in the control group. Effectively eliminating browning and reducing the degradation of 2,5-DKG will help increase the conversion of 2,5-DKG to 2-KLG, and finally, establish a one-step D-glucose to 2-KLG fermentation pathway.
Visualization of Zika Virus Infection via a Light-Initiated Bio-Orthogonal Cycloaddition Labeling Strategy
Authors: Zheng Judun , Yue Rui , Yang Ronghua , Wu Qikang , Wu Yunxia , Huang Mingxing , Chen Xu , Lin Weiqiang , Huang Jialin , Chen Xiaodong , Jiang Yideng , Yang Bin , Liao Yuhui
Published: July 2022

Zika virus (ZIKV) is a re-emerging flavivirus that leads to devastating consequences for fetal development. It is crucial to visualize the pathogenicity activities of ZIKV ranging from infection pathways to immunity processes, but the accurate labeling of ZIKV remains challenging due to the lack of a reliable labeling technique. We introduce the photo-activated bio-orthogonal cycloaddition to construct a fluorogenic probe for the labeling and visualizing of ZIKV. Via a simple UV photoirradiation, the fluorogenic probes could be effectively labeled on the ZIKV. We demonstrated that it can be used for investigating the interaction between ZIKV and diverse cells and avoiding the autofluorescence phenomenon in traditional immunofluorescence assay. Thus, this bioorthogonal-enabled labeling strategy can serve as a promising approach to monitor and understand the interaction between the ZIKV and host cells.
Elimination of Senescent Cells by Senolytics Facilitates Bony Endplate Microvessel Formation and Mitigates Disc Degeneration in Aged Mice
Authors: Chen Bolin , Zhu Runjiu , Hu Hao , Zhan Mingbin , Wang Tingxuan , Huang Fangli , Wei Fuxin , Chai Yu , Ling Zemin , Zou Xuenong
Published: July 2022

Senolytics are a class of drugs that selectively eliminate senescent cells and ameliorate senescence-associated disease. Studies have demonstrated the accumulation of senescent disc cells and the production of senescence-associated secretory phenotype decrease the number of functional cells in degenerative tissue. It has been determined that clearance of senescent cell by senolytics rejuvenates various cell types in several human organs, including the largest avascular structure, intervertebral disc (IVD). The microvasculature in the marrow space of bony endplate (BEP) are the structural foundation of nutrient exchange in the IVD, but to date, the anti-senescence effects of senolytics on senescent vascular endothelial cells in the endplate subchondral vasculature remains unclear. In this study, the relationships between endothelial cellular senescence in the marrow space of the BEP and IVD degeneration were investigated using the aged mice model. Immunofluorescence staining was used to evaluate the protein expression of P16, P21, and EMCN in vascular endothelial cells. Senescence-associated β-galactosidase staining was used to investigate the senescence of vascular endothelial cells. Meanwhile, the effects of senolytics on cellular senescence of human umbilical vein endothelial cells were investigated using a cell culture model. Preliminary results showed that senolytics alleviate endothelial cellular senescence in the marrow space of BEP as evidenced by reduced senescence-associated secretory phenotype. In the aged mice model, we found decreased height of IVD accompanied by vertebral bone mass loss and obvious changes to the endplate subchondral vasculature, which may lead to the decrease in nutrition transport into IVD. These findings may provide evidence that senolytics can eliminate the senescent cells and facilitate microvascular formation in the marrow space of the BEP. Targeting senescent cellular clearance mechanism to increase nutrient supply to the avascular disc suggests a potential treatment value of senolytics for IVD degenerative diseases.
Analysis of the Effect of SNAI Family in Breast Cancer and Immune Cell
Authors: Tu Yifei , Fang Pengfei , Zhang Long , Sun Kewang
Published: July 2022

SNAI family members are transcriptional repressors that induce epithelial-mesenchymal transition during biological development. SNAIs both have tumor-promoting and tumor-inhibiting effect. There are key regulatory effects on tumor onset and development, and patient prognosis in infiltrations of immune cell and tumor microenvironmental changes. However, the relationships between SNAIs and immune cell infiltration remain unclear. We comprehensively analyzed the roles of SNAIs in cancer. We used Oncomine and TCGA data to analyze pan-cancer SNAI transcript levels. By analyzing UALCAN data, we found correlations between SNAI transcript levels and breast cancer patient characteristics. Kaplan–Meier plotter analysis revealed that SNAI1 and SNAI2 have a bad prognosis, whereas SNAI3 is the opposite. Analysis using the cBio Cancer Genomics Portal revealed alterations in SNAIs in breast cancer subtypes. Gene Ontology analysis and gene set enrichment analysis were used to analyze differentially expressed genes related to SNAI proteins in breast cancer. We used TIMER to analyze the effects of SNAI transcript levels, mutations, methylation levels, and gene copy number in the infiltration of immune cell. Further, we found the relationships between immune cell infiltration, SNAI expression levels, and patient outcomes. To explore how SNAI proteins affect immune cell, we further studied the correlations between immunomodulator expression, chemokine expression, and SNAI expression. The results showed that SNAI protein levels were correlated with the expression of several immunomodulators and chemokines. Through analysis of PharmacoDB data, we identified antitumor drugs related to SNAI family members and analyzed their IC50 effects on various breast cancer cell lines. In summary, our study revealed that SNAI family members regulate different immune cells infiltrations by gene copy number, mutation, methylation, and expression level. SNAI3 and SNIA1/2 have opposite regulatory effects. They all play a key role in tumor development and immune cell infiltration, and can provide a potential target for drug therapy.
Physiological and Functional Roles of Neurotrophin-4 During In Vitro Maturation of Porcine Cumulus–Oocyte Complexes
Authors: Kim Mirae , Hwang Seon-Ung , Yoon Junchul David , Lee Joohyeong , Kim Eunhye , Cai Lian , Choi Hyerin , Oh Dongjin , Lee Gabsang , Hyun Sang-Hwan
Published: July 2022

Neurotrophin-4 (NT-4), a granulosa cell-derived factor and a member of the neurotrophin family, is known to promote follicular development and oocyte maturation in mammals. However, the physiological and functional roles of NT-4 in porcine ovarian development are not yet known. The aim of this study was to investigate the physiological role of NT-4-related signaling in the in vitro maturation (IVM) of porcine cumulus–oocyte complexes (COCs). The NT-4 protein and its receptors were detected in matured porcine COCs via immunofluorescence analysis. NT-4 was shown to promote the maturation of COCs by upregulating NFKB1 transcription via the neurotrophin/p75NTR signaling pathway. Notably, the mRNA expression levels of the oocyte-secreted factors GDF9 and BMP15, sperm–oocyte interaction regulator CD9, and DNA methylase DNMT3A were significantly upregulated in NT-4-treated than in untreated porcine oocytes. Concurrently, there were no significant differences in the levels of total and phosphorylated epidermal growth factor receptor and p38 mitogen-activated protein kinase between NT-4-treated and untreated cumulus cells (CCs); however, the level of phosphorylated ERK1/2 was significantly higher in NT-4-treated CCs. Both total and phosphorylated ERK1/2 levels were significantly higher in NT-4-treated than in untreated oocytes. In addition, NT-4 improved subsequent embryonic development after in vitro fertilization and somatic cell nuclear transfer. Therefore, the physiological and functional roles of NT-4 in porcine ovarian development include the promotion of oocyte maturation, CC expansion, and ERK1/2 phosphorylation in porcine COCs during IVM.
Microtubules in Pancreatic β Cells: Convoluted Roadways Toward Precision
Authors: Bracey Kai M. , Gu Guoqiang , Kaverina Irina
Published: July 2022

Pancreatic islet β cells regulate glucose homeostasis via glucose-stimulated insulin secretion (GSIS). Cytoskeletal polymers microtubules (MTs) serve as tracks for the transport and positioning of secretory insulin granules. MT network in β cells has unique morphology with several distinct features, which support granule biogenesis (via Golgi-derived MT array), net non-directional transport (via interlocked MT mesh), and control availability of granules at secretion sites (via submembrane MT bundle). The submembrane MT array, which is parallel to the plasma membrane and serves to withdraw excessive granules from the secretion hot spots, is destabilized and fragmented downstream of high glucose stimulation, allowing for regulated secretion. The origin of such an unusual MT network, the features that define its functionality, and metabolic pathways that regulate it are still to a large extent elusive and are a matter of active investigation and debate. Besides the MT network itself, it is important to consider the interplay of molecular motors that drive and fine-tune insulin granule transport. Importantly, activity of kinesin-1, which is the major MT-dependent motor in β cells, transports insulin granules, and has a capacity to remodel MT network, is also regulated by glucose. We discuss yet unknown potential avenues toward understanding how MT network and motor proteins provide control for secretion in coordination with other GSIS-regulating mechanisms.
Comparative Morphological, Metabolic and Transcriptome Analyses in elmo1−/−, elmo2−/−, and elmo3−/− Zebrafish Mutants Identified a Functional Non-Redundancy of the Elmo Proteins
Authors: Boger Mike , Bennewitz Katrin , Wohlfart David Philipp , Hausser Ingrid , Sticht Carsten , Poschet Gernot , Kroll Jens
Published: July 2022

The ELMO protein family consists of the homologues ELMO1, ELMO2 and ELMO3. Several studies have shown that the individual ELMO proteins are involved in a variety of cellular and developmental processes. However, it has poorly been understood whether the Elmo proteins show similar functions and act redundantly. To address this question, elmo1−/−, elmo2−/− and elmo3−/− zebrafish were generated and a comprehensive comparison of the phenotypic changes in organ morphology, transcriptome and metabolome was performed in these mutants. The results showed decreased fasting and increased postprandial blood glucose levels in adult elmo1−/−, as well as a decreased vascular formation in the adult retina in elmo1−/−, but an increased vascular formation in the adult elmo3−/− retina. The phenotypical comparison provided few similarities, as increased Bowman space areas in adult elmo1−/− and elmo2−/− kidneys, an increased hyaloid vessel diameter in elmo1−/− and elmo3−/− and a transcriptional downregulation of the vascular development in elmo1−/−, elmo2−/−, and elmo3−/− zebrafish larvae. Besides this, elmo1−/−, elmo2−/−, and elmo3−/− zebrafish exhibited several distinct changes in the vascular and glomerular structure and in the metabolome and the transcriptome. Especially, elmo3−/− zebrafish showed extensive differences in the larval transcriptome and an impaired survivability. Together, the data demonstrated that the three zebrafish Elmo proteins regulate not only similar but also divergent biological processes and mechanisms and show a low functional redundancy.
dDAVP Downregulates the AQP3-Mediated Glycerol Transport via V1aR in Human Colon HCT8 Cells
Authors: Centrone Mariangela , D’Agostino Mariagrazia , Ranieri Marianna , Mola Maria Grazia , Faviana Pinuccia , Lippolis Piero Vincenzo , Silvestris Domenico Alessandro , Venneri Maria , Di Mise Annarita , Valenti Giovanna , Tamma Grazia
Published: July 2022

Vasopressin (AVP) plays a key function in controlling body water and salt balance through the activation of the vasopressin receptors V1aR and V2R. Abnormal secretion of AVP can cause the syndrome of inappropriate antidiuresis that leads to hyponatremia, which is an electrolyte disorder often observed in the elderly hospitalized and oncologic patients. Beyond kidneys, the colonic epithelium modulates water and salt homeostasis. The water channel AQP3, expressed in villus epithelial cells is implicated in water absorption across human colonic surface cells. Here, the action of dDAVP, a stable vasopressin analog, was evaluated on the AQP3 expression and function using human colon HCT8 cells as an experimental model. Confocal and Western Blotting analysis revealed that HCT8 cells express both V1aR and V2R. Long-term (72 h) treatment with dDAVP reduced glycerol uptake and cell viability. These effects were prevented by SR49059, a synthetic antagonist of V1aR, but not by tolvaptan, a specific V2R antagonist. Of note, the SR49059 action was impaired by DFP00173, a selective inhibitor of AQP3. Interestingly, compared to the normal colonic mucosa, in the colon of patients with adenocarcinoma, the expression of V1aR was significantly decreased. These findings were confirmed by gene expression analysis with RNA-Seq data. Overall, data suggest that dDAVP, through the V1aR dependent pathway, reduces AQP3 mediated glycerol uptake, a process that is reversed in adenocarcinoma, suggesting that the AVP-dependent AQP3 pathway may represent a novel target in colon diseases associated with abnormal cell growth.
Establishment of a Necroptosis Related Genes Signature to Predict Prognosis and Therapeutic Response in Colon Cancer
Authors: Wang Yuan , Huang Yongbiao , Li Chunya , Wang Xi , Yang Mu , Xu Duo , Liu Bo , Yuan Xianglin
Published: July 2022

Necroptosis, as a form of programmed cell death, is involved in many physiological and pathological processes. However, its role in cancer progression and therapeutic response remains controversial. Colon cancer is one of the leading causes of cancer death and patients’ response to immune checkpoint blockade vary to a large degree. In this study, we investigated necroptosis related genes (NRGs) alterations in colon cancer by bioinformatics analysis. Colon cancer patients were classified into two subtypes with distinct clinical and molecular features based on NRGs. After finding differentially expressed genes and lasso regression, a prognostic model based on four necroptosis signature genes was constructed. The necroptosis signature was also a good predictor in the field of chemotherapy and immunotherapy in colon cancer. Altogether, this study illustrates the relationship between necroptosis and colon cancer, and establishes a novel scoring method to predict prognosis and therapeutic response in colon cancer patients.
Brain-Derived Neurotrophic Factor Inhibits the Function of Cation-Chloride Cotransporter in a Mouse Model of Viral Infection-Induced Epilepsy
Authors: Patel Dipan C. , Thompson Emily G. , Sontheimer Harald
Published: July 2022

Well over 100 different viruses can infect the brain and cause brain inflammation. In the developing world, brain inflammation is a leading cause for epilepsy and often refractory to established anti-seizure drugs. Epilepsy generally results from an imbalance in excitatory glutamatergic and inhibitory GABAergic neurotransmission. GABAergic inhibition is determined by the intracellular Cl− concentration which is established through the opposing action of two cation chloride cotransporters namely NKCC1 and KCC2. Brain-derived neurotrophic factor (BDNF) signaling is known to regulate expression of KCC2. Hence we hypothesized that viral induced epilepsy may result from aberrant BDNF signaling. We tested this hypothesis using a mouse model of Theiler’s murine encephalomyelitis virus (TMEV) infection-induced epilepsy. We found that BDNF levels in the hippocampus from TMEV-infected mice with seizures was increased at the onset of acute seizures and continued to increase during the peak of acute seizure as well as in latent and chronic phases of epilepsy. During the acute phase of epilepsy, we found significant reduction in the expression of KCC2 in hippocampus, whereas the level of NKCC1 was unaltered. Importantly, inhibiting BDNF using scavenging bodies of BDNF in live brain slices from TMEV-infected mice with seizures normalized the level of KCC2 in hippocampus. Our results suggest that BDNF can directly decrease the relative expression of NKCC1 and KCC2 such as to favor accumulation of chloride intracellularly which in turn causes hyperexcitability by reversing GABA-mediated inhibition. Although our attempt to inhibit the BDNF signaling mediated through tyrosine kinase B–phospholipase Cγ1 (TrkB-PLCγ1) using a small peptide did not change the course of seizure development following TMEV infection, alternative strategies for controlling the BDNF signaling could be useful in preventing seizure generation and development of epilepsy in this model.
Updating Urinary Microbiome Analyses to Enhance Biologic Interpretation
Authors: Siddiqui Nazema Y. , Ma Li , Brubaker Linda , Mao Jialiang , Hoffman Carter , Dahl Erin M. , Wang Zhuoqun , Karstens Lisa
Published: July 2022

Objective

An approach for assessing the urinary microbiome is 16S rRNA gene sequencing, where analysis methods are rapidly evolving. This re-analysis of an existing dataset aimed to determine whether updated bioinformatic and statistical techniques affect clinical inferences.

Methods

A prior study compared the urinary microbiome in 123 women with mixed urinary incontinence (MUI) and 84 controls. We obtained unprocessed sequencing data from multiple variable regions, processed operational taxonomic unit (OTU) tables from the original analysis, and de-identified clinical data. We re-processed sequencing data with DADA2 to generate amplicon sequence variant (ASV) tables. Taxa from ASV tables were compared to the original OTU tables; taxa from different variable regions after updated processing were also compared. Bayesian graphical compositional regression (BGCR) was used to test for associations between microbial compositions and clinical phenotypes (e.g., MUI versus control) while adjusting for clinical covariates. Several techniques were used to cluster samples into microbial communities. Multivariable regression was used to test for associations between microbial communities and MUI, again while adjusting for potentially confounding variables.

Results

Of taxa identified through updated bioinformatic processing, only 40% were identified originally, though taxa identified through both methods represented >99% of the sequencing data in terms of relative abundance. Different 16S rRNA gene regions resulted in different recovered taxa. With BGCR analysis, there was a low (33.7%) probability of an association between overall microbial compositions and clinical phenotype. However, when microbial data are clustered into bacterial communities, we confirmed that bacterial communities are associated with MUI. Contrary to the originally published analysis, we did not identify different associations by age group, which may be due to the incorporation of different covariates in statistical models.

Conclusions

Updated bioinformatic processing techniques recover different taxa compared to earlier techniques, though most of these differences exist in low abundance taxa that occupy a small proportion of the overall microbiome. While overall microbial compositions are not associated with MUI, we confirmed associations between certain communities of bacteria and MUI. Incorporation of several covariates that are associated with the urinary microbiome improved inferences when assessing for associations between bacterial communities and MUI in multivariable models.
Saccharomyces boulardii Allows Partial Patients to Avoid Reusing Bismuth Quadruple for Helicobacter pylori Rescue Therapy: A Single-Center Randomized Controlled Study
Authors: Qu Peng , Liu Xiaoming , Xia Xiujuan , Xie Xiaoran , Luo Ju , Cheng Sha , Chi Jingshu , Liu Peng , Li Huan , Zhao Wenfang , Yang Huihao , Xu Canxia
Published: July 2022

Background

The increasing rate of drug resistance often leads to Helicobacter pylori (H. pylori) eradication failure and needs the rescue therapy. Thus, the exploration of new rescue therapeutic regimens is important. The present study was designed to test the beneficial effects of Saccharomyces boulardii (S.boulardii) prior to H. pylori rescue therapy basing on bismuth quadruple.

Methods

One hundred H. pylori-infected patients were randomly divided into two groups: study group and control group. Patients in the study group (n=50) underwent two-stages therapy: patients started with S.boulardii monotherapy for 2 weeks, and then tested for H. pylori infection after resting for 4 weeks without any therapy, patients who were still positive for H. pylori continued with bismuth quadruple eradication therapy. For the control group (n=50), all patients were observed and were not treated with any gastric drugs or antibiotics for 6 weeks, then those who were still positive for H. pylori received the same eradication therapy as the study group. Eradication rate, adverse events and the cost-effectiveness of two regimens were analyzed in this study.

Results

The H.pylori eradication rate of ITT (intent-to-treat) analysis and PP (per-protocol) analysis in the first phase of treatment were significantly higher in the study group than the control groups respectively (28.0% vs 2.0%, p<0.001 and 30.4% vs 2.1% p<0.001). For the total treatment effect, there were no significant differences in the eradication rate of ITT analysis (78.0% vs 80.0%) or PP analysis (90.7% vs 88.9%) between the study group and the control group. The cost‐effectiveness ratio of the study group was slightly higher than that of the control group (8.95 vs 8.55). There were two patients in the study group and four patients in the control group with the adverse events, respectively. There was no significant difference on the incidence of adverse events between the two groups (p=0.68).

Conclusion

S.boulardii may serve as a beneficial treatment option before H. pylori rescue therapy since it callowed partial patients to avoid reusing bismuth quadruple.
Rapid Detection of Neisseria gonorrhoeae Genomic DNA Using Gold Nanoprobes Which Target the Gonococcal DNA Uptake Sequence
Authors: Carter Ella , Davis Sean A. , Hill Darryl J.
Published: July 2022

The rapid spread of antimicrobial resistant Neisseria gonorrhoeae continues to pose a serious threat to global health. To successfully treat and control gonococcal infections, rapid diagnosis is critical. Currently, nucleic acid amplification tests are the recommended diagnostic, however, these are both technically demanding and time consuming, making them unsuitable for resource-poor clinics. Consequently, there is a substantial need for an affordable, point-of-care diagnostic to use in these settings. In this study, DNA-functionalised gold nanoparticles (gold nanoprobes), with the ability to specifically detect the DNA Uptake Sequence (DUS) of Neisseria gonorrhoeae, were prepared. Using complementary annealing, the gold nanoprobes were shown to hybridise to genomic gonococcal DNA, causing a significant shift in their salt stability. By exploiting the shift in nanoprobe stability under the presence of target DNA, a solution-based colorimetric diagnostic for gonococcal DNA was prepared. Detection of purified genomic DNA was achieved in under 30 minutes, with a detection limit of 15.0 ng. Significantly, testing with DNA extracted from an off-target control organism suggested specificity for Neisseria. These results highlight the potential of DUS-specific gold nanoprobes in the rapid point-of-care diagnosis of gonococcal infections.
Mycoplasma hyopneumoniae Infection Activates the NOD1 Signaling Pathway to Modulate Inflammation
Authors: Liu Wei , Jiang Pengcheng , Yang Keli , Song Qiqi , Yuan Fangyan , Liu Zewen , Gao Ting , Zhou Danna , Guo Rui , Li Chang , Sun Pei , Tian Yongxiang
Published: July 2022

Mycoplasma hyopneumoniae is a highly contagious pathogen causing porcine enzootic pneumonia, which elicits prolonged inflammatory response modulated by pattern recognition receptors (PRRs). Although significant advances have been achieved in understanding the Toll-Like receptors that recognize M. hyopneumoniae, the role of nucleotide-binding oligomerization domain 1 (NOD1) in M. hyopneumoniae infected cells remains poorly understood. This study revealed that M. hyopneumoniae activates the NOD1-RIP2 pathway and is co-localized with host NOD1 during infection. siRNA knockdown of NOD1 significantly impaired the TRIF and MYD88 pathway and blocked the activation of TNF-α. In contrast, NOD1 overexpression significantly suppressed M. hyopneumoniae proliferation. Furthermore, we for the first time investigated the interaction between M. hyopneumoniae mhp390 and NOD1 receptor, and the results suggested that mhp390 and NOD1 are possibly involved in the recognition of M. hyopneumoniae. These findings may improve our understanding of the interaction between PRRs and M. hyopneumoniae and the function of NOD1 in host defense against M. hyopneumoniae infection.
Cinnamomum: The New Therapeutic Agents for Inhibition of Bacterial and Fungal Biofilm-Associated Infection
Authors: Didehdar Mojtaba , Chegini Zahra , Tabaeian Seidamir Pasha , Razavi Shabnam , Shariati Aref
Published: July 2022

Due to the potent antibacterial properties of Cinnamomum and its derivatives, particularly cinnamaldehyde, recent studies have used these compounds to inhibit the growth of the most prevalent bacterial and fungal biofilms. By inhibiting flagella protein synthesis and swarming motility, Cinnamomum could suppress bacterial attachment, colonization, and biofilm formation in an early stage. Furthermore, by downregulation of Cyclic di‐guanosine monophosphate (c‐di‐GMP), biofilm-related genes, and quorum sensing, this compound suppresses intercellular adherence and accumulation of bacterial cells in biofilm and inhibits important bacterial virulence factors. In addition, Cinnamomum could lead to preformed biofilm elimination by enhancing membrane permeability and the disruption of membrane integrity. Moreover, this substance suppresses the Candida species adherence to the oral epithelial cells, leading to the cell wall deformities, damage, and leakages of intracellular material that may contribute to the established Candida’s biofilm elimination. Therefore, by inhibiting biofilm maturation and destroying the external structure of biofilm, Cinnamomum could boost antibiotic treatment success in combination therapy. However, Cinnamomum has several disadvantages, such as poor solubility in aqueous solution, instability, and volatility; thus, the use of different drug-delivery systems may resolve these limitations and should be further considered in future investigations. Overall, Cinnamomum could be a promising agent for inhibiting microbial biofilm-associated infection and could be used as a catheter and other medical materials surface coatings to suppress biofilm formation. Nonetheless, further in vitro toxicology analysis and animal experiments are required to confirm the reported molecular antibiofilm effect of Cinnamomum and its derivative components against microbial biofilm.