bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustainable Development in Leisure Events. Case Study of “Granatos Live”
Authors: Užkurytė Rasa , Simanavičius Artūras
Published: April 2024

Relevance of the research. After assessing the fact that the collected information about the currently declared aspirations of the music festival “Granatos Live” to implement the principles of sustainable development during the festival shows, that the aspirations of sustainable development are not declared either on the official website of the festival or among the organisers themselves, it was decided to conduct a quantitative study, applying the survey method and interviewing the visitors of this festival. This helps to gather information on how the participants themselves perceive the implementation of sustainable development principles during the festival. It is determined that the festival visitors want the implementation of the principles of sustainable development, a more sustainable festival, recommendations, and proposals can be made to the organisers to prepare a plan for the implementation of the principles of sustainable development and consider it when organising festivals in the future.
The object of the research is the need for the implementation of the principles of sustainable development from the point of view of the participants of the “Granatos Live” festival.
The aim of the research is to determine how the participants of the “Granatos Live” festival evaluate the implementation of the principles of sustainable development during the festival, and what the needs of the participants are related to the principles of sustainable development.
The tasks of the research:

To investigate how the participants of the “Granatos Live” festival perceive the essence and principles of sustainable development.
To determine the main expectations of the participants, related to the implementation of the principles of sustainable development during the music festival “Granatos Live”
Submit recommendations and suggestions to the organizers of the music festival “Granatos Live”.

Outcomes and conclusions. After examining the expression of festival sustainability indicators at the “Granatos Live” festival, sustainability deficiencies were identified in the following areas of the festival: education of the participants and the festival organization team on the topic of sustainable development; the selection of traders does not focus on fair trade, local regional or organic goods; there are too few actions of the festival organisers to ensure environmental protection because environmental specialists are not consulted; it is not observed what economic benefits the festival creates for the local region, although such calculations are more beneficial for the local region, it shows that there is lack of communication between them; a small cost to keep the festival going. Therefore, it is necessary for the festival organisers to take the actions that the festival participants want from them and to introduce more sustainable development principles during the festival.
Keywords: principles of sustainable development, leisure events.
Development of a Network Monitoring System
Authors: Adieva G. , Muratbek-uulu A.
Published: April 2024

In modern conditions, when huge amounts of information are transmitted over data networks, there is an urgent need for software products that allow you to quickly analyze network traffic. Using this program, you can scan the network and obtain information about connected computers in a convenient form, view IP configurations, find out your IP address and conduct a comprehensive network check. A distinctive feature of the developed method is its low demands on the resources of the machine on which the analysis is performed, fast and effective results.
Bibliometrical Analysis of Articles in the WoS Database on Women’s Entrepreneurship
Authors: Beishenova A. , Najimudinova S.
Published: April 2024

Women’s entrepreneurship is a topic that has garnered significant attention from researchers and is becoming increasingly important. Research shows that entrepreneurial activity is particularly high in more developed countries. However, the significance of entrepreneurship extends beyond developed nations to encompass less developed ones as well. The role of women in entrepreneurship stands as a pivotal issue requiring examination in the context of economic development and gender equality. Therefore, it is paramount to diversify research on women's entrepreneurship and provide support for studies in this field. The main purpose of this study is to examine and evaluate articles on women’s entrepreneurship in the Web of Science (WoS) database using bibliometric analysis. The study includes 4301 articles on women’s entrepreneurship published in the WoS database between 1990 and 2023. To achieve this goal, the articles were analyzed by year of publication, language, country, and other relevant factors. According to the main results obtained from the study, it was found that the highest number of articles were published in 2022, with the majority of them being written in English. The results of the study have revealed that the number of publications on women’s entrepreneurship in the Turkic republics of Central Asia is significantly inadequate. These findings underscore the imperative to broaden the academic literature on women’s entrepreneurship in the region and attract more attention to it.
The Specifics of Socio-Political Transformations in Kyrgyzstan
Authors: Nazarkulova A.
Published: April 2024

Examines the key aspects of Kyrgyz society's development in the context of the most recent period of the country’s history. Special attention is given to the issues of national identity, inter-ethnic relations, economic and political processes, and ideological trends that shape the current state of affairs in Kyrgyzstan. Both internal and external factors that influence the social and political dynamics of the country are also considered.
Analysis of Legal Regulation of a Retail Purchase and Sale Agreement by Remote Method and Problem Issues when Considering Disputes of Its Termination
Authors: Ablyatipova N. , Bandurina Ya.
Published: April 2024

Discusses the contract of remote retail sale, as well as a number of problems of judicial practice. In addition, the provisions of the current legislation in the field of distance trading, relevant at the time of the study, are analyzed. The judicial practice on issues related to the resolution of civil law disputes on the termination of a concluded retail purchase agreement on large Russian online trading platforms has been studied. As a result of the analysis of the materials of judicial practice, the problems arising when consumers apply for replacement of goods, termination of the contract are formulated, and possible methods of their solution are proposed.
Ideologists of Regionalism on the Territorial Status, Population and Development Prospects of Siberia (End of XIX - Beginning of XX centuries)
Authors: Protasova O.
Published: April 2024

The article analyzes the ideological views of the leading representatives of the Siberian regionalism: A. P. Schapov, N. M. Yadrintsev, G. N. Potanin and others. It is shown that regionalism (autonomism) as an ideological and political trend that started in the middle of the XIX century, it was replenished with supporters from among Siberian natives and sympathizers, mainly from the populist environment, familiar with the life of Siberia through hard labor and exile. The oblasts and their allies criticized the official state policy towards Siberia, its natural resources and indigenous peoples; They saw huge economic, economic and socio-cultural prospects in this territory. The issue of the assessment by representatives of the regional trend of the situation of the Siberian peasantry, its relations with the peasants who migrated from the European part of Russia is highlighted. The psychological type of a Siberian is characterized, which differs from the “average” type of a resident of the Russian “metropolis” and in a number of features is similar to a Western European or North American colonist. Natural conditions and the absence of serfdom traditions in Siberia contributed to the formation of such traits as independence, enterprise, and utilitarianism in the character of Siberians. It is concluded that the ideological program of the regionalism did not contain separatist aspirations but was aimed at attracting the attention of the public and the authorities to the problems of Siberia, the solution of which, according to the regionalists, could optimally be realized in the conditions of federalization of the state, with the granting of autonomy status to Siberia.
Dish Names in Diwan Lughat at-Turk Dictionary by Mahmud Kashari and Their Connection with Modern Kyrgyz Language
Authors: Davlatova S.
Published: April 2024

When determining whether the modern Kyrgyz language is one of the ancient Turkic languages, the article becomes relevant in Diwan Lughat at-Turk dictionary by Kashgari, defining the degree of usage of dish names in the modern Kyrgyz language. The object of the investigation is the translations of Kashgari’s dictionary into English. The aim of the article is to compare dish names in Mahmud Kashgari’s dictionary Diwan Lughat at-Turk with their appearance in modern Kyrgyz language, determining the level of usage of individual linguistic phenomena in the process of phonetic changes of words. The research is conducted based on the historical-comparative method. The obtained results provide materials for the comparative study of the history, historical lexicology of Turkic languages, including Kyrgyz: 1. Words used in modern Kyrgyz lexicon without changes in meaning or sound: ajaq - leg, cup, Cup; 2. Words that have semantic shifts, used by changing vowels: tiküç — stamping, közäç — eye, tiküç — stamping, etc. 3. Names of dishes not used in modern Kyrgyz lexicon and becoming obsolete: ivrıq — jug, pitcher, alma — pitcher, sasıq — clay pot, tamgalıq — small pitcher, etc.
Representation of Worship in the Epic of Manas (According to Zhusup Mamai)
Authors: Myrzataeva B.
Published: April 2024

The Epic of Manas is an unforgettable great heritage, reminding us that man and nature are one. We all know that the attitude of the Kyrgyz people to nature in the epic was of a special nature. In almost all versions of the Epic of Manas one can observe traces of ancient beliefs. In the oaths of the heroes, led by Manas, we find that they worship the moon, the sun, the earth and the water. We often find in the epic that they considered the “blue roof”, “hairy earth”, and sometimes weapons of war (Ak tinte, Ach albars) sacred, and they asked and asked. The Kyrgyz, like other peoples, had a rich understanding of nature. One of their main beliefs was to wait for help from nature before embarking on any serious work. The main objective of this article was to determine the close connection between man and nature through the Epic of Manas.
Pengawasan Pegawai Pajak dalam Pandangan Abu Yusuf
Authors: Sarifudin Muhamad
Published: April 2024

As a well-known figure, Abu Yusuf has phenomenal work in the field of taxes, namely the book Al-Kharaj. This book, written at the request of Caliph Harun Ar-Rasyid, is used as a guide in tax management. The purpose of this writing is to find out how professionalism tax officials are in Abu Yusuf's view. Apart from that, this article also aims to understand the concept of tax written by Abu Yusuf. The method used in this writing is included in the type of qualitative research and the data collection method is through library research. Literary research (library research) means that the data sources used come from written materials. The results of the research found that Abu Yusuf's thoughts regarding the criteria for a good and professional tax manager. Good religion, trustworthy, mastery of jurisprudence, smart, likes deliberation, maintains self-respect (afif), dares to defend the truth, orientation to the afterlife in carrying out obligations, honest and not unjust. Apart from that, Abu Yusuf places great emphasis on strict supervision of tax collectors, in order to avoid fraud such as corruption, acts of oppression, and so on.

 Keywords: Abu Yusuf, Tax Supervision, Tax Employee
Self-Efficacy, Computer Anxiety, Trait Anxiety, and Cognitive Distortions Influence Students' Interest in Learning Mind Your Own Business
Authors: Sibarani Blasius Erik
Published: April 2024

The purpose of this study was to determine the effect of self-efficacy, computer anxiety, trait anxiety, and cognitive distortions on students' interest in learning Mind Your Own Business (MYOB). This research is a quantitative study using raw data obtained from questionnaires and data analysis. This study used multiple linear regression and data collection techniques in the form of questionnaires. The data obtained were analyzed by f-test, t-test, and multiple linear regression analysis. The results showed that partially the self-efficacy variable affected students' interest in learning MYOB, computer anxiety influenced students' interest in learning MYOB, trait anxiety had an impact on students' interest in learning MYOB, and cognitive distortions affected students' interest in learning MYOB. The practical implication of this research is that it is essential to ensure that students have good self-efficacy, low anxiety levels, and no cognitive deviations.
Ny avhandling: Jansson, Tobias (2023)
Authors: Lundberg Anna
Published: April 2024

Det har snart gått ett decennium sedan vi fick ett paradigmskifte i Sveriges migrationspolitik. Skiftet aviserades för allmänhet och media den 24 november 2015. Vi minns alla den omtalade presskonferens där Stefan Löfven (S) och Åsa Romson (MP) talade om en ohållbar situation och om att Sverige behövde ett ”andrum”. I internationell media beskrevs regeringens nya hållning i asylfrågan som en igenkastad dörr i ansiktet på flyktingar (Crouch, 2015). Frivilligorganisationerna varnade för allvarliga konsekvenser och skulle få sina farhågor besannade (se Asylkommissionen, 2022). Så småningom skulle även synen på rättigheter, välfärd och integration påverkas i grunden (Larsson, 2020).
När jag skriver denna anmälan i juli 2023 är det snart ett år sedan Tidöpartierna tog initiativ till ännu ett paradigmskifte på migrationsområdet, nämligen i ”synen på asylmottagande” (Tidöavtalet 2022, s. 29). En rad utredningar tillsätts i skrivande stund för att ytterligare strama åt asylpolitiken. Senvåren 2023 har ett antal lagförslag presenterats om en effektiviserad så kallad inre utlänningskontroll, asylcenter, anmälningsplikt, återvändandecenter med mera.
Hur kunde det hända? Varför blev det ett så stort problem att människor på flykt bereds en fristad? Och hur har asylrätten villkorats över längre tid i Sverige?
De här frågorna behandlas i en doktorsavhandling i socialt arbete som försvarades våren 2023 vid Göteborgs universitet: Vem får stanna? Om politiska problemrepresentationer av rätten att stanna i Sverige 1936–1989 av Tobias Jansson.
Om aktörskap och självbestämmandets villkor inom LSS
Authors: Puaca Goran , Palmqvist Lina , Carlén Margareta
Published: April 2024

On agency and the conditions for self-determination in “Service for Persons with Certain Functional Impairments”
In this article, we approach the significance of moral stands in professional practices among practitioners in Support and Service for Persons with Certain Functional Impairments from the perspective of Bourdieu's concept of symbolic order and ethos.  Our study illustrates how negotiations about agency takes place within a network of relationships, where the normative and professional judgment of staff in practice becomes crucial in relation to how self-determination for users is conditioned in everyday life. This involves questions about how rights, obligations and norms are conveyed, negotiated and implemented. These everyday practices involve individual planning, follow-up, and relationships with support staff in various professional categories. The results illustrate how staff motivation in regard of their work to support and help others rests on emotional and ethical attributes linked to the professions. These ethic dispositions become indicative of the meaning that the concept of self-determination has for the staff. Ethos, is in this context regarded as a focal professional attribute of being able to place the ideal of users as active subjects within a social service context.
Unlocking the potential of exosomes: a breakthrough in the theranosis of degenerative orthopaedic diseases
Authors: Yue Yaohang , Dai Wei , Wei Yihao , Cao Siyang , Liao Shuai , Li Aikang , Liu Peng , Lin Jianjing , Zeng Hui
Published: April 2024

Degenerative orthopaedic diseases pose a notable worldwide public health issue attributable to the global aging population. Conventional medical approaches, encompassing physical therapy, pharmaceutical interventions, and surgical methods, face obstacles in halting or reversing the degenerative process. In recent times, exosome-based therapy has gained widespread acceptance and popularity as an effective treatment for degenerative orthopaedic diseases. This therapeutic approach holds the potential for “cell-free” tissue regeneration. Exosomes, membranous vesicles resulting from the fusion of intracellular multivesicles with the cell membrane, are released into the extracellular matrix. Addressing challenges such as the rapid elimination of natural exosomes in vivo and the limitation of drug concentration can be effectively achieved through various strategies, including engineering modification, gene overexpression modification, and biomaterial binding. This review provides a concise overview of the source, classification, and preparation methods of exosomes, followed by an in-depth analysis of their functions and potential applications. Furthermore, the review explores various strategies for utilizing exosomes in the treatment of degenerative orthopaedic diseases, encompassing engineering modification, gene overexpression, and biomaterial binding. The primary objective is to provide a fresh viewpoint on the utilization of exosomes in addressing bone degenerative conditions and to support the practical application of exosomes in the theranosis of degenerative orthopaedic diseases.
Cellugyrin (synaptogyrin-2) dependent pathways are used by bacterial cytolethal distending toxin and SARS-CoV-2 virus to gain cell entry
Authors: Boesze-Battaglia Kathleen , Cohen Gary H. , Bates Paul F. , Walker Lisa M. , Zekavat Ali , Shenker Bruce J.
Published: April 2024

Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) is capable of intoxicating lymphocytes macrophages, mast cells and epithelial cells. Following Cdt binding to cholesterol, in the region of membrane lipid rafts, the CdtB and CdtC subunits are internalized and traffic to intracellular compartments. These events are dependent upon, cellugyrin, a critical component of synaptic like microvesicles (SLMVCg+). Target cells, such as Jurkat cells, rendered unable to express cellugyrin are resistant to Cdt-induced toxicity. Similar to Cdt, SARS-CoV-2 entry into host cells is initiated by binding to cell surface receptors, ACE-2, also associated with cholesterol-rich lipid rafts; this association leads to fusion and/or endocytosis of viral and host cell membranes and intracellular trafficking. The similarity in internalization pathways for both Cdt and SARS-CoV-2 led us to consider the possibility that cellugyrin was a critical component in both processes. Cellugyrin deficient Calu-3 cells (Calu-3Cg-) were prepared using Lentiviral particles containing shRNA; these cells were resistant to infection by VSV/SARS-CoV-2-spike pseudotype virus and partially resistant to VSV/VSV-G pseudotype virus. Synthetic peptides representing various regions of the cellugyrin protein were prepared and assessed for their ability to bind to Cdt subunits using surface plasmon resonance. Cdt was capable of binding to a region designated the middle outer loop (MOL) which corresponds to a region extending into the cytoplasmic surface of the SLMVCg+. SARS-CoV-2 spike proteins were assessed for their ability to bind to cellugyrin peptides; SARS-CoV-2 full length spike protein preferentially binds to a region within the SLMVCg+ lumen, designated intraluminal loop 1A. SARS-CoV-2-spike protein domain S1, which contains the receptor binding domains, binds to cellugyrin N-terminus which extends out from the cytoplasmic surface of SLMV. Binding specificity was further analyzed using cellugyrin scrambled peptide mutants. We propose that SLMVCg+ represent a component of a common pathway that facilitates pathogen and/or pathogen-derived toxins to gain host cell entry.
Dynamic change of soil aggregate stability and infiltration properties during crop growth under four tillage measures in Mollisols region of northeast China
Authors: Xu Chong , Liu Wenli , Li Jianming , Wu Jinggui , Zhou Yinuo , kader Rehanguli
Published: April 2024

Introduction: Previous studies have proven that different tillage measures have significant different effects on soil structure, hydrology properties and soil erosion. However, few studies have clarified the dynamic changes in soil aggregate stability and infiltration properties during crop growth under four tillage measures.

Methods: Four field plots (150 m × 15 m) managed by four tillage methods including wide ridge tillage (DT), no-tillage (NT), contour ridge tillage (CT) and traditional tillage (CK) were built in 2021 to evaluate their effects on dynamic changes of soil structure and water conductivity during crop growth. Soybean was the seasonal crop. Soil bulk density, soil porosity, soil aggregate stability and soil infiltration characteristics were measured to assess dynamic changes in soil aggregate stability and infiltration from June to October 2022.

Results: The results showed that NT significantly increased soil bulk density by up to 21.62% compared with CK, while DT did not show significantly increase in soil bulk density. DT, NT and CT could greatly increase the capillary porosity and proportion of capillary porosity to total porosity. DT and NT also improved the stability of soil water-stable aggregates by 3.37% and 10.6%. In terms of soil infiltration properties, all three tillage methods increased the initial, stable and average infiltration rates by 8.4%–52.94%, of which the DT and NT showed the greatest improvement. The soil infiltration process of four tillage measures could be better fitted by Horton model than Kostiakov and Philip models. Soil saturated hydraulic conductivity (SHC) of CK exhibited a significant negative correlation with soil bulk density and capillary porosity, and showed a positive correlation with total porosity and geometric average diameter of water-stable aggregate (GMD), whereas the other three treatments only displayed a significant correlation with the stability of soil water-stable aggregate.

Conclusion: The results suggest that DT, NT and CT have potential to improve soil structure and infiltration capacity compared with CK, and contribute to preventing and controlling soil erosion in sloping farmland of Northeast China.
Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: advancements and implications
Authors: Herlin Morten Krogh
Published: April 2024

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital anomaly characterized by agenesis/aplasia of the uterus and upper part of the vagina in females with normal external genitalia and a normal female karyotype (46,XX). Patients typically present during adolescence with complaints of primary amenorrhea where the diagnosis is established with significant implications including absolute infertility. Most often cases appear isolated with no family history of MRKH syndrome or related anomalies. However, cumulative reports of familial recurrence suggest genetic factors to be involved. Early candidate gene studies had limited success in their search for genetic causes of MRKH syndrome. More recently, genomic investigations using chromosomal microarray and genome-wide sequencing have been successful in detecting promising genetic variants associated with MRKH syndrome, including 17q12 (LHX1, HNF1B) and 16p11.2 (TBX6) deletions and sequence variations in GREB1L and PAX8, pointing towards a heterogeneous etiology with various genes involved. With uterus transplantation as an emerging fertility treatment in MRKH syndrome and increasing evidence for genetic etiologies, the need for genetic counseling concerning the recurrence risk in offspring will likely increase. This review presents the advancements in MRKH syndrome genetics from early familial occurrences and candidate gene searches to current genomic studies. Moreover, the review provides suggestions for future genetic investigations and discusses potential implications for clinical practice.
Efficient eradication of organotin utilizing K2FeO4 augmented by nZVI: revelations on influential factors, kinetic dynamics, and mechanistic insights
Authors: Huang Yuanyuan , Yang Qingwei , Song Ling , Ran Hongjie , Jiang Hui , Sun Da
Published: April 2024

In this study, we investigated the oxidative mechanisms of nano zero-valent iron (nZVI) enhanced potassium ferrate (K2FeO4), focusing on tributyltin (TBT) and triphenyltin (TPhT) as target pollutants. The addition of nZVI enhanced the degradation of both organic tin compounds by K2FeO4, exhibiting pseudo-first-order kinetics influenced by pH, carbonate, and fulvic acid. nZVI, as a reducing agent, facilitated the generation of stronger oxidizing species Fe (V) and Fe (IV) from K2FeO4 through electron transfer. The presence of hydroxyl radicals (OH) was confirmed by tert-butyl alcohol (TBA) verification. Intermediate products of TBT degradation by nZVI-enhanced K2FeO4 were identified using GC-MS, confirming de-alkylation leading to stepwise oxidation to inorganic tin ions. Due to excessively long Sn-C bonds in diphenyltin, rendering them unstable, Density Functional Theory (DFT) calculations were employed. Results indicated that Fe (IV) and Fe (V) predominantly attacked the Sn-C bonds of TPhT, while OH primarily targeted the benzene ring. HOMO energy levels suggested that Fe (V) was more prone to oxidizing TPhT than Fe (IV). Gibbs free energy calculations demonstrated that, in the presence of Fe (IV) and Fe (V), the energy barrier for breaking bonds and oxidizing into inorganic tin ions decreased, favoring the process over the self-decomposition of TPhT. Additionally, the lower energy barrier for OH indicated an easier degradation of TPhT. This study reveals that nZVI-enhanced K2FeO4 effectively removes TBT and TPhT, contributing to the understanding of the ferrate-mediated degradation mechanism of organic tin compounds. The findings offer insights and theoretical guidance for remediating organic tin pollution in aquatic environments.
Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy
Authors: Adhikarla Vikram , Awuah Dennis , Caserta Enrico , Minnix Megan , Kuznetsov Maxim , Krishnan Amrita , Wong Jefferey Y. C. , Shively John E. , Wang Xiuli , Pichiorri Flavia , Rockne Russell C.
Published: April 2024

Introduction

Cancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies.

Methods

Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies.

Results

Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy.

Discussion

Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.
Changes in the N-glycosylation of porcine immune globulin G during postnatal development
Authors: Zlatina Kristina , Isernhagen Lisa , Galuska Christina E. , Murani Eduard , Galuska Sebastian P.
Published: April 2024

N-glycosylation influences the effectiveness of immune globulin G (IgG) and thus the immunological downstream responses of immune cells. This impact arises from the presence of N-glycans within the Fc region, which not only alters the conformation of IgG but also influences its steric hindrance. Consequently, these modifications affect the interaction between IgG and its binding partners within the immune system. Moreover, this posttranslational modification vary according to the physiological condition of each individual. In this study, we examined the N-glycosylation of IgG in pigs from birth to five months of age. Our analysis identified a total of 48 distinct N-glycan structures. Remarkably, we observed defined changes in the composition of these N-glycans during postnatal development. The presence of agalactosylated and sialylated structures increases in relation to the number of N-glycans terminated by galactose residues during the first months of life. This shift may indicate a transition from passively transferred antibodies from the colostrum of the sow to the active production of endogenous IgG by the pig’s own immune system.
Development of a nano-emulsion based multivalent protein subunit vaccine against Pseudomonas aeruginosa
Authors: Howlader Debaki R. , Mandal Rahul Shubhra , Lu Ti , Maiti Suhrid , Dietz Zackary K. , Das Sayan , Whittier Sean K. , Nagel Aaron C. , Biswas Satabdi , Varisco David J. , Gardner Francesca M. , Ernst Robert K. , Picking William D. , Picking Wendy L.
Published: April 2024

Pseudomonas aeruginosa (Pa) is an opportunistic bacterial pathogen responsible for severe hospital acquired infections in immunocompromised and elderly individuals. Emergence of increasingly drug resistant strains and the absence of a broad-spectrum prophylactic vaccine against both T3SA+ (type III secretion apparatus) and ExlA+/T3SA- Pa strains worsen the situation in a post-pandemic world. Thus, we formulated a candidate subunit vaccine (called ExlA/L-PaF/BECC/ME) against both Pa types. This bivalent vaccine was generated by combining the C-terminal active moiety of exolysin A (ExlA) produced by non-T3SA Pa strains with our T3SA-based vaccine platform, L-PaF, in an oil-in-water emulsion. The ExlA/L-PaF in ME (MedImmune emulsion) was then mixed with BECC438b, an engineered lipid A analogue and a TLR4 agonist. This formulation was administered intranasally (IN) to young and elderly mice to determine its potency across a diverse age-range. The elderly mice were used to mimic the infection seen in elderly humans, who are more susceptible to serious Pa disease compared to their young adult counterparts. After Pa infection, mice immunized with ExlA/L-PaF/BECC/ME displayed a T cell-mediated adaptive response while PBS-vaccinated mice experienced a rapid onset inflammatory response. Important genes and pathways were observed, which give rise to an anti-Pa immune response. Thus, this vaccine has the potential to protect aged individuals in our population from serious Pa infection.
Unravelling B cell heterogeneity: insights into flow cytometry-gated B cells from single-cell multi-omics data
Authors: Pernes Jane I. , Alsayah Atheer , Tucci Felicia , Bashford-Rogers Rachael J. M.
Published: April 2024

Introduction

B cells play a pivotal role in adaptive immunity which has been extensively characterised primarily via flow cytometry-based gating strategies. This study addresses the discrepancies between flow cytometry-defined B cell subsets and their high-confidence molecular signatures using single-cell multi-omics approaches.

Methods

By analysing multi-omics single-cell data from healthy individuals and patients across diseases, we characterised the level and nature of cellular contamination within standard flow cytometric-based gating, resolved some of the ambiguities in the literature surrounding unconventional B cell subsets, and demonstrated the variable effects of flow cytometric-based gating cellular heterogeneity across diseases.

Results

We showed that flow cytometric-defined B cell populations are heterogenous, and the composition varies significantly between disease states thus affecting the implications of functional studies performed on these populations. Importantly, this paper draws caution on findings about B cell selection and function of flow cytometric-sorted populations, and their roles in disease. As a solution, we developed a simple tool to identify additional markers that can be used to increase the purity of flow-cytometric gated immune cell populations based on multi-omics data (AlliGateR). Here, we demonstrate that additional non-linear CD20, CD21 and CD24 gating can increase the purity of both naïve and memory populations.

Discussion

These findings underscore the need to reconsider B cell subset definitions within the literature and propose leveraging single-cell multi-omics data for refined characterisation. We show that single-cell multi-omics technologies represent a powerful tool to bridge the gap between surface marker-based annotations and the intricate molecular characteristics of B cell subsets.
Immunogenicity of COVID-19 booster vaccination in IEI patients and their one year clinical follow-up after start of the COVID-19 vaccination program
Authors: van Leeuwen Leanne P. M. , Grobben Marloes , GeurtsvanKessel Corine H. , Ellerbroek Pauline M. , de Bree Godelieve J. , Potjewijd Judith , Rutgers Abraham , Jolink Hetty , van de Veerdonk Frank L. , van Gils Marit J. , de Vries Rory D. , Dalm Virgil A. S. H. ,   VACOPID Research Group
Published: April 2024

Purpose

Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign.

Methods

This study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections.

Results

After booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer.

Conclusion

Our study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.
Patient-reported assessment of medical care for chronic inflammatory skin diseases: an enterprise-based survey
Authors: Wolk Kerstin , Schielein Maximilian , Maul Julia-Tatjana , Widmayer Fontaine , Wanke Kerstin , Fischmann Wolfgang , Nathan Petra , Sabat Robert
Published: April 2024

Background

Chronic inflammatory skin diseases (CISDs) are among the most common diseases in the Western world. Current estimates of medical care for CISDs are primarily based on surveys among patients in medical care facilities and on health insurance data.

Aim

Survey-based examination to what extent CISD patients in health-aware environment consider their skin disease to be controlled.

Methods

The survey of CISD patients was carried out in 2022 among the employees of a pharmaceutical company located in Germany and Switzerland. Software-based, anonymous, self-reported questionnaires were used.

Results

The number of employees, who answered the questionnaire, was 905. Of these, 222 participants (24.5%) reported having at least one CISD. 28.7% of participants with CISD described their disease as being hardly or not controlled. Regarding the nature of disease, more than one third of participants suffering from hidradenitis suppurativa (HS) or psoriasis fell into the hardly/not controlled category. In contrast, the largest proportion of participants with chronic spontaneous urticaria (43%) or atopic dermatitis (42%) considered their CISD to be completely or well controlled. Only 35.5% of CISD sufferers stated that they were currently under medical care for their skin condition. Being under medical care, however, had no influence on the extent CISD sufferers considered their skin disease to be controlled. The number of active CISD episodes but not the total number of symptomatic days per year was negatively associated with poor disease control (p = 0.042 and p = 0.856, respectively). Poor disease control had a negative effect on the personal and professional lives of those affected, as deduced from its positive association with the extent of daily activity impairment and presenteeism (p = 0.005 and p = 0.005, respectively). Moreover, 41.4 and 20.7% of participants with hardly/not controlled disease stated that their CISD had a moderate and severe or very severe impact on their overall lives (p < 0.001), respectively. A severe or very severe impact of their CISD on their overall life was most commonly reported by participants with HS.

Conclusion

Medical care for CISDs, even in an environment with high socio-economic standard and high health-awareness, still appears to be limited and has a negative impact on individuals and society.
ED50 of remimazolam combined with different doses butorphanol for first trimester artificial abortion
Authors: Chen Jinming , Li Xiaoling , Hu Zilan , Zheng Yuling , Mai Ying , Zhang Zhongqi
Published: April 2024

Introduction

Remimazolam (RMZ) is a novel intravenous sedative drug of ultra-short benzodiazepine. The optimal dose of RMZ plus butorphanol for sedation during first trimester artificial abortion is unknown. Therefore, the present study aimed to evaluate the median effective dose (ED50) of RMZ combined with different doses of butorphanol on the sedative effect for first-trimester artificial abortion.

Methods

Sixty-one female patients were randomly assigned to Group B10 (31 patients) and Group B15 (30 patients). RMZ was administered 5 min after IV butorphanol at doses of 10 μg/kg (Group B10) and 15 μg/kg (Group B15). Cervical dilatation at the time of using a cervical dilating rod, if the patient has body movement and affects the gynecologist’s operation, we define it as “Ineffective.” Therefore, the dose of RMZ was increased in the next patient. Otherwise, it was defined as “Effective,” and the dose of RMZ was reduced in the next patient. According to the pre-experiment, the first dose of RMZ in the first patient was 0.35 mg/kg, and the adjacent geometric dose ratio was 0.9. The centered isotonic regression was performed to determine the ED50 of RMZ. The total RMZ dose administered, recovery time, and anesthesia-related adverse events were all recorded.

Results

The ED50 (90% CI) of RMZ was 0.263 (0.215–0.310) mg/kg in Group B10, and 0.224 (0.191–0.261) mg/kg in Group B15, respectively. The recovery time in Group B10 was significantly shorter than in Group B15 (9.8 ± 2.3 vs. 12.5 ± 3.6 min, p ≤ 0.001). There was no significant difference in the incidence rate of all anesthesia-related adverse events between the two groups (p > 0.05).

Conclusion

The ED50 of RMZ combined with a 10 μg/kg or 15 μg/kg dose of butorphanol was 0.263 and 0.224 mg/kg during painless first trimester artificial abortion. However, RMZ combined with a 10 μg/kg dose of butorphanol seems to have a shorter recovery time.

Clinical trial registration

https://www.chictr.org.cn/bin/project/edit?pid=166623.
Classical and novel properties of Holliday junction resolvase SynRuvC from Synechocystis sp. PCC6803
Authors: Gu Yanchao , Yang Yantao , Kou Chunhua , Peng Ying , Yang Wenguang , Zhang Jiayu , Jin Han , Han Xiaoru , Wang Yao , Shen Xihui
Published: April 2024

Cyanobacteria, which have a photoautotrophic lifestyle, are threatened by ultraviolet solar rays and the reactive oxygen species generated during photosynthesis. They can adapt to environmental conditions primarily because of their DNA damage response and repair mechanisms, notably an efficient homologous recombination repair system. However, research on double-strand break (DSB) repair pathways, including the Holliday junction (HJ) resolution process, in Synechocystis sp. PCC6803 is limited. Here, we report that SynRuvC from cyanobacteria Synechocystis sp. PCC6803 has classical HJ resolution activity. We investigated the structural specificity, sequence preference, and biochemical properties of SynRuvC. SynRuvC strongly preferred Mn2+ as a cofactor, and its cleavage site predominantly resides within the 5′-TG↓(G/A)-3′ sequence. Interestingly, novel flap endonuclease and replication fork intermediate cleavage activities of SynRuvC were also determined, which distinguish it from other reported RuvCs. To explore the effect of SynRuvC on cell viability, we constructed a knockdown mutant and an overexpression strain of Synechocystis sp. PCC6803 (synruvCKD and synruvCOE) and assessed their survival under a variety of conditions. Knockdown of synruvC increased the sensitivity of cells to MMS, HU, and H2O2. The findings suggest that a novel RuvC family HJ resolvase SynRuvC is important in a variety of DNA repair processes and stress resistance in Synechocystis sp. PCC6803.
Carcinogenic effect of human tumor-derived cell-free filtrates in nude mice
Authors: Berlanga-Acosta Jorge , Arteaga-Hernandez Ernesto , Garcia-Ojalvo Ariana , Duvergel-Calderin Dayanis , Rodriguez-Touseiro Marisol , Lopez-Marin Laura , Suarez-Alba Jose , Fuentes-Morales Dasha , Mendoza-Fuentes Osmany , Fernández-Puentes Sheyla , Nuñez-Figueredo Yanier , Guillen-Nieto Gerardo
Published: April 2024

Cancer remains a worldwide cause of morbidity and mortality. Investigational research efforts have included the administration of tumor-derived extracts to healthy animals. Having previously demonstrated that the administration of non-transmissible, human cancer-derived homogenates induced malignant tumors in mice, here, we examined the consequences of administering 50 or 100 µg of protein of crude homogenates from mammary carcinoma, pancreatic adenocarcinoma, and melanoma samples in 6 inoculations per week during 2 months. The concurrent control mice received homogenates of healthy donor-skin cosmetic surgery fragments. Mammary carcinoma homogenate administration did not provoke the deterioration or mortality of the animals. Multiple foci of lung adenocarcinomas with a broad expression of malignity histomarkers coexisting with small cell-like carcinomas were found. Disseminated cells, positive to classic epithelial markers, were detected in lymphoid nodes. The administration of pancreatic tumor and melanoma homogenates progressively deteriorated animal health. Pancreatic tumor induced poorly differentiated lung adenocarcinomas and pancreatic islet hyperplasia. Melanoma affected lungs with solid pseudopapillary adenocarcinomas. Giant atypical hepatocytes were also observed. The kidney exhibited dispersed foci of neoplastic cells within a desmoplastic matrix. Nuclear overlapping with hyperchromatic nuclei, mitotic figures, and prominent nuclear atypia was identified in epidermal cells. None of these changes were ever detected in the control mice. Furthermore, the incubation of zebrafish embryos with breast tumor homogenates induced the expression of c-Myc and HER-2 as tumor markers, contrasting to embryos exposed to healthy tissue-derived material. This study confirms and extends our hypothesis that tumor homogenates contain and may act as vectors for “malignancy drivers,” which ultimately implement a carcinogenesis process in otherwise healthy mice.
Case report: A case of anti-glycine receptor encephalomyelitis triggered by post-transplant or COVID-19 infection?
Authors: Zhang Zhengxue , Zhang Xiang , Dai Mingming , Wu Yingying , You Yong
Published: April 2024

Even though long-term immunosuppressant drugs (ISD) are employed to inhibit immune system activity, enhancing graft functionality and patient survival in solid organ transplantation (SOT), these transplants often lead to immune complications, with post-transplant autoimmune diseases of the central nervous system (CNS) being uncommon. Here, we detail the case of a 66-year-old woman who underwent a renal transplantation 8 months prior, who was admitted with subacute onset of encephalomyelitis, accompanied by headaches, paraplegia, weakness, vomiting, and abdominal pain, with a positive COVID-19 nasopharyngeal swab test 1 month before admission. MRI scans of the brain revealed multiple lesions in the white matter of the bilateral deep frontal lobe, the left temporal lobe and insula lobe. Additionally, there were multiple short segment lesions in the spinal cord and subdural hematoma at T1, T6-T7 posterior. The serum revealed a positive result for GlyR-IgG. Following the administration of corticosteroid and intravenous immunoglobulin, there was a significant improvement in the patient’s symptoms within 2 weeks, and her brain MRI showed a reduction in the lesion. Despite its rarity, we believe this to be the inaugural documentation of anti-GlyR encephalomyelitis occurring during renal transplantation. A full panel of antibodies for autoimmune encephalomyelitis is the key leading to the diagnosis.