bluuebunny/crossref_metadata_2025 huggingface dataset:
ВІДМІННОСТІ ПРИПИНЕННЯ ТРУДОВОГО ДОГОВОРУ ВІД ПОНЯТТЯ ЙОГО ПРИЗУПИНЕННЯ В ПЕРІОД ДІЇ ВОЄННОГО СТАНУ: АКТУАЛЬНІ АСПЕКТИ
Authors: Прогонюк Л. Ю.
Published: April 2023

Статтю присвячено актуальним аспектам пошуку відмінних ознак припинення трудового договору від новели трудового законодавства призупинення трудового договору на період дії воєнного стану. У межах дослідження автор розглядає теоретичні питання як інституту призупинення трудових відносин, так й інституту припинення трудових відносин. Основну увагу при тому приділено виділенню відмінних ознак між цими категоріями через характеристику понятійного апарату, чіткого визначення умов та порядку застосування того чи іншого інституту. Опрацьовано низку нормативно-правових актів, як чинного законодавства, так і нормативно-правові акти Республіки Молдови та Литовської Республіки. Запропоновано звернути увагу на досвід цих країн у розробці питання призупинення трудового договору у проєкті Трудового Кодексу України. Проведено аналіз наукових досліджень провідних спеціалістів науки трудового права, наведено їх найважливіші гіпотези та наукові надбання. Наголошено, що для законності призупинення дії трудового договору в умовах воєнного стану необхідна наявність одночасно кількох умов, як-то: 1) факт збройної агресії та існування правового режиму воєнного стану; 2) абсолютна неможливість надання роботодавцем та виконання працівником роботи. Причому, недоліком відповідної правової норми є відсутність чіткого визначення чи принаймні ознак неможливості виконання сторонами трудового договору своїх обов’язків. Дослідження проблематики здійснювалось завдяки застосуванню методів порівняння, абстракції, аналізу та узагальнення, а також методу системно-структурного дослідження. У висновках визначені недоліки правової норми щодо призупинення дії трудових відносин наголошено на встановлені матеріальної відповідальності роботодавця перед працівником у разі визнання такого призупинення незаконним. Обгрунтовано необхідність внесення змін до трудового законодавства задля гарантування і працівникам права скасувати призупинення дії трудового договору.
АНТИКОРУПЦІЙНА СПЕЦІАЛІЗАЦІЯ В ДІЯЛЬНОСТІ ПРОКУРАТУРИ: ІНСТИТУЦІЙНІ ТА ПРАВОВІ ЗАСАДИ1
Authors: Бондаренко О. С. , Янішевська К. Д. , Миргород-Карпова В. В.
Published: April 2023

В умовах трансформаційних змін, зумовлених євроінтеграційними прагненнями України та фактичним набуттям нашою державою статусу кандидата на вступ до Європейського Союзу, загострюється питання протидії корупції на належному рівні. Антикорупційний підхід не має бути декларативним i повинен передбачати ряд змін інституційного, правового, просвітницького та освітнього характеру. Одним із найбільш важливих аспектів антикорупційних змін стало утворення значної кількості антикорупційних інституцій. Зазначене обумовлене різними управлінськими моделями антикорупційних інституцій та вимогами міжнародних антикорупційних конвенцій, прийнятих у рамках ООН та Ради Європи. Так у структурі органів прокуратури було утворено Спеціалізовану антикорупційну прокуратуру. Враховуючи значущість міжнародного досвіду для протидії корупції, метою статті є вивчення особливостей та значення діяльності спеціалізованих антикорупційних підрозділів прокуратури у зарубіжних державах та моделі організації Спеціалізованої антикорупційної прокуратури в Україні. Методологічний інструментарій дослідження представлений комплексним поєднанням загально-логічних та спеціально-юридичних методів наукового пізнання. Комплексне компонування яких дозволило досягти цілей наукового дослідження. Зокрема, було використано метод аналізу, синтезу, узагальнення, а також формально-юридичний, порівняльно-правовий та інші. З’ясовано, що діяльність антикорупційних інституцій у цілому та окремі аспекти діяльності спеціалізованих антикорупційних підрозділів у структурі органів прокуратури як в Україні, так і за кордоном були предметом наукового інтересу багатьох учених. У статті на основі критичного аналізу висвітлено питання кореляції діяльності спеціальних антикорупційних підрозділів у зарубіжних державах та рівня корупції. Охарактеризовано сутність, значення та рівень успішності діяльності Спеціалізованої антикорупційної прокуратури. Зроблено висновок, що обрана Україною модель організації діяльності спеціального антикорупційного підрозділу в структурі Офісу Генерального прокурора є раціональною та ефективною. Водночас для результативності її діяльності важливим є забезпечення єдності та взаємоузгодженості дій, як у межах системи органів прокуратури України, так і в контексті співпраці антикорупційних інституцій у цілому. Перспективи подальших наукових розвідок вбачаємо в порівняльно-правовій характеристиці результативності основних антикорупційних інституційних моделей.
ВІДПОВІДАЛЬНІСТЬ ВІЙСЬКОВОСЛУЖБОВЦІВ ЗА САМОВІЛЬНЕ ЗАЛИШЕННЯ ВІЙСЬКОВОЇ ЧАСТИНИ АБО МІСЦЯ СЛУЖБИ В УМОВАХ ВОЄННОГО СТАНУ: ОКРЕМА ДУМКА ЩОДО НОВЕЛ У ЗАКОНОДАВСТВІ
Authors: Веселов Ю. М. , Єпринцев П. С.
Published: April 2023

У статті розглянуто нововведення до національного законодавства в частині адміністративної та кримінальної відповідальності за військові правопорушення, пов’язані із самовільним залишенням військової частини або місця служби. Метою дослідження є окреслення теоретичних і прикладних проблем законодавчих змін у частині виключення обставин скоєння окремих військових адміністративних правопорушень в умовах воєнного стану. На підставі ґрунтовного аналізу висловлено низку критичних зауважень наукового та прикладного характеру з приводу окремих нововведень: перспектива перевантаження органів досудового розслідування, прокуратури та судів кримінальними провадженнями за даними фактами військових правопорушень, що може негативно вплинути на якість та своєчасність розгляду даної категорії справ; кваліфікація всіх випадків самовільного залишення військової частини або місця служби в умовах воєнного стану без урахування обставин і тривалості відсутності військовослужбовця на службі за кримінальними нормами порушує принцип пропорційності відповідальності; за умови оформлення та розгляду даних діянь у порядку адміністративно-деліктного провадження (що продовжує мати місце на практиці через малозначність правопорушення), з урахуванням чинної правової регламентації по факту втрачається можливість надавати відповідну правову оцінку цим проступкам в умовах воєнного стану, що насправді має підвищену суспільну небезпеку в порівнянні до типових ситуацій.
ІНТЕГРАЦІЯ СМАРТ-КОНТРАКТІВ НА ОСНОВІ БЛОКЧЕЙНУ В СПОРТИВНЕ ПРАВО ТА НОВА ЮРИДИЧНА ПРАКТИКА
Authors: Діордіца І. В. , Бегма А. П. , Соловйов А. С.
Published: April 2023

У статті автори здійснили дослідження процесів інтеграції смарт-контрактів на основі блокчейну в спортивне право в їх теоретичному та практичному сенсі. Актуальність дослідження обумовлена значним збільшенням інтересу до даного питання у фінансово-правовій та інших сферах людської діяльності. Прогнозується, що блокчейн стане критично важливим для всіх фінансових установ, які працюють над автоматизацією бізнес-процесів. Встановлено, що смарт-контракти на основі блокчейну містять такий самий рівень деталізації, як і фізичні контракти, та роблять те, що не може бути реалізовано за допомогою звичайного контракту: виконують такі завдання, як узгодження цін і моніторинг рівня запасів. Дана можливість замінює дорогі ручні зусилля динамічним автоматизованим відстеженням ланцюгів постачання, рівня запасів і витрат, щоб зменшити витрати та збільшити прибуток. При цьому важливими аспектами дослідження стали акценти щодо: 1) переваг смарт-контрактів на основі блокчейну (висока точність і надійність; оновлення в реальному часі; зменшення кількості посередників; нижча вартість; адаптація до різних бізнес-моделей) та 2) недоліків, оскільки дана технологія перебуває на ранніх стадіях впровадження та потребує розвитку в певних напрямах (швидкість обробки та масштабованість; за-лежність від програмістів; конфіденційність; висока затримка). Доведено, що блокчейн пропонує нові джерела зростання для спортивної індустрії: клуби та спортивні організації можуть удосконалити свої бізнес-моделі, управління квитками та спортсменами може стати все більш оптимізованим і дозволить командам отримувати нові джерела доходу за допомогою токенів фанатів, цифрових сувенірів і монетизації даних. Визначено найактуальніші випадки використання технології блокчейн у спортивній екосистемі, зокрема: фан-токени та залучення фанів; NFT-токени; квитки на ігри; токенізація майбутніх спортсменів і платежі в криптовалюті; управління даними та результативністю спортсмена; тестування на наркотики; потокове передавання; ставки блокчейн. Установлено, що цивілізований світ потребує розвинене спортивне криптопартнерство.
Análisis crítico del modelo de la conexión social propuesto desde la psicoterapia analítica funcional
Authors: Ferro García Rafael , Calvillo Mazarro Manuel , López Bermúdez Miguel Ángel
Published: April 2023

La Psicoterapia Analítica Funcional (FAP) es una terapia contextual. Realiza un análisis funcional de la conducta del cliente dentro de la sesión clínica, aplicando contingencias de reforzamiento natural y el moldeamiento, y establece una equivalencia funcional entre el contexto clínico y la vida diaria del cliente. A pesar de los númerosos estudios que demuestran su eficacia para el tratamiento de trastornos psicológicos de muy diversa índole, su carácter eminentemente funcional e ideográfico, basándose en el estudio de casos clínicos de sujeto único, supone un claro inconveniente a la hora de adaptarse a los sistemas diagnósticos nosológicos y a los criterios de validez (el ensayo controlado aleatorizado y el metaanálisis) mayoritariamente aceptados por la comunidad científica. El presente trabajo expone el Modelo de Conexión Social como una alternativa a las limitaciones de FAP, reconociendo su utilidad clínica. Además, hace un análisis crítico de este modelo,señalando los riesgos de recurrir a términos de nivel medio (consciencia, coraje, amor, intimidad, etc.) y desviar el enfoque funcional e idiográfico característico de FAP.
Barcode demultiplexing of nanopore sequencing raw signals by unsupervised machine learning
Authors: Papetti Daniele M. , Spolaor Simone , Nazari Iman , Tirelli Andrea , Leonardi Tommaso , Caprioli Chiara , Besozzi Daniela , Vlachou Thalia , Pelicci Pier Giuseppe , Cazzaniga Paolo , Nobile Marco S.
Published: April 2023

Introduction: Oxford Nanopore Technologies (ONT) is a third generation sequencing approach that allows the analysis of individual, full-length nucleic acids. ONT records the alterations of an ionic current flowing across a nano-scaled pore while a DNA or RNA strand is threading through the pore. Basecalling methods are then leveraged to translate the recorded signal back to the nucleic acid sequence. However, basecall generally introduces errors that hinder the process of barcode demultiplexing, a pivotal task in single-cell RNA sequencing that allows for separating the sequenced transcripts on the basis of their cell of origin.

Methods: To solve this issue, we present a novel framework, called UNPLEX, designed to tackle the barcode demultiplexing problem by operating directly on the recorded signals. UNPLEX combines two unsupervised machine learning methods: autoencoders and self-organizing maps (SOM). The autoencoders extract compact, latent representations of the recorded signals that are then clustered by the SOM.

Results and Discussion: Our results, obtained on two datasets composed of in silico generated ONT-like signals, show that UNPLEX represents a promising starting point for the development of effective tools to cluster the signals corresponding to the same cell.
Muscle preflex response to perturbations in locomotion: In vitro experiments and simulations with realistic boundary conditions
Authors: Araz Matthew , Weidner Sven , Izzi Fabio , Badri-Spröwitz Alexander , Siebert Tobias , Haeufle Daniel F. B.
Published: April 2023

Neuromuscular control loops feature substantial communication delays, but mammals run robustly even in the most adverse conditions. In vivo experiments and computer simulation results suggest that muscles’ preflex—an immediate mechanical response to a perturbation—could be the critical contributor. Muscle preflexes act within a few milliseconds, an order of magnitude faster than neural reflexes. Their short-lasting action makes mechanical preflexes hard to quantify in vivo. Muscle models, on the other hand, require further improvement of their prediction accuracy during the non-standard conditions of perturbed locomotion. Our study aims to quantify the mechanical work done by muscles during the preflex phase (preflex work) and test their mechanical force modulation. We performed in vitro experiments with biological muscle fibers under physiological boundary conditions, which we determined in computer simulations of perturbed hopping. Our findings show that muscles initially resist impacts with a stereotypical stiffness response—identified as short-range stiffness—regardless of the exact perturbation condition. We then observe a velocity adaptation to the force related to the amount of perturbation similar to a damping response. The main contributor to the preflex work modulation is not the change in force due to a change in fiber stretch velocity (fiber damping characteristics) but the change in magnitude of the stretch due to the leg dynamics in the perturbed conditions. Our results confirm previous findings that muscle stiffness is activity-dependent and show that also damping characteristics are activity-dependent. These results indicate that neural control could tune the preflex properties of muscles in expectation of ground conditions leading to previously inexplicable neuromuscular adaptation speeds.
Towards the controlled enzymatic synthesis of LNA containing oligonucleotides
Authors: Sabat Nazarii , Katkevica Dace , Pajuste Karlis , Flamme Marie , Stämpfli Andreas , Katkevics Martins , Hanlon Steven , Bisagni Serena , Püntener Kurt , Sladojevich Filippo , Hollenstein Marcel
Published: April 2023

Enzymatic, de novo XNA synthesis represents an alternative method for the production of long oligonucleotides containing chemical modifications at distinct locations. While such an approach is currently developed for DNA, controlled enzymatic synthesis of XNA remains at a relative state of infancy. In order to protect the masking groups of 3′-O-modified LNA and DNA nucleotides against removal caused by phosphatase and esterase activities of polymerases, we report the synthesis and biochemical characterization of nucleotides equipped with ether and robust ester moieties. While the resulting ester-modified nucleotides appear to be poor substrates for polymerases, ether-blocked LNA and DNA nucleotides are readily incorporated into DNA. However, removal of the protecting groups and modest incorporation yields represent obstacles for LNA synthesis via this route. On the other hand, we have also shown that the template-independent RNA polymerase PUP represents a valid alternative to the TdT and we have also explored the possibility of using engineered DNA polymerases to increase substrate tolerance for such heavily modified nucleotide analogs.
Research progress of biomass carbon materials as anode materials for potassium-ion batteries
Authors: Li Xiang , Zhou Yimiao , Deng Bin , Li Jiani , Xiao Zuowei
Published: April 2023

Biochar materials have attracted people’s attention because of their environmental friendliness, abundant resources, and the use of waste resources for reuse. As a potassium-ion anode material, biomass char materials synthesized by different methods have broad application prospects. However, due to the problems of low initial magnification and limited potassium-storage capacity, it is necessary to improve the electrochemical performance through modifications, such as atomic doping. Atomic doping is an effective way to improve battery conductivity and potassium storage. In this paper, the synthesis method of biochar as an anode material for potassium-ion batteries and the influence of atomic doping on its modification in recent years are reviewed.
Drug repurposing approach against chikungunya virus: an in vitro and in silico study
Authors: Kasabe Bhagyashri , Ahire Gunwant , Patil Poonam , Punekar Madhura , Davuluri Kusuma Sai , Kakade Mahadeo , Alagarasu Kalichamy , Parashar Deepti , Cherian Sarah
Published: April 2023

The chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes mosquitoes. There are no licenced antivirals or vaccines for treatment or prevention. Drug repurposing approach has emerged as a novel concept to find alternative uses of therapeutics to battle pathogens. In the present study, anti CHIKV activity of fourteen FDA-approved drugs was investigated by in vitro and in silico approaches. Focus-forming unit assay, immunofluorescence test, and quantitative RT-PCR assay were used to assess the in vitro inhibitory effect of these drugs against CHIKV in Vero CCL-81 cells. The findings showed that nine compounds, viz., temsirolimus, 2-fluoroadenine, doxorubicin, felbinac, emetine, lomibuvir, enalaprilat, metyrapone and resveratrol exhibit anti chikungunya activity. Furthermore, in silico molecular docking studies performed by targeting CHIKV structural and non-structural proteins revealed that these drugs can bind to structural protein targets such as envelope protein, and capsid, and non-structural proteins NSP2, NSP3 and NSP4 (RdRp). Findings from in vitro and in silico studies reveal that these drugs can suppress the infection and replication of CHIKV and further in vivo studies followed by clinical trials are warranted.
Changes in the gut microbiota structure and function in rats with doxorubicin-induced heart failure
Authors: Fan Yawen , Liang Lichang , Tang Xinzheng , Zhu Jinxian , Mu Lei , Wang Mengni , Huang Xuecheng , Gong Shenglan , Xu Jinghan , Liu Tianjiao , Zhang Tianfeng
Published: April 2023

Objectives

The rat model of heart failure (HF) induced by doxorubicin (DOX), a broad spectrum and highly effective chemotherapeutic anthracycline with high-affinity to myocardial tissue that causes severe dose-dependent irreversible cardiotoxicity has been widely recognized and applied in HF pathogenesis and drug therapy studies. The gut microbiota (GM) has attracted significant attention due to its potential role in HF, and research in this area may provide beneficial therapeutic strategies for HF. Considering the differences in the route, mode, and total cumulative dose of DOX administration used to establish HF models, the optimal scheme for studying the correlation between GM and HF pathogenesis remains to be determined. Therefore, focusing on establishing the optimal scheme, we evaluated the correlation between GM composition/function and DOX-induced cardiotoxicity (DIC).

Methods

Three schemes were investigated: DOX (at total cumulative doses of 12, 15 or 18 mg/kg using a fixed or alternating dose via a tail vein or intraperitoneal injection) was administered to Sprague Dawley (SD) for six consecutive weeks. The M-mode echocardiograms performed cardiac function evaluation. Pathological changes in the intestine were observed by H&E staining and in the heart by Masson staining. The serum levels of N-terminal pre-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) were measured by ELISA. The GM was analysed by 16S rRNA gene sequencing.

Key findings

Strikingly, based on the severity of cardiac dysfunction, there were marked differences in the abundance and grouping of GM under different schemes. The HF model established by tail vein injection of DOX (18 mg/kg, alternating doses) was more stable; moreover, the degree of myocardial injury and microbial composition were more consistent with the clinical manifestations of HF.

Conclusions

The model of HF established by tail vein injection of doxorubicin, administered at 4mg/kg body weight (2mL/kg) at weeks 1, 3 and 5, and at 2mg/kg body weight (1mL/kg) at weeks 2, 4 and 6, with a cumulative total dose of 18mg/kg, is a better protocol to study the correlation between HF and GM.
Antifungal prophylaxis with nebulized amphotericin-B in solid-organ transplant recipients with severe COVID-19: a retrospective observational study
Authors: Rombauts Alexander , Bodro Marta , Daniel Gumucio Victor , Carbonell Irene , Favà Àlex , Lladó Laura , González-Costello José , Oppenheimer Federico , Castel-Lavilla María Ángeles , Len Oscar , Marquez-Algaba Ester , Nuvials-Casals Xavier , Martínez González Daniel , Lacasa Judith Sacanell , Carratalà Jordi , Sabé Nuría
Published: April 2023

COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a frequent complication in the intensive care unit (ICU). However, little is known about this life-threatening fungal superinfection in solid organ transplant recipients (SOTRs), including whether targeted anti-mold prophylaxis might be justified in this immunosuppressed population. We performed a multicentric observational retrospective study of all consecutive ICU-admitted COVID-19 SOTRs between August 1, 2020 and December 31, 2021. SOTRs receiving antifungal prophylaxis with nebulized amphotericin-B were compared with those without prophylaxis. CAPA was defined according the ECMM/ISHAM criteria. Sixty-four SOTRs were admitted to ICU for COVID-19 during the study period. One patient received antifungal prophylaxis with isavuconazole and was excluded from the analysis. Of the remaining 63 SOTRs, nineteen (30.2%) received anti-mold prophylaxis with nebulized amphotericin-B. Ten SOTRs who did not receive prophylaxis developed pulmonary mold infections (nine CAPA and one mucormycosis) compared with one who received nebulized amphotericin-B (22.7% vs 5.3%; risk ratio 0.23; 95%CI 0.032-1.68), but with no differences in survival. No severe adverse events related to nebulized amphotericin-B were recorded. SOTRs admitted to ICU with COVID-19 are at high risk for CAPA. However, nebulized amphotericin-B is safe and might reduce the incidence of CAPA in this high-risk population. A randomized clinical trial to confirm these findings is warranted.
Contribution of adipocyte Na/K-ATPase α1/CD36 signaling induced exosome secretion in response to oxidized LDL
Authors: Pillai Sneha S. , Pereira Duane G. , Zhang Jue , Huang Wenxin , Beg Mirza Ahmar , Knaack Darcy A. , de Souza Goncalves Bruno , Sahoo Daisy , Silverstein Roy L. , Shapiro Joseph I. , Sodhi Komal , Chen Yiliang
Published: April 2023

Introduction

Adipose tissue constantly secretes adipokines and extracellular vesicles including exosomes to crosstalk with distinct tissues and organs for whole-body homeostasis. However, dysfunctional adipose tissue under chronic inflammatory conditions such as obesity, atherosclerosis, and diabetes shows pro-inflammatory phenotypes accompanied by oxidative stress and abnormal secretion. Nevertheless, molecular mechanisms of how adipocytes are stimulated to secrete exosomes under those conditions remain poorly understood.

Methods

Mouse and human in vitro cell culture models were used for performing various cellular and molecular studies on adipocytes and macrophages. Statistical analysis was performed using Student's t-test (two-tailed, unpaired, and equal variance) for comparisons between two groups or ANOVA followed by Bonferroni's multiple comparison test for comparison among more than two groups.

Results and discussion

In this work, we report that CD36, a scavenger receptor for oxidized LDL, formed a signaling complex with another membrane signal transducer Na/K-ATPase in adipocytes. The atherogenic oxidized LDL induced a pro-inflammatory response in in vitro differentiated mouse and human adipocytes and also stimulated the cells to secrete more exosomes. This was largely blocked by either CD36 knockdown using siRNA or pNaKtide, a peptide inhibitor of Na/K-ATPase signaling. These results showed a critical role of the CD36/Na/K-ATPase signaling complex in oxidized LDL-induced adipocyte exosome secretion. Moreover, by co-incubation of adipocyte-derived exosomes with macrophages, we demonstrated that oxidized LDL-induced adipocyte-derived exosomes promoted pro-atherogenic phenotypes in macrophages, including CD36 upregulation, IL-6 secretion, metabolic switch to glycolysis, and mitochondrial ROS production. Altogether, we show here a novel mechanism through which adipocytes increase exosome secretion in response to oxidized LDL and that the secreted exosomes can crosstalk with macrophages, which may contribute to atherogenesis.
Intracardiac biopsy of cardiac tumors with echocardiographic guidance: Case report
Authors: Zhu Jinyun , Zhang Ning , Ma Qunchao , Jin Luhang , Pan Xiaohong
Published: April 2023

Background

Primary cardiac tumors are very rare, and about 20–30% of them are malignant tumors. Since early signs of cardiac tumors are non-specific, diagnosis can be challenging. There is a lack of the recommended guidelines or standardized strategies for diagnosis and optimal treatment for this disease. As the definite diagnoses of most tumors are made by pathologic confirmation, biopsied tissue is essential in determining the treatment for patients with cardiac tumors. Recently, intracardiac echocardiography (ICE) has been introduced to assist biopsy procedures of cardiac tumors and it provides high-quality imaging.

Case Description

Due to its low prevalence and variable presentation, cardiac malignant tumors usually are easily missed. Hereby, we report three cases of patients who presented with non-specific signs of cardiac disorder and was initially suspended diagnosis as lung infection or cancer. Under the guidance of ICE, cardiac biopsies were successfully on cardiac masses, giving critical data for diagnosis and treatment planning. No procedural complications were obtained in our cases. These cases are intended to highlight the clinical value and importance of ICE-guided biopsy of intracardiac mass.

Conclusions

The diagnosis of primary cardiac tumors relies on the histopathological results. In our experience, using ICE for biopsy of an intracardiac mass is an attractive tool to increase diagnostic results and reduce the risk of cardiac complications associated with inadequate targeting of the biopsy catheters.
WGCNA and molecular docking identify hub genes for cardiac aging
Authors: Ping Ping , Guan Lixun , Ning Chaoxue , Liu Qiong , Zhao Yali , Zhu Xiang , Yang Ting , Fu Shihui
Published: April 2023

Background

Cardiac aging and ageing-related cardiovascular diseases remain increase medical and social burden. Discovering the molecular mechanisms associated with cardiac aging is expected to provide new perspectives for delaying aging and related disease treatment.

Methods

The samples in GEO database were divided into older group and younger group based on age. Age-associated differentially expressed genes (DEGs) were identified by limma package. Gene modules significantly associated with age were mined using weighted gene co-expression network analysis (WGCNA). Protein-protein interaction networks (PPI) networks were developed using genes within modules, and topological analysis on the networks was performed to identify hub genes in cardiac aging. Pearson correlation was used to analyze the association among hub genes and immune and immune-related pathways. Molecular docking of hub genes and the anti-aging drug Sirolimus was performed to explore the potential role of hub genes in treating cardiac aging.

Results

We found a generally negative correlation between age and immunity, with a significant negative correlation between age and b_cell_receptor_signaling_pathway, fc_gamma_r_mediated_phagocytosis, chemokine signaling pathway, t-cell receptor signaling pathway, toll_like_receptor_signaling_pathway, and jak_stat_signaling_pathway, respectively. Finally, 10 cardiac aging-related hub genes including LCP2, PTPRC, RAC2, CD48, CD68, CCR2, CCL2, IL10, CCL5 and IGF1 were identified. 10-hub genes were closely associated with age and immune-related pathways. There was a strong binding interaction between Sirolimus-CCR2. CCR2 may be a key target for Sirolimus in the treatment of cardiac aging.

Conclusion

The 10 hub genes may be potential therapeutic targets for cardiac aging, and our study provided new ideas for the treatment of cardiac aging.
Platelet accumulation in an endothelium-coated elastic vein valve model of deep vein thrombosis is mediated by GPIbα—VWF interaction
Authors: Baksamawi Hosam Alden , Alexiadis Alessio , Vigolo Daniele , Brill Alexander
Published: April 2023

Deep vein thrombosis is a life-threatening disease that takes millions of people's lives worldwide. Given both technical and ethical issues of using animals in research, it is necessary to develop an appropriate in vitro model that would recapitulate the conditions of venous thrombus development. We present here a novel microfluidics vein-on-a-chip with moving valve leaflets to mimic the hydrodynamics in a vein, and Human Umbilical Vein Endothelial Cell (HUVEC) monolayer. A pulsatile flow pattern, typical for veins, was used in the experiments. Unstimulated human platelets, reconstituted with the whole blood, accumulated at the luminal side of the leaflet tips proportionally to the leaflet flexibility. Platelet activation by thrombin induced robust platelet accrual at the leaflet tips. Inhibition of glycoprotein (GP) IIb-IIIa did not decrease but, paradoxically, slightly increased platelet accumulation. In contrast, blockade of the interaction between platelet GPIbα and A1 domain of von Willebrand factor completely abolished platelet deposition. Stimulation of the endothelium with histamine, a known secretagogue of Weibel-Palade bodies, promoted platelet accrual at the basal side of the leaflets, where human thrombi are usually observed. Thus, platelet deposition depends on the leaflet flexibility, and accumulation of activated platelets at the valve leaflets is mediated by GPIbα-VWF interaction.
Changes in oral health-related quality of life before and after dental treatment in 8–12-year-old Costa Rican schoolchildren
Authors: Jiménez-Lobo Juliana , Batista-Cárdenas Daniela , Aguilar-Cubillo Ariadna , Gómez-Fernández Adrián , Ramírez Karol
Published: April 2023

Aims

The aims of this study were to (1) evaluate oral health-related quality of life (OHRQoL) in 8–12-year-old Costa Rican schoolchildren before and after dental treatment and (2) collect clinical and sociodemographic characteristics.

Methods

Schoolchildren completed the Child Oral Health Impact Profile-Short Form (COHIP-SF-19) questionnaire before and after dental treatment. One of the parents was asked to complete a sociodemographic survey. Patients were treated for caries, hypomineralizations, and dental malocclusions. The prevalence of these conditions was assessed from the patient's electronic dental record.

Results

Eighty participants (39 male and 41 female, average age: 9.4 ± 1.0 years) were recruited. The prevalence of dental caries was 56.1% with a mean deft and DMFT score of 3.15 ± 0.96 and 2.22 ± 0.77, respectively. The prevalence of hypomineralization and dental malocclusions was 53.7% and 82.9%, respectively. The Simplified Oral Hygiene Index before treatment was 1.45 ± 0.45 and after was 1.42 ± 0.43. The mean COHIP-SF-19 total score decreased from 53.7 ± 7.8 before dental treatment to 31.4 ± 4.2 after treatment. Improvements in all subdomains were also observed. Regarding sociodemographic characteristics, 65% of the patients lived in San José, Costa Rica's capital city, and 56.3% of the studied population belonged to a low-income family. Most parents did not complete high school. Regarding the number of family members living in the same house as the patient, an average of four people was reported. In relation to family structure, 58.8% of the children's parents lived together, either married or free union. As for household ownership, 53.8% of parents reported owning their house, 36.3% lived in a rented house, and 10% lived in a borrowed home.

Conclusion

The prevalence of caries, hypomineralizations, and dental malocclusions were high before dental treatment. Reported sociodemographic characteristics unlikely changed after dental treatment, suggesting dental care played a pivotal role in improving self-perceptions of oral health and quality of life in our clinical setting.
The relationships between thyroid functions of short-term rapid hypothyroidism and blood lipid levels in post-thyroidectomy patients of differentiated thyroid cancer
Authors: Yao Jinming , Zhao Junyu , Liu Jing , Jiang Shan , Guo Siyi , Xu Lusi , Zhang Xinzhong , Sheng Qiqi , Wang Kaili , Liao Lin , Dong Jianjun
Published: April 2023

Objective

To explore the relationship between short-term rapid hypothyroidism and blood lipid levels in patients with differentiated thyroid cancer (DTC).

Methods

Seventy-five DTC patients scheduled to receive radioactive iodine ablation were enrolled. Levels of thyroid hormone and serum lipids were tested at two time points: the euthyroid before thyroidectomy, and the hypothyroid (off thyroxine). Then the collected data were analyzed.

Results

Totally 75 DTC patients enrolled, among them, 5o were female (66.67%) and 25 were male (33. 33%), with an average age of 52.24 ± 1.24 years old. The short-term rapid severe hypothyroidism induced by thyroid hormone withdrawal significantly aggravated dyslipidemia, particularly in patients with dyslipidemia before thyroidectomy (All P < 0.01). However, there was no significant differences between blood lipid levels with different thyroid stimulating hormone (TSH) levels. And our study showed significant negative correlations between free triiodothyronine levels and the changes from euthyjroidism to hypothyroidism in total cholesterol (r=-0.31, P=0.03), triglycerides (r=-0.39, P=0.006), high density lipoprotein-cholesterol (HDL-C) (r=-0.29, P=0.042), and significant positive correlations between free thyroxine and the changes of HDL-C (r=-0.32, P=0.027) were identified in females, however, which were not observed in males.

Conclusion

Short-term rapids severe hypothyroidism caused by thyroid hormone withdrawal can lead to rapid significant changes in blood lipid levels. It is necessary to pay attention to dyslipidemia and its long-term effects after thyroid hormone withdrawal, especially in patients with dyslipidemia before thyroidectomy.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT03006289?term=NCT03006289&draw=2&rank=1, identifier NCT03006289.
Vitamin D deficiency linked to abnormal bone and lipid metabolism predicts high-risk multiple myeloma with poorer prognosis
Authors: Bao Li , Wang Yu-tong , Lu Min-qiu , Chu Bin , Shi Lei , Gao Shan , Fang Li-juan , Xiang Qiu-qing , Ding Yue-hua , Liu Xi , Zhao Xin , Wang Meng-zhen , Chen Yuan , Hu Wei-kai
Published: April 2023

Purpose

Vitamin D deficiency is frequent in patients with multiple myeloma (MM), however, its prognostic relevance in MM was rather inconclusive. We first investigated the association of vitamin D deficiency with abnormal bone and lipid metabolism in newly diagnosed multiple myeloma (NDMM), and next assessed the impact of serum ratio of vitamin D to carboxy-terminal telopeptide of type I collagen (β-CTX) on progression-free survival (PFS) and overall free survival (OS) in patients with NDMM.

Methods

The data of 431 consecutive patients with NDMM at Beijing Jishuitan Hospital from September 2013 to December 2022 were collected and retrospectively reviewed through our electronic medical record system. The measurement of 25-hydroxyvitamin D in the blood is an indicator of an individual’s overall vitamin D status.

Results

The serum levels of vitamin D were negatively correlated with β-CTX in NDMM patients. Of note, positive correlation between vitamin D and cholesterol levels in the serum was found in this study. The cohort (n = 431) was divided into two groups based on the serum ratio of vitamin D to β-CTX. Compared to the group with a higher vitamin D to β-CTX ratio, the group with a lower vitamin D to β-CTX ratio (n = 257, 60%) exhibited hypocholesterolemia, inferior PFS and OS, along with increased cases of ISS stage-III and R-ISS stage-III, a higher number of plasma cells in the bone marrow, and elevated serum calcium levels. Consistent with this, multivariate analysis confirmed that the vitamin D to β-CTX ratio was an independent unfavorable indicator for survival in NDMM patients.

Conclusion

Our data demonstrated the ratio of vitamin D to β-CTX in the serum is a unique biomarker for NDMM patients to identify the high-risk cases with poor prognosis, which is superior to vitamin D itself for predicting PFS and OS in NDMM. Also, it is worth mentioning that our data on the connection between vitamin D deficiency and hypocholesterolemia might help clarify novel mechanistic aspects of myeloma development.
Ecological strategies of Hyphantria cunea (Lepidoptera: Arctiidae) response to different larval densities
Authors: Zhao XuDong , Geng YiShu , Hu TianYi , Xie ChuXia , Xu WenXuan , Zuo Zhuang , Xue MingYu , Hao DeJun
Published: April 2023

Population density is an essential factor affecting the life history traits of insects and their trade-off relationships, as increasing density intensifies intraspecific competition. It decreases the average resources available to individuals within a population, affecting their morphology, physiology, behavior, and fitness. The fall webworm, Hyphantria cunea (Drury) (Lepidoptera: Arctiidae), has been an invasive pest of forest trees, ornamental plants, and fruit trees in China for many years. The larvae have a typical aggregation habit before the fourth instar and keep spitting silk to gather the damaged leaves into silk webs. However, the fitness of H. cunea in response to population density remains unclear. In this study, the critical biological parameters, food utilization, and population parameters of H. cunea in response to different rearing densities were investigated. The results showed that under high population density, H. cunea larvae showed better performance, with faster development, higher survival rates, and shorter generation time, but pupal weight and female fecundity decreased as population density increased. In contrast, for larvae raised in low density, the developmental period was prolonged, and mortality was increased, while higher food utilization, greater body size, and female fecundity were observed. Both males and females had similar development strategies in response to the density, but females may be more resistant to crowding than males. In conclusion, H. cunea could adopt different ecological strategies against the stress of density. High population densities result in shorter generation cycles and higher survival rates. Conversely, the low-density generation period becomes longer but with greater fecundity. The results may help determine the possible outbreak mechanism and develop effective population monitoring and forecasting measures for H. cunea.
Short exposure to photo-oxidative damage triggers molecular signals indicative of early retinal degeneration
Authors: Wooff Yvette , Cioanca Adrian V. , Wills Elly , Chu-Tan Joshua A. , Sekar Rakshanya , Natoli Riccardo
Published: April 2023

Introduction

Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, currently affecting over 350 billion people globally. For the most prevalent late-stage form of this disease, atrophic AMD, there are no available prevention strategies or treatments, in part due to inherent difficulties in early-stage diagnosis. Photo-oxidative damage is a well-established model for studying inflammatory and cell death features that occur in late-stage atrophic AMD, however to date has not been investigated as a potential model for studying early features of disease onset. Therefore, in this study we aimed to determine if short exposure to photo-oxidative damage could be used to induce early retinal molecular changes and advance this as a potential model for studying early-stage AMD.

Methods

C57BL/6J mice were exposed to 1, 3, 6, 12, or 24h photo-oxidative damage (PD) using 100k lux bright white light. Mice were compared to dim-reared (DR) healthy controls as well as mice which had undergone long periods of photo-oxidative damage (3d and 5d-PD) as known timepoints for inducing late-stage retinal degeneration pathologies. Cell death and retinal inflammation were measured using immunohistochemistry and qRT-PCR. To identify retinal molecular changes, retinal lysates were sent for RNA sequencing, following which bioinformatics analyses including differential expression and pathway analyses were performed. Finally, to investigate modulations in gene regulation as a consequence of degeneration, microRNA (miRNA) expression patterns were quantified using qRT-PCR and visualized using in situ hybridization.

Results

Short exposure to photo-oxidative damage (1-24h-PD) induced early molecular changes in the retina, with progressive downregulation of homeostatic pathways including metabolism, transport and phototransduction observed across this time-course. Inflammatory pathway upregulation was observed from 3h-PD, preceding observable levels of microglia/macrophage activation which was noted from 6h-PD, as well as significant photoreceptor row loss from 24h-PD. Further rapid and dynamic movement of inflammatory regulator miRNA, miR-124-3p and miR-155-5p, was visualized in the retina in response to degeneration.

Conclusion

These results support the use of short exposure to photo-oxidative damage as a model of early AMD and suggest that early inflammatory changes in the retina may contribute to pathological features of AMD progression including immune cell activation and photoreceptor cell death. We suggest that early intervention of these inflammatory pathways by targeting miRNA such as miR-124-3p and miR-155-5p or their target genes may prevent progression into late-stage pathology.
TLR7 modulates extramedullary splenic erythropoiesis in P. yoelii NSM-infected mice through the regulation of iron metabolism of macrophages with IFN-γ
Authors: Li Jiajie , Liu Lin , Xing Junmin , Chen Dianhui , Fang Chao , Mo Feng , Gong Yumei , Tan Zhengrong , Liang Guikuan , Xiao Wei , Tang Shanni , Wei Haixia , Zhao Shan , Xie Hongyan , Pan Xingfei , Yin Xiaomao , Huang Jun
Published: April 2023

Splenomegaly is a prominent clinical manifestation of malaria and the causes remain incompletely clear. Anemia is induced in malaria and extramedullary splenic erythropoiesis is compensation for the loss of erythrocytes. However, the regulation of extramedullary splenic erythropoiesis in malaria is unknown. An inflammatory response could facilitate extramedullary splenic erythropoiesis in the settings of infection and inflammation. Here, when mice were infected with rodent parasites, Plasmodium yoelii NSM, TLR7 expression in splenocytes was increased. To explore the roles of TLR7 in splenic erythropoiesis, we infected wild-type and TLR7-/- C57BL/6 mice with P. yoelii NSM and found that the development of splenic erythroid progenitor cells was impeded in TLR7-/- mice. Contrarily, the treatment of the TLR7 agonist, R848, promoted extramedullary splenic erythropoiesis in wild-type infected mice, which highlights the implication of TLR7 on splenic erythropoiesis. Then, we found that TLR7 promoted the production of IFN-γ that could enhance phagocytosis of infected erythrocytes by RAW264.7. After phagocytosis of infected erythrocytes, the iron metabolism of RAW264.7 was upregulated, evidenced by higher iron content and expression of Hmox1 and Slc40a1. Additionally, the neutralization of IFN-γ impeded the extramedullary splenic erythropoiesis modestly and reduced the iron accumulation in the spleen of infected mice. In conclusion, TLR7 promoted extramedullary splenic erythropoiesis in P. yoelii NSM-infected mice. TLR7 enhanced the production of IFN-γ, and IFN-γ promoted phagocytosis of infected erythrocytes and the iron metabolism of macrophages in vitro, which may be related to the regulation of extramedullary splenic erythropoiesis by TLR7.
A novel vaccine formulation candidate based on lipooligosaccharides and pertussis toxin against Bordetella pertussis
Authors: Gao Jingjing , Huang Linlin , Luo Shuquan , Qiao Ruijie , Liu Fanglei , Li Xin
Published: April 2023

Pertussis is a severe human respiratory tract infectious disease caused by Bordetella pertussis that primarily affects infants and young children. However, the acellular pertussis vaccine currently administered can induce antibody and Th2 immune responses but fails to prevent the nasal colonization and transmission of B. pertussis, causing a resurgence of pertussis, so improved pertussis vaccines are urgently needed. In this study, we created a two-component pertussis vaccine candidate containing a conjugate prepared from oligosaccharides and pertussis toxin. After demonstrating the ability of the vaccine to induce a mixed Th1/Th2/Th17 profile in a mouse model, the strong in vitro bactericidal activity and IgG response of the vaccine were further demonstrated. In addition, the vaccine candidate further induced efficient prophylactic effects against B. pertussis in a mouse aerosol infection model. In summary, the vaccine candidate in this paper induces antibodies with bactericidal activity to provide high protection, shorten the duration of bacterial existence, and further reduce disease outbreaks. Therefore, the vaccine has the potential to be the next generation of pertussis vaccines.
Proteomic profiling of extracellular vesicles in synovial fluid and plasma from Oligoarticular Juvenile Idiopathic Arthritis patients reveals novel immunopathogenic biomarkers
Authors: Raggi Federica , Bartolucci Martina , Cangelosi Davide , Rossi Chiara , Pelassa Simone , Trincianti Chiara , Petretto Andrea , Filocamo Giovanni , Civino Adele , Eva Alessandra , Ravelli Angelo , Consolaro Alessandro , Bosco Maria Carla
Published: April 2023

Introduction

New early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients.

Methods

Fourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples.

Results

We first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gender-matched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PL-derived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups.

Discussion

These data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease.