bluuebunny/crossref_metadata_2025 huggingface dataset:
Penerapan Mengkonsumsi Air Rebusan Daun Sirsak Terhadap Penurunan Kadar Asam Urat Pada Lansia: Case Study
Authors: Retnaningsih Dwi , Amalia Rizki
Published: April 2023

Background: Uric acid is an inflammation of the joints caused by high purines in the blood which causes pain in the joints. This gout disease often attacks the elderly, the prevalence in Central Java who suffers from uric acid is around 5.1%, gout in Central Java is the second disease that is often suffered by the elderly. One of the non-pharmacological treatments for gout sufferers is soursop leaves. Soursop leaves contain flavonoids and alkaloids which are antioxidants. Purpose: This study aims to determine the application of consuming boiled water of soursop leaves to decrease uric acid levels in the blood of the elderly in Bandungsari Village, Tambangan Village, Mijen District, Semarang City. Methods: The study used a descriptive method with a case approach to elderly people suffering from gout from 27 July to 2 August 2020. The instrument used was a data observation sheet using an interview, measuring uric acid using a measuring device for uric acid levels in the blood (mg / dL). The target is the elderly, giving soursop leaf therapy is given for 7 days, 2x a day in the morning and in the evening as much as 200ml. Results: The average value of uric acid levels before intervention (pre-test) was 8.7 - 9.0 mg / dl and the uric acid levels after intervention (posttest) were 5.5 - 5.8 mg / dl. Conclusion: this study proved to be effective in consume boiled water soursop leaf decoction to reduce uric acid levels in the blood.
Penerapan Terapi Relaksasi Benson Terhadap Penurunan Nyeri Pada Pasien Kanker Di Yayasan Kanker Inisiatif Zakat Indonesia Semarang
Authors: Fatmawati Diyah Ayu , Sugianto Emilia Puspisatari
Published: April 2023

Nyeri telah menjadi keluhan utama yang paling sering dirasakan oleh penderita kanker. Salah satu cara mengatasi nyeri pada pasien kanker dengan terapi non farmakologi yaitu pemberian terapi relaksasi benson yang dapat menghambat kegiatan saraf simpatis yang kemudian bisa menurunkan konsumsi oksigen oleh tubuh yang kemudian akan membuat otot – otot tubuh menjadi lebih santai dan memicu timbulnya rasa tenang serta nyaman. Tujuan studi kasus ini menyusun resume asuhan keperawatan dalam pemberian terapi relaksasi benson untuk mengurangi nyeri pada pasien kanker di yayasan kanker IZI Semarang. Metode penelitian ini adalah deskriptif dengan metode studi kasus pendekatan asuhan keperawatan penerapan relaksasi benson untuk mengurangi nyeri pada pasien kanker. Responden penelitian ini adalah 2 pasien dewasa dengan penyakit kanker yang merasakan nyeri dengan skala 3 – 6 (nyeri ringan hingga nyeri sedang). Hasil studi kasus menunjukkan bahwa terjadi penurunan nyeri kepada kedua responden dimana pada responden I merasakan nyeri dengan skala awal 6 berkurang menjadi 2 dan pada responden II merasakan nyeri dengan skala awal 4 berkurang menjadi 2 setelah diberikan terapi relaksasi benson selama 3 hari. Kesimpulan dari penelitian ini adalah terapi relaksasi benson mampu menurunkan nyeri pada pasien kanker dengan skala ringan hingga sedang.
Dukungan Emosional Dalam Perawatan Diabetes Mellitus Di Puskesmas Karangsambung
Authors: Yuwono Podo , Erna Ernawati , Marsito Marsito , Wardani Nada Rahma
Published: April 2023

Penyakit Diabetes Mellitus (DM) mengalami peningkatan ditiap tahunnya, kondisi ini memerlukan penatalaksanaan yang serius untuk mencegah komplikasi. Waktu perawatan yang cukup lama derdampak pada fisik dan psikologis penderita DM. Dampak psikologis muncul akibat beban dan kehawatiran terhadap perawatan, serta akses perawatan penyakit yang diderita. Dukungan emosional keluarga diperlukan dalam mengatasi kekhawatiran, beban emosional, dan support sistem untuk menurunkan tingkat stress pada penderita DM tipe 2 dalam pengobatan. Untuk mengetahui dukungan emosional dalam perawatan DM tipe 2 diPuskesmas Karangsambung. Penelitian ini menggunakan metode deskriptiff dengan pendekatan survey. Jumlah sampel 63 responden menggunakan teknik purposive sampling. Pengambilan data menggunakan kuesioner dukungan emosional keluarga. Penderita DM sebagian besar berjenis kelamin perempuan dengan usia lebih dari 63 tahun, dan semua responden berstatus menikah. Tingkat pendidikan, responden sebagian besar berpendidikan SD. Hasil dukungan emosional keluarga pada penderita Diabetes Mellitus menunjukkan bahwa sebagian besar responden memiliki dukungan emosional kategori cukup. Hasil penelitian ini menunjukkan dukungan emosional keluarga dalam perawatan diabetes mellitus pada kategori cukup, diharapkan membantu dalam pengendalian emosi berpengaruh pada semangat dalam perawatan diabetes mellitus.
Hubungan Pengunaan Gadget Terhadap Interaksi Sosial dan Kecemasan (Nomophobia) pada Remaja Di RW 02 Dusun Keling
Authors: Juwariyah Siti , Sari Ni Made Ayu Wulan , Amalia Putri
Published: April 2023

Interaksi sosial merupakan hubungan yang erat kaitannya dengan hubungan antar individu. Interaksi sosial individu ini terjadi saat individu satu dengan individu yang lain saling bertemu, berjabat tangan, saling berbicara dan saling mempengaruhi dalam pikiran dan tindakan. Seseorang menjadi sulit bertahan hidup jika tidak menjalin interaksi sosial. Dampak negatif penggunaan gadget yang ditimbulkan ini dapat menyebabkan remaja menjadi sering cemas dan tegang, bahkan dampaknya juga dapat menyerang mental para remaja dan mereka cenderung menjadi pribadi yang penakut dan tidak percaya diri, karena kecanduan gadget ini, para remaja menjadi tidak memiliki banyak teman berbicara. Tujuan penelitian ini untuk menganalisis hubungan penggunaan gadget terhadap interaksi sosial dan kecemasan (normophobia). Metode penelitian menggunakan desain penelitian deskriptif analitik dengan pendekatan cross sectional. Hasil penelitian di dapatkan hasil analisis statistik dengan uji Chi Square untuk menilai hubungan penggunaan gadget terhadap interaksi sosial pada remaja, didapatkan nilai ⍴-value 0,006 (⍴<0,05) sehingga dapat disimpulkan bahwa ada hubungan antara penggunaan gadget terhadap interaksi sosial pada remaja. Uji Chi square untuk menilai hubungan penggunaan gadget dengan kecemasan nomophobia di dapatkan nilai ⍴-value 0,023 (⍴<0,05) yang berarti terdapat hubungan antara penggunaan gadget terhadap nomophobia pada remaja.   Semakin sering gadget mendampingi penggunanya dalam kehidupan sehari-hari maka semakin tinggi tingkat kecemasan yang dialami ketika remaja tidak memiliki akses terhadap gadget nya. Faktor yang mempengaruhi kecemasan (nomophobia) selain penggunaan gawai adalah kontrol diri. Kontrol diri yang baik akan menjauhkan seseorang dari kecanduan pada gadget, dan tentunya individu akan terhindar dari masalah kecemasan bila berada jauh dari gadget atau kecemasan (nomophobia). Kontrol diri yang baik akan membuat individu mengatur penggunaan gadget nya agar sesuai dengan kebutuhan dan tidak berlebihan.
Le Roman graphique face aux tragédies contemporaines: le cas de Lamia Ziadé et de Zeina Abirached
Authors: Bernard Isabelle
Published: April 2023

This article explores the theme of war in the main graphic novels of Lamia Ziadé and Zeina Abirached, two Franco-Lebanese artists. Following a tripartite plan, it scrutinizes the pictorial and scriptural aesthetics of the artists in Bye Bye Babylond (2010), Ô nuit, Ô mes yeux (2015) and Ma très grande mélancolie arabe (2017) by Ziadé and in Le Jeu des hirondelles: mourir partir revenir (2007), Je souviens: Beirut (2008) and Prendre refuge (2018) by Abirached. The article examines each author’s approach to the history of the Middle East, especially that of Lebanon, as well as the impact of the so-called ‘duty of memory’ on bandes dessinés that manifest a clear autobiographical temptation.
Réinventer le toucher dans La Démangeaison de Laurence Nobécourt
Authors: Carlini Versini Dominique
Published: April 2023

This article examines the question of touch in Laurence Nobécourt's La Démengeaison. It seeks to connect Nobécourt's text to recent research on the tactile and more broadly the haptic function of literature. In this article, I will show that skin forms a border in the text, which prevents touch and contact with the world. I will discuss firstly the ways in which the surface/depth paradigm is applied to the untouchable skin of the narrator, excluding her from humanity. Thus, in the second part of my analysis, I will reflect on the ways in which the skin's touchability is reconfigured through the narrator's compulsive itching, and particularly through the exploration of the skin's erogenous dimension. Although this reconfiguration fails in the diegesis and leads only to violence, I will argue that the text succeeds in its haptic aesthetics, and its attempt to touch the reader.
Scientific justification of the need for balanced development of medicinal plant growing
Authors: Drebot O. , Zaptalova A.
Published: April 2023

Medicinal plant growth plays a significant role in the development of the national economy as a component of the processing industry, agriculture and forestry nowadays. Its resource base is a valuable natural resource, an indispensable functional part of the biosphere, and the basis for maintaining the potential of human health. An important aspect of balanced development is the preservation of medicinal plant resources in the natural conditions of their growth to preserve the species composition of commodity products and the biological diversity of the ecosystem. The global trend, including Ukrainian, testifies to the rapid increase in the importance of preserving the species diversity of the natural fauna and wild herbs in particular. There are two directions of medicinal plant cultivation: the use of natural plant resources (the collection of wild species) and the cultivation of medicinal plants. The specificity of the development of this industry directly depends on the way of its management for the production of medicinal plant material, about 160 species of wild plants and about 60 species of cultivated medicinal plants are currently used. That is, over 70% of medicinal plants are wildlife, and they constitute the fund of comprehensive renewable resources of the state that are harvested in Ukraine, ad this, in turn, attaches great importance to this area of harvesting of medicinal plants, since it is predominant. The following research methods were used to perform the tasks set in the work: economic-statistical, abstract-logical, system-structural and comparative, graphic and design-constructive, and others like that. The current state of medicinal plant growing shows a significant gap in production processes, logistics, environmental management, certification, and other financial and organizational aspects. Solving of these issues will contribute to the development of the greening agriculture, the development of rural areas, the stabilization of the volume of cultivation of medicinal plants, and the regulation of market relations for the production of medicinal plants. Additional attention needs to be paid to the systematization of priorities, and search for ways to optimize the direction of development of medicinal plant growth in order to balance. In particular, taking into account the ecological, economic, and social features of the development of this industry involves solving the problems of preserving the natural resources of medicinal plants, the instability of the volumes of their harvesting and growing, the low weight of environmentally clean (from chemical and radiation pollution) quality of products that meet the quality requirements for its certification, as well as the low level of innovation implementation in the development of Ukrainian industry.
The Relationship Between Antisemitism and COVID-19 Conspiracy on Twitter
Authors: Garner Grace , McGrann Madeleine , Klug Daniel , Kranson Rachel , Yoder Michael Miller
Published: April 2023

Social media platforms are known to foster extremist rhetoric and ideologies, including antisemitism. Antisemitic conspiracy theories are often spread via mainstream social media platforms, including Twitter, especially during times of civic unrest. The COVID-19 pandemic has created an opportunity for the alignment of long-standing antisemitic conspiracies with an international health crisis. This paper applies a mixed-methods approach of data analysis and qualitative coding to examine connections between COVID-19 conspiracy theories and antisemitism in tweets in the U.S. We identify six prominent categories of COVID-19 conspiracy present on Twitter, each of which overlaps with common themes seen in antisemitic conspiracies. This conspiratorial content may be less likely to violate social media hate speech policies but nonetheless contributes to extremist discourse. [Note: this is a full paper to accompany the presentation at the International Communication Associations (ICA) Conference 2023.]
Safety of pedestrian on the road in the dark time of the day in the conditions of rolling blackouts and emergency power outages in Ukraine
Authors:   SE “State Road Transport Research Institute”, Gorpyniuk Andrii , Gorpyniuk Lyudmyla , Taraban Serhii , Variukhno Serhii ,   SE “State Road Transport Research Institute”
Published: April 2023

The issue of ensuring the safety of pedestrians during their movement in the dark, in particular in the absence of street lighting (in connection with rolling blackouts and emergency power outages caused by massive Russian missile attacks on the energy infrastructure of Ukraine) was considered, with the coverage of this aspect traffic safety, like the behavior of pedestrian. An analysis of the experience of European countries in the issue of pedestrian safety at night has been carried out. In particular, it was found out that in the legislation of certain European countries (in particular, such as Norway, Great Britain, Finland, Lithuania, Latvia, Estonia, the Czech Republic), norms are defined regarding the mandatory use of light-reflecting elements (flickers) by pedestrians in the dark. At the same time, the factors affecting the risk of traffic accidents in conditions of insufficient visibility were considered, in particular, such as insufficient lighting or the complete absence of road lighting, pedestrians not using light-reflecting elements (flickers) or bright clothing, especially at dusk and in night time. Recommendations were also made regarding possible actions to strengthen the safety of pedestrians at the national level during their movement in the dark, in particular in the part related to the introduction of changes to the tasks and measures for the implementation of the State program for improving the level of road safety in Ukraine for the period until 2023 of the year, approved by the Resolution of the Cabinet of Ministers of Ukraine dated 21.12.2020 No. 1287 (as amended by the Resolution of the Cabinet of Ministers of Ukraine dated 12.07.2021 No. 706), paying due attention to measures aimed at improving pedestrian safety. Keywords: car, traffic safety, pedestrian, light-reflecting element, flicker.
Improving field legume nodulation by crushing nodules onto seeds: implications for small-scale farmers
Authors: Pudasaini Roshan , Hewedy Omar A. , Raizada Manish N.
Published: April 2023

One billion people globally suffer from protein (amino acid) malnutrition. Grain legumes represent a solution. They recruit symbiotic rhizobia bacteria from soil into root nodules, where the rhizobia convert atmospheric nitrogen gas (N2) into ammonia (NH3) which serves as a building block for chlorophyll and protein. However, when a legume species is newly introduced to a region, yields can be low due to incompatible soil rhizobia. Millions of subsistence legume farmers can benefit from inoculation with exotic rhizobia bacteria, but many subsistence farmers especially in Africa do not benefit from commercial inoculants due to real-world constraints. Here, in a sequential series of indoor and outdoor experiments, we show that root nodules (rhizobia habitats) can be harvested and crushed onto legume seeds, ultimately improving nodulation and chlorophyll under field conditions. 16S rRNA metagenomic sequencing confirmed that nodule crushing onto seeds effectively transferred rhizobia to next-generation nodules. Therefore, nodule crushing represents a simple method to diffuse elite rhizobia strains. However, exotic rhizobia come with risks and limitations. Therefore, in addition to diffusing elite rhizobia, we propose that this simple, decentralized technology can also empower smallholders to improve indigenous strains or indigenize exotic strains by repeated nodule crushing from healthy plants.
Statistical analysis of ionospheric vertical total electron content anomalies before global Mw≥6.0 shallow earthquakes during 2000–2020
Authors: Ma Yifang , Zhou Xiaohui , Yang Yilin , Hu Leyin , Dong Hongyan , Yan Rui
Published: April 2023

To quantitatively investigate the relationship between earthquakes and ionospheric anomalies, this paper presents a statistical study of pre-earthquake vertical total electron content (VTEC) variations. A total of 1522 shallow (≤60 km) strong (Mw≥6.0) earthquakes in the global area during 2000-2020 are selected, and classified according to different magnitudes, latitudes and focal depths. A quartile-based process with different lengths of sliding windows, equaling 10 days, 15 days and 27 days, respectively, has been utilized to detect VTEC anomalies. The abnormal level is first defined, and then VTEC anomalies occurrence probabilities (Po) and occurrence rates (PE) within 1-10 days before 1522 earthquakes have been calculated. Besides, VTEC anomalies occurrence rates of the background days (PN) are also calculated. The results show that the significant correlation between Po and epicentral latitudinal locations could be observed within 1-10 days before earthquakes. The values of Po increase with larger magnitudes in the equatorial and low-latitude regions, but decrease with greater magnitudes in the mid- and high-latitude regions to some degree. Within 1-5 days before earthquakes, the overall trend of PE shows an increase with larger magnitudes, but the correlation between the values of PE and magnitudes is relatively weak in the southern mid- and high-latitude regions. There is no evident causality between PN and the magnitude, and most of the values of PE/PN are larger than 1, indicating that VTEC anomalies within a few days before earthquakes are probably related with the forthcoming earthquakes. Moreover, when the abnormal level exceeds 60%, different sliding window lengths have a significant impact on the values of Po and PE in the mid- and high-latitude regions. In particular, there are obvious systematic deviations between the values of Po obtained from different sliding windows in the southern mid- and high-latitude regions. However, the selection of the optimal sliding window needs to be further studied.
Numerical simulation inversion of creep laws of composite salt layers based on reaming while drilling
Authors: Li Shiyuan , Li Chenglong , Chen Zhaowei , Zhai Wenbao , Chen Xuefeng , Cao Jiawei
Published: April 2023

The composite salt layer of the Kuqa piedmont zone in the Tarim Basin is characterized by deep burial, complex tectonic stress, and interbedding between salt rocks and mudstone. Drilling such salt layers is associated with frequent salt rock creep and inter-salt rock lost circulation, which results in high challenges for safe drilling. Especially, the drilling and completion processes of the salt-gypsum layers of one typical group are found with frequent downhole accidents and complex issues, such as hole shrinkage, sticking, well kick, and lost circulation, which leads to high difficulties in delivering desirable cementing quality and severely hinders the subsequent safe rapid drilling. Reaming while drilling can effectively enlarge the wellbore diameter, provide extra tolerance for creep shrinkage of salt layers, and ultimately help to shorten drilling time, reduce accidents and complex issues, and improve the lifecycle of wells. In this research, a numerical simulation method was developed to invert the creep laws of composite salt layers, based on reaming while drilling. It is generally believed that the dislocation creep mechanism is dominant in coarse-grained salt rocks, while the pressure solution creep mechanism is dominant in fine-grained salt rocks. Here a well in the Dabei area was taken as an example and the numerical simulation of hole shrinkage at the wellbore scale was performed, based on the actual data before and after reaming and also the theoretical analysis of the two salt rock creep mechanisms and corresponding laws. Furthermore, the inversion results were validated using field data. This research discussed the selection of creep parameters and their variation, in cases of the dominance of the dislocation creep and pressure solution creep mechanisms. This presented method can accurately predict the creep behavior of salt layers and can be used as an effective supplement tool for other test methods like laboratory experiments.
Experienced, trauma-informed teachers working in remote Australia: What is required for their work to be effective?
Authors: Brown Meegan , L’Estrange Lyra
Published: April 2023

Introduction

In remote education settings in Australia, experienced teachers who can effectively support students impacted by trauma are essential. Remote communities are unique yet are in many ways vulnerable to trauma as they face higher rates of disadvantage and exposure to traumatic events, including natural disasters and domestic and family violence. This is compounded by a lack of access to effective supports due to the tyranny of distance. Also, First Nations peoples living in remote areas continue to endure the ongoing and traumatic impacts of a violent and disruptive colonization.

Methods

The qualitative research study detailed in this article explored the requirements for the work of experienced, trauma-informed teachers in remote Australia to be effective, adding an important and unique perspective to the research evidence that is not often considered. Seven teachers from remote Australia completed a short, online questionnaire and participated in a focus group interview which was analyzed thematically.

Results

Themes emerging from the focus group data indicated that specific and contextualized preparation and support for teachers is required for them to do their work effectively. For remote Australian settings this means preparing teachers with cultural awareness and relevant trauma-informed training. Further, the wellbeing of these remote educators is often compromised, and addressing systemic factors such as adequate preparation of their colleagues and support to access relevant ongoing professional learning is needed.

Discussion

Remote teaching work in Australia is complex, and while the current study is small and exploratory in nature, the findings highlight some of the real-world impacts of these issues at a community and individual teacher level that have not been previously explored.
Bone marrow mesenchymal stem cells derived exosomal miRNAs can modulate diabetic bone-fat imbalance
Authors: Han Fei , Wang Chao , Cheng Peng , Liu Ting , Wang Wei-Shan
Published: April 2023

Background

Diabetes mellitus is a chronic metabolic disease with systemic complications. Patient with diabetes have increased risks of bone fracture. Previous studies report that diabetes could affect bone metabolism, however, the underlying mechanism is still unclear.

Methods

We isolated exosomes secreted by bone marrow mesenchymal stem cells of normal and diabetic mice and test their effects on osteogenesis and adipogenesis. Then we screened the differential microRNAs by high-throughput sequencing and explored the function of key microRNA in vitro and in vivo.

Results

We find that lower bone mass and higher marrow fat accumulation, also called bone-fat imbalance, exists in diabetic mouse model. Exosomes secreted by normal bone marrow mesenchymal stem cells (BMSCs-Exos) enhanced osteogenesis and suppressed adipogenesis, while these effects were diminished in diabetic BMSCs-Exos. miR-221, as one of the highly expressed miRNAs within diabetic BMSCs-Exos, showed abilities of suppressing osteogenesis and promoting adipogenesis both in vitro and in vivo. Elevation of miR-221 level in normal BMSCs-Exos impairs the ability of regulating osteogenesis and adipogenesis. Intriguingly, using the aptamer delivery system, delivery normal BMSCs-Exos specifically to BMSCs increased bone mass, reduced marrow fat accumulation, and promoted bone regeneration in diabetic mice.

Conclusion

We demonstrate that BMSCs derived exosomal miR-221 is a key regulator of diabetic osteoporosis, which may represent a potential therapeutic target for diabetes-related skeletal disorders.
Comparative efficacy of aromatase inhibitors and gonadotropin-releasing hormone analogue in increasing final height of idiopathic short stature boys: a network meta-analysis
Authors: Wang Siqi , Wu Zhixin , Chen Yang , Luo Kuanhong , Cui Zhenhai , Zhang Jiaoyue , Zheng Juan , Xiao Kangli , Li Huiqing
Published: April 2023

Objective

To investigate the efficacy of monotherapy with AIs or GnRHa in improving the height of boys with idiopathic short stature (ISS).

Method

We performed a systematic search in Pubmed, The Cochrane Library, Chinese National Knowledge Infrastructure databases, and Wanfang Database for eligible studies. The network meta-analysis was conducted using STATA software.

Results

We identified a total of four studies that included 136 individuals. We used FAH/PAH as the main outcome of final height. The results revealed a statistically higher final height after treatment with AI or GnRHa in idiopathic short stature children(MD= 4.63, 95% CI[3.29,5.96]). In network meta-analysis, the direct and indirect comparison between AI and GnRHa was presented in the forest plot. Compared with control group, both AI and GnRHa were effective in increasing the final height, with the mean effect of 4.91(95%CI:1.10,8.17) and 5.55(95%CI:1.12,9.98) respectively. However, there was no statistical difference between the GnRHa and AI treatment, of which the mean effect was 0.65(95%CI: -4.30,5.60).

Conclusion

Both AIs and GnRHa monotherapy were effective in augmenting the final height of boys with idiopathic short stature when compared to placebo groups. However, there was no statistical difference between the GnRHa and AI treatments.
Exosomal circRNAs as promising liquid biopsy biomarkers for glioma
Authors: Wu Xiaoke , Shi Mengmeng , Lian Yajun , Zhang Haifeng
Published: April 2023

Liquid biopsy strategies enable the noninvasive detection of changes in the levels of circulating biomarkers in body fluid samples, providing an opportunity to diagnose, dynamically monitor, and treat a range of diseases, including cancers. Glioma is among the most common forms of intracranial malignancy, and affected patients exhibit poor prognostic outcomes. As such, diagnosing and treating this disease in its early stages is critical for optimal patient outcomes. Exosomal circular RNAs (circRNAs) are involved in both the onset and progression of glioma. Both the roles of exosomes and methods for their detection have received much attention in recent years and the detection of exosomal circRNAs by liquid biopsy has significant potential for monitoring dynamic changes in glioma. The present review provides an overview of the circulating liquid biopsy biomarkers associated with this cancer type and the potential application of exosomal circRNAs as tools to guide the diagnosis, treatment, and prognostic evaluation of glioma patients during disease progression.
Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways
Authors: Xu Jing , Zhang Xinxin , Zhou Mingming , Lu Peizhe , Xu Yuting , Wu Lihong , Zhang Qianyue , Wu Zhihua , Xu Xiaoyu , Shi Pengfei , Wei Qingda , Li Xiaoyu , Song Qiaoling
Published: April 2023

The JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body’s inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related diseases and mortality, pointing to an urgent need for drug development targeting JAK/STAT and/or NFκB signaling. In this study, we screened 18,840 compounds using our well-established dual STAT-NFκB driven luciferase reporter based high-throughput screening system and identified a bioactive compound C498-0670, which inhibits both JAK/STAT and NFκB signaling. C498-0670 inhibits the activation of STATs and p-IKKα/β in both the immortalized cell lines and primary peritoneal macrophages, while suppressing the expression of LPS-induced inflammatory mediators in vitro. In addition, the overall anti-inflammatory effects of C498-0670 were investigated using transcriptome sequencing and bioinformatics approaches. C498-0670 was predicted to alleviate sepsis/septic shock by disease/function analysis using IPA software, which was further verified in the LPS-induced mouse sepsis model in vivo. C498 reduced LPS-induced liver and kidney damage, myeloid cell infiltration, and pro-inflammatory cytokine and chemokine production in vivo. Furthermore, the SPR-HPLC-MS-based target fishing approach was used to identify the putative drug targets, and the high affinities of JAK2 (JAK/STAT signaling), NFKBIA (NFκB signaling), and IL-1β, NLRP1b (inflammasome signaling) for C498-0670 were verified by molecular docking approach. These results suggest that C498-0670 can be used as a dual-target inhibitor of JAK/STAT and NFκB signaling pathways for the treatment of various inflammatory diseases, especially septic shock.
Inhibition of macrophages inflammasome activation via autophagic degradation of HMGB1 by EGCG ameliorates HBV-induced liver injury and fibrosis
Authors: He Minjing , Chu Tianhao , Wang Ziteng , Feng Ying , Shi Runhan , He Muyang , Feng Siheng , Lu Lin , Cai Chen , Fang Fang , Zhang Xuemin , Liu Yi , Gao Bo
Published: April 2023

Background

Liver fibrosis is a reversible wound-healing response that can lead to end-stage liver diseases without effective treatment, in which HBV infection is a major cause. However, the underlying mechanisms for the development of HBV-induced fibrosis remains elusive, and efficacious therapies for this disease are still lacking. In present investigation, we investigated the effect and mechanism of green tea polyphenol epigallocatechin-3-gallate (EGCG) on HBV-induced liver injury and fibrosis.

Methods

The effect of EGCG on liver fibrosis was examined in a recombinant cccDNA (rcccDNA) chronic HBV mouse model by immunohistochemical staining, Sirius red and Masson’s trichrome staining. The functional relevance between high mobility group box 1 (HMGB1) and inflammasome activation and the role of EGCG in it were analyzed by Western blotting. The effect of EGCG on autophagic flux was determined by Western blotting and flow cytometric analysis.

Results

EGCG treatment efficiently was found to alleviate HBV-induced liver injury and fibrosis in a recombinant cccDNA (rcccDNA) chronic HBV mouse model, a proven suitable research platform for HBV-induced fibrosis. Mechanistically, EGCG was revealed to repress the activation of macrophage NLRP3 inflammasome, a critical trigger of HBV-induced liver fibrosis. Further study revealed that EGCG suppressed macrophage inflammasome through downregulating the level of extracellular HMGB1. Furthermore, our data demonstrated that EGCG treatment downregulated the levels of extracellular HMGB1 through activating autophagic degradation of cytoplasmic HMGB1 in hepatocytes. Accordingly, autophagy blockade was revealed to significantly reverse EGCG-mediated inhibition on extracellular HMGB1-activated macrophage inflammasome and thus suppress the therapeutic effect of EGCG on HBV-induced liver injury and fibrosis.

Conclusion

EGCG ameliorates HBV-induced liver injury and fibrosis via autophagic degradation of cytoplasmic HMGB1 and the subsequent suppression of macrophage inflammasome activation. These data provided a new pathogenic mechanism for HBV-induced liver fibrosis involving the extracellular HMGB1-mediated macrophage inflammasome activation, and also suggested EGCG administration as a promising therapeutic strategy for this disease.
Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies
Authors: García-Calderón Clara Beatriz , Sierro-Martínez Belén , García-Guerrero Estefanía , Sanoja-Flores Luzalba , Muñoz-García Raquel , Ruiz-Maldonado Victoria , Jimenez-Leon María Reyes , Delgado-Serrano Javier , Molinos-Quintana Águeda , Guijarro-Albaladejo Beatriz , Carrasco-Brocal Inmaculada , Lucena José-Manuel , García-Lozano José-Raúl , Blázquez-Goñi Cristina , Reguera-Ortega Juan Luis , González-Escribano María-Francisca , Reinoso-Segura Marta , Briones Javier , Pérez-Simón José Antonio , Caballero-Velázquez Teresa
Published: April 2023

Purpose

CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes.

Experimental design

In this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed.

Results

Validation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control.

Conclusions

These data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy.
Characterization of a novel Plasmodium falciparum merozoite surface antigen and potential vaccine target
Authors: Niaré Karamoko , Chege Timothy , Rosenkranz Micha , Mwai Kennedy , Saßmannshausen Zoe , Odera Dennis , Nyamako Lydia , Tuju James , Alfred Tiono , Waitumbi John N. , Ogutu Bernhards , Sirima Sodiomon B. , Awandare Gordon , Kouriba Bourema , Rayner Julian C. , Osier Faith H. A.
Published: April 2023

Introduction

Detailed analyses of genetic diversity, antigenic variability, protein localization and immunological responses are vital for the prioritization of novel malaria vaccine candidates. Comprehensive approaches to determine the most appropriate antigen variants needed to provide broad protection are challenging and consequently rarely undertaken.

Methods

Here, we characterized PF3D7_1136200, which we named Asparagine-Rich Merozoite Antigen (ARMA) based on the analysis of its sequence, localization and immunogenicity. We analyzed IgG and IgM responses against the common variants of ARMA in independent prospective cohort studies in Burkina Faso (N = 228), Kenya (N = 252) and Mali (N = 195) using a custom microarray, Div-KILCHIP.

Results

We found a marked population structure between parasites from Africa and Asia. African isolates shared 34 common haplotypes, including a dominant pair although the overall selection pressure was directional (Tajima’s D = -2.57; Fu and Li’s F = -9.69; P < 0.02). ARMA was localized to the merozoite surface, IgG antibodies induced Fc-mediated degranulation of natural killer cells and strongly inhibited parasite growth in vitro. We found profound serological diversity, but IgG and IgM responses were highly correlated and a hierarchical clustering analysis identified only three major serogroups. Protective IgG and IgM antibodies appeared to target both cross-reactive and distinct epitopes across variants. However, combinations of IgG and IgM antibodies against selected variants were associated with complete protection against clinical episodes of malaria.

Discussion

Our systematic strategy exploits genomic data to deduce the handful of antigen variants with the strongest potential to induce broad protection and may be broadly applicable to other complex pathogens for which effective vaccines remain elusive.
Gut microbiota-derived short-chain fatty acids regulate gastrointestinal tumor immunity: a novel therapeutic strategy?
Authors: Dong Yue , Zhang Kexin , Wei Jingge , Ding Yiyun , Wang Xin , Hou Huiqin , Wu Jingyi , Liu Tianyu , Wang Bangmao , Cao Hailong
Published: April 2023

Tumor immune microenvironment (TIME), a tumor-derived immune component, is proven to be closely related to the development, metastasis, and recurrence of tumors. Gut microbiota and its fermented-metabolites short-chain fatty acids (SCFAs) play a critical role in maintaining the immune homeostasis of gastrointestinal tumors. Consisting mainly of acetate, propionate, and butyrate, SCFAs can interact with G protein-coupled receptors 43 of T helper 1 cell or restrain histone deacetylases (HDACs) of cytotoxic T lymphocytes to exert immunotherapy effects. Studies have shed light on SCFAs can mediate the differentiation and function of regulatory T cells, as well as cytokine production in TIME. Additionally, SCFAs can alter epigenetic modification of CD8+ T cells by inhibiting HDACs to participate in the immune response process. In gastrointestinal tumors, the abundance of SCFAs and their producing bacteria is significantly reduced. Direct supplementation of dietary fiber and probiotics, or fecal microbiota transplantation to change the structure of gut microbiota can both increase the level of SCFAs and inhibit tumor development. The mechanism by which SCFAs modulate the progression of gastrointestinal tumors has been elucidated in this review, aiming to provide prospects for the development of novel immunotherapeutic strategies.
CD4+ T cell memory is impaired by species-specific cytotoxic differentiation, but not by TCF-1 loss
Authors: Hofland Tom , Danelli Luca , Cornish Georgina , Donnarumma Tiziano , Hunt Deborah M. , de Carvalho Luiz P. S. , Kassiotis George
Published: April 2023

CD4+ T cells are typically considered as ‘helper’ or ‘regulatory’ populations that support and orchestrate the responses of other lymphocytes. However, they can also develop potent granzyme (Gzm)-mediated cytotoxic activity and CD4+ cytotoxic T cells (CTLs) have been amply documented both in humans and in mice, particularly in the context of human chronic infection and cancer. Despite the established description of CD4+ CTLs, as well as of the critical cytotoxic activity they exert against MHC class II-expressing targets, their developmental and memory maintenance requirements remain elusive. This is at least in part owing to the lack of a murine experimental system where CD4+ CTLs are stably induced. Here, we show that viral and bacterial vectors encoding the same epitope induce distinct CD4+ CTL responses in challenged mice, all of which are nevertheless transient in nature and lack recall properties. Consistent with prior reports, CD4+ CTL differentiation is accompanied by loss of TCF-1 expression, a transcription factor considered essential for memory T cell survival. Using genetic ablation of Tcf7, which encodes TCF-1, at the time of CD4+ T cell activation, we further show that, contrary to observations in CD8+ T cells, continued expression of TCF-1 is not required for CD4+ T cell memory survival. Whilst Tcf7-deficient CD4+ T cells persisted normally following retroviral infection, the CD4+ CTL subset still declined, precluding conclusive determination of the requirement for TCF-1 for murine CD4+ CTL survival. Using xenotransplantation of human CD4+ T cells into murine recipients, we demonstrate that human CD4+ CTLs develop and persist in the same experimental conditions where murine CD4+ CTLs fail to persist. These observations uncover a species-specific defect in murine CD4+ CTL persistence with implications for their use as a model system.
Nrf2 orchestrates transition from acute to chronic otitis media through inflammatory macrophages
Authors: Fan Wenyan , Xu Hongming , Shen Chenling , Fang Jia , Li Xiaoyan
Published: April 2023

Introduction

Acute and chronic otitis media (AOM and COM) are common middle ear infections that can lead to hearing loss and other complications. Recent research has shown that both macrophages and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway are involved in the immune response to and the resolution of otitis media. However, the specific effects of Nrf2 on macrophages in the transition of AOM to COM are not well understood, and a practical approach to prevent this transition by targeting Nrf2/macrophages has not been established.

Methods

In an AOM mouse model using lipopolysaccharide (LPS) injection into the middle ear, middle ear effusion (OME)-macrophages were isolated and analyzed for Nrf2 expression. M2-like polarization of macrophages was induced by Nrf2 activation and its effects on inflammatory resolution were studied by examining inflammatory neutrophils and macrophages, proinflammatory cytokines, and oxidative levels. The survival of human middle ear epithelial cells (HMMECs) co-cultured with Nrf2-modified macrophages was also evaluated. Furthermore, restoration of Nrf2 in macrophages with adeno-associated virus (AAV) vectors was performed to determine the effect on the transition of AOM to COM in experimental mice.

Results

Reduced Nrf2 in OME-macrophages during the recovery phase was associated with uncured AOM or its development into COM, demonstrated by persistent increases in inflammatory neutrophils and macrophages, proinflammatory cytokines, and oxidative levels. Nrf2 activation induced M2-like polarization of macrophages, which improved the survival of co-cultured HMMECs treated with LPS in vitro. Restoration of Nrf2 in OME-derived low-Nrf2-expressing macrophages with AAV vectors significantly inhibited the transition of AOM to COM in experimental mice.

Discussion

Nrf2 in macrophages plays a critical role in the immune response to and resolution of otitis media Restoration of Nrf2 expression in OME-macrophages could be a promising therapeutic approach to prevent the development of COM in AOM patients.
Bloodmeal host identities among sympatric Glossina austeni and Glossina pallidipes tsetse flies in Shimba Hills National Reserve, Kwale, Kenya
Authors: Ogolla Kennedy O. , Onyango Tevin , Bwana Billiah K. , Otiende Moses Y. , Mang’era Clarence M. , Ochieng Benard , Omolo Maurice O. , Mugambi John M. , Hassanali Ahmed , Omondi Patrick , Mireji Paul O.
Published: April 2023

Odor from preferred/non-preferred tsetse fly vertebrate hosts have been exploited in R&D of attractants/repellents of the fly for human and livestock protection. Odors from vertebrate hosts ofGlossina austeniandGlossina pallidipestsetse flies can facilitate formulation of novel attractants effective againstG. austenior improvement of existing attractant blends forG. pallidipes.We compared vertebrate blood meal sources of both fly species at Shimba Hills National Reserve, Kenya, to establish putative preferred host of either species, hence potential source ofG. austeniorG. pallidipesspecific odors. We trapped sympatric adult flies in 2021 and 2022 using NGU traps/sticky panels baited with 3-propylphenol, octenol, p-cresol, and acetone (POCA), collected their blood meals and characterized the meals using High Resolution Melting (HRM) vertebrate 16S rRNA- PCR (for host identification), and compared host profiles using GLM and Fisher’s exact tests. We collected 168 and 62 sympatricG. pallidipesandG. austeniwith bloodmeal, respectively in 2021 and, 230 and 142 respectively in 2022. In 2021, we identified putative hosts of 65.48 and 69.35% of theG. pallidipesandG. austenirespectively and 82.61 and 80.28%, respectively in 2022. In 2021, we detected harnessed bushbuck, buffalo, common warthog and cattle putative host bloodmeals, and additionally bushpig and suni antelope bloodmeals in 2022. Putative vertebrate bloodmeal sources were significantly different by tsetse fly species (χ²(1, N=457)= 43.215,p< 0.001) and sampling year (χ²(1, N=457)= 8.044,p= 0.005). Frequency of common warthog bloodmeals was higher inG. pallidipes(65.79%) than inG. austeni(38.60%), and that of suni antelope and harnessed bushbuck putative bloodmeals higher inG. austeni(21.05-28.07%) than inG. pallidipes(6.84 - 17.37%) in 2022. There was an apparent change in putative feeding preference/host choices in both fly species between 2021 and 2022. Host bloodmeals inG. pallidipesorG. austenipredominantly from putative harnessed bushbuck, suni antelope or common warthog reveal that these vertebrates have potential odors that can be harnessed and formulated into appropriate attractants for respective species and integrated into routine control regiment forG. pallidipesand/orG. austeni.
Wave attenuation by flattened vegetation (Scirpus mariqueter)
Authors: Ma Yuxi , Zhu Longhuan , Peng Zhong , Xue Liming , Zhao Wenzhen , Li Tianyou , Lin Shiwei , Bouma Tjeerd J. , Hofland Bas , Dong Chuning , Li Xiuzhen
Published: April 2023

With the capacity to reduce wave energy and trap sediment, Scirpus mariqueter has become an important native species of annual grass for ecology restoration at the Yangtze Estuary in eastern China. Due to seasonal variances of biophysical characteristics, S. mariqueter usually bends and breaks in winter, resulting in flattened stems that may reduce its wave attenuation capacity. To investigate the effects of vegetation flattening on wave attenuation, a set of flume experiments were conducted for flattened and standing vegetation under different wave conditions. The model vegetation was designed to represent the wilted S. mariqueter collected in winter with dynamic similarity. Results showed that the wave damping coefficient for flattened vegetation (βF) was 33.6%-72.4% of that for standing vegetation (βS) with the same vegetation length. Both βF and βS increased with wave height but decreased with water depth. A wave attenuation indicator (WAI) was defined to generate empirical formulas for βS and βF as well as their ratio βF/βS. The empirical formulas were then applied to modify the existing standing vegetation-based wave attenuation model for flattened vegetation and performed successfully. Understanding the wave attenuation characteristics of flattened vegetation is essential for the management of ecological restoration and coastal protection.