bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of Mobile Ad-Hoc Network Using BATMAN Routing Protocol (Better Approach To Mobile Ad-hoc Network) for Salinity Monitoring in Vaname Shrimp Farms
Authors: Larasati Fadila , Suharto Nugroho , Hariyadi Aad
Published: July 2023

Salinity is the key parameters in the shrimp culture environment. Conventional method is by visiting each pond plot. But,due to the large number and distance between the plots, this method is less effective. This ineffectiveness can lead to less than optimal yields. Manet is applied to increase the effectiveness of checking salinity using the BATMAN routing protocol. In this study, 2 units of laptops were used that act as Node 1 and Node 4, 2 units of Orange Pi Zero as Node 2, and 3. Each device is connected to a conductivity sensor to measure the salinity. The four devices are configured with an adhoc network using the BATMAN routing protocol. This research was conducted to provide an alternative for monitoring salinity to make it more effective. Based on the results of testing and analysis of network quality, the average delay value is 22.285 ms. The low delay value affects the percentage of packet loss in the four test scenarios with an average percentage of 0.999759613 %. Memory and CPU usage in testing 4 transition scenarios resulted in an average memory usage of 0.225% and CPU usage of 0.725%. The BATMAN routing protocol does not use a lot of memory and CPU usage because it only forwards data packets without the need to process data. From these data, it can be concluded that manet with batman routing protocol can be used as an alternative communication to provide communication network services in areas where there is no fixed network infrastructure.
Automated Water Heating Management with Internet of Things
Authors: Susanti Hera , Musyafiq Afrizal Abdi , Purnata Hendi , Ilahi Novita Asma , Rahmat Saepul
Published: July 2023

IoT devices can range from smart home devices such as thermostats and security systems to industrial control systems used in manufacturing and other industries. One focus of the IoT-based monitoring and control concept is monitoring and controlling water heaters based on IoT technology to support the creation of a smart home. The purpose of this research is to create a system that can control and monitor water heaters remotely using the Android Studio application so that the water temperature in the heater can be ensured for safety, comfort, reliability, and energy efficiency. The system is designed using temperature sensors and water flow sensors, and then the data is processed with the NodeMCU microcontroller and then sent to the Firebase website to be displayed on the application. The application built can set a large amount of water and heat it to the desired temperature before sending it to Firebase and then to NodeMCU. The result of this research is an application that is able to control and monitor a water heater with an average measurement difference of 0.38 liters and an average error percentage of 7.11% The relay control system in the application has an average delay time of 3.6 seconds.
Evaluation and Implementation of WISE-4051-AE Communications in Process Level Laboratory Module
Authors: Wijanarko Heru , Simanungkalit Hermanto , Futra Asrizal Deri , Darmoyono Aditya Gautama , Prebianto Nanta Fakih , Gozali Muhammad Syafei
Published: July 2023

This research discusses the design and implementation of wireless communication using WISE-4051-AE for optimizing process-level practical modules. The WISE-4051-AE wireless device is an integrated IoT (Internet of Things) device that combines data acquisition, processing, and control functionalities. Continuing previous research, this study focuses on creating practical modules for process control, including flow meter calibration, cascade control, feedforward control, and ratio control. By utilizing the WISE-4051-AE wireless device in a plant setting, the processed data can be accessed through laptops, personal computers, and other devices that support communication with the WISE-4051-AE device. To get the data, a device must be connected to the WISE-4051-AE wireless device. By employing the WISE-4051-AE wireless device for data transmission, users of the process-level practical modules can receive real-time plant data, regardless of whether the modules are indoors or outdoors, without encountering any data alteration during the transmission process. In this research, the WISE-4051-AE wireless device has a maximum range limitation. As long as the user's device remains within the signal range of the WISE-4051-AE device, the transmitted data will not undergo any changes. The signal range was tested under two conditions: without signal obstacles and with signal obstacles. The results of the signal range testing revealed a maximum range of 90 meters without obstacles and 40 meters with obstacles.
CONSTRUÇÃO DO CONHECIMENTO HISTÓRICO ESCOLAR E A NOÇÃO DE TEMPO:
Authors: Vago Moschen Franscielly , Alcantara Salim Maria Alayde
Published: July 2023

O presente trabalho resultou de uma experiência de ensino, desenvolvida com alunos do sexto ano de uma escola pública do município de São Mateus, no norte do Espírito Santo, que analisou a construção das noções de temporalidades por meio da materialidade. A partir do método da pesquisa-ação, examinamos o processo de elaboração do museu histórico temporário, constituído por fontes históricas familiares, e investigamos, mediante aplicação de intervenções de ensino, como se deu a construção das noções temporais utilizando a materialidade como recurso didático. A conclusão a que se chegou foi que a utilização de recursos concretos, documentos históricos transformados em materiais didáticos, como mediadores na construção de conceitos históricos abstratos, como as noções de temporalidade, apresentou grande potencialidade como estratégia de ensino, desde que o alunado participasse de todo o processo de elaboração conceitual e não recebesse conceitos prontos.
UTILIZAÇÃO DE RECURSOS TECNOLÓGICOS DIGITAIS COMO POSSIBILIDADE PEDAGÓGICA PARA O ENSINO DE ARTE SOB AS LENTES DE PESQUISAS BRASILEIRAS
Authors: Tibúrcio Giuliano Alencar , Borges Fábio Alexandre , Cibotto Rosefran Adriano Gonçales
Published: July 2023

O presente artigo se sustenta a partir de uma pesquisa bibliográfica, na qual se analisou quais são os aspectos que se destacam nas investigações brasileiras em nível de especialização stricto sensu acerca do uso de recursos tecnológicos digitais como possibilidade pedagógica para o ensino de Arte. Para tanto, foram consideradas teses e dissertações publicadas na Biblioteca Digital Brasileira de Teses e Dissertações (BDTD). Os resultados demonstram que os professores, de maneira geral, legitimam a relevância das tecnologias de forma a ampliar as possibilidades de ensino dos conteúdos de Arte, apresentando experiências significativas neste contexto, tais como produção e edição de vídeos, filmes e passeios virtuais em ambientes de divulgação artística.
Finitude e ética do cuidar
Authors: Machado Gustavo Joaquim Marques Martins
Published: July 2023

O presente trabalho visa apresentar e debater as ideias expostas pelo professor Newton Aquiles von Zuben, sobre a ética do cuidar em consonância, dentre outras coisas com a filosofia existencialista; somada a possíveis leituras e entendimentos de uma ética pautada por um entendimento materialista, ou seja, um entendimento que diz respeito ao existir concreto do humano em suas várias formas de existência. Assim, o trabalho se inicia apresentando parte de um dos diálogos de Epicuro a seu amigo Meneceu para darmos inicio a discussões sobre a finitude e como lidar com ela. Disso seguimos para um caminho que tenta sair de vieses idealistas sobre o humano para pauta-lo no existir sociomaterial. Disso dialogamos com o professor Zuben para entrelaçar estes pensamentos a um fazer filosófico e de práticas voltadas ao cuidar.
mergulho profundo na jornada do luto e na busca por autenticidade em “Notas sobre o luto” de Chimamanda Ngozi Adichie
Authors: Grigoleto Netto Jose Valdeci , Zucco João Vitor Gabiati
Published: July 2023

O texto traz uma resenha da obra intitulada Notas sobre o luto, da autora Chimamanda Ngozi Adichie. O livro foi publicado em 2021 e traduzido no mesmo ano no Brasil. São abordados temas como: a experiência autobiográfica da perda pela morte do pai, bem como discussões sobre as representações da morte em diferentes culturas e espaços.
Deep learning in CRISPR-Cas systems: a review of recent studies
Authors: Lee Minhyeok
Published: July 2023

In genetic engineering, the revolutionary CRISPR-Cas system has proven to be a vital tool for precise genome editing. Simultaneously, the emergence and rapid evolution of deep learning methodologies has provided an impetus to the scientific exploration of genomic data. These concurrent advancements mandate regular investigation of the state-of-the-art, particularly given the pace of recent developments. This review focuses on the significant progress achieved during 2019–2023 in the utilization of deep learning for predicting guide RNA (gRNA) activity in the CRISPR-Cas system, a key element determining the effectiveness and specificity of genome editing procedures. In this paper, an analytical overview of contemporary research is provided, with emphasis placed on the amalgamation of artificial intelligence and genetic engineering. The importance of our review is underscored by the necessity to comprehend the rapidly evolving deep learning methodologies and their potential impact on the effectiveness of the CRISPR-Cas system. By analyzing recent literature, this review highlights the achievements and emerging trends in the integration of deep learning with the CRISPR-Cas systems, thus contributing to the future direction of this essential interdisciplinary research area.
Investigating walkability and bikeability in compact vs. new extensions: the case of Greater Cairo
Authors: Eldeeb Sally , Masoumi Houshmand
Published: July 2023

Despite the urgent need to adopt sustainable transportation methods to reduce pollution, some cities, particularly in developing countries, are still prioritizing the construction of roads for private cars. The Greater Cairo Region is experiencing increased reliance on cars, causing strain on the road network, leading to traffic congestion, decreased walkability, and social isolation, especially in gated communities. Old Cairo downtown has implemented sustainable transportation options, but more action is needed from city authorities to prioritize sustainable transportation methods for pedestrians, cyclists, and public transit users to create livable cities and promote public health. The objective of this study is to assess the walkability and bikeability of three distinct city centers: Old Cairo, which represents the historic area of the Greater Cairo Region, and the newer extensions, namely, New Cairo and 6th October City. The analysis of walkability and bikeability will be based on the Walk Score metric, while the relationship with urban form integration will be evaluated using space syntax in-depth maps. The results indicate that the walkability rates in Old Cairo downtown surpass those of the newer extensions of the Greater Cairo Region due to the compact urban fabric and highly integrated street network and activities. In conclusion, this study sheds light on the reasons for car dependency in the new extensions of Greater Cairo and emphasizes the significance of collaboration between local public transportation authorities, the Ministry of Housing, global organizations, and international agendas.
Perilipin 3 promotes the formation of membrane domains enriched in diacylglycerol and lipid droplet biogenesis proteins
Authors: Khaddaj Rasha , Stribny Jiri , Cottier Stéphanie , Schneiter Roger
Published: July 2023

Lipid droplets (LDs) serve as intracellular stores of energy-rich neutral lipids. LDs form at discrete sites in the endoplasmic reticulum (ER) and they remain closely associated with the ER during lipogenic growth and lipolytic consumption. Their hydrophobic neutral lipid core is covered by a monolayer of phospholipids, which harbors a specific set of proteins. This LD surface is coated and stabilized by perilipins, a family of soluble proteins that specifically target LDs from the cytosol. We have previously used chimeric fusion proteins between perilipins and integral ER membrane proteins to test whether proteins that are anchored to the ER bilayer could be dragged onto the LD monolayer. Expression of these chimeric proteins induces repositioning of the ER membrane around LDs. Here, we test the properties of membrane-anchored perilipins in cells that lack LDs. Unexpectedly, membrane-anchored perilipins induce expansion and vesiculation of the perinuclear membrane resulting in the formation of crescent-shaped membrane domains that harbor LD-like properties. These domains are stained by LD-specific lipophilic dyes, harbor LD marker proteins, and they transform into nascent LDs upon induction of neutral lipid synthesis. These ER domains are enriched in diacylglycerol (DAG) and in ER proteins that are important for early steps of LD biogenesis, including seipin and Pex30. Formation of the domains in vivo depends on DAG levels, and we show that perilipin 3 (PLIN3) binds to liposomes containing DAG in vitro. Taken together, these observations indicate that perilipin not only serve to stabilize the surface of mature LDs but that they are likely to exert a more active role in early steps of LD biogenesis at ER subdomains enriched in DAG, seipin, and neutral lipid biosynthetic enzymes.
ROS-responsive exogenous functional mitochondria can rescue neural cells post-ischemic stroke
Authors: Li Yanjiao , Wang Yachao , Yang Weiqi , Wu Zhen , Ma Daiping , Sun Jianxiu , Tao Huixian , Ye Qinlian , Liu Jingnan , Ma Zhaoxia , Qiu Lihua , Li Weiping , Li Liyan , Hu Min
Published: July 2023

Background: The transfer of mitochondria from healthy mesenchymal stem cells (MSCs) to injured MSCs has been shown to have potential therapeutic benefits for neural cell post-ischemic stroke. Specifically, functional mitochondria can perform their normal functions after being internalized by stressed cells, leading to host cell survival. However, while this approach shows promise, there is still a lack of understanding regarding which neural cells can internalize functional mitochondria and the regulatory mechanisms involved. To address this gap, we investigated the ability of different neural cells to internalize exogenous functional mitochondria extracted from MSCs.

Methods: Functional mitochondria (F-Mito) isolated from umbilical cord derived-MSCs (UCMSCs) were labeled with lentivirus of HBLV-mito-dsred-Null-PURO vector. The ability of stressed cells to internalize F-Mito was analyzed using a mouse (C57BL/6 J) middle cerebral artery occlusion (MCAO) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) cell model. The cell viability was measured by CCK-8 kit. Time-course of intracellular ROS levels in stressed cells were analyzed by DCFH-DA staining after OGD/R and F-Mito treatment. MitoSOX, Mitotracker and WGA labeling were used to assess the relationship between ROS levels and the uptake of F-Mito at the single-cell level. Pharmacological modulation of ROS was performed using acetylcysteine (ROS inhibitor).

Results: Our findings demonstrate that neurons and endothelial cells are more effective at internalizing mitochondria than astrocytes, both in vitro and in vivo, using an ischemia-reperfusion model. Additionally, internalized F-Mito decreases host cell reactive oxygen species (ROS) levels and rescues survival. Importantly, we found that the ROS response in stressed cells after ischemia is a crucial determinant in positively mediating the internalization of F-Mito by host cells, and inhibiting the generation of ROS chemicals in host cells may decrease the internalization of F-Mito. These results offer insight into how exogenous mitochondria rescue neural cells via ROS response in an ischemic stroke model. Overall, our study provides solid evidence for the translational application of MSC-derived mitochondria as a promising treatment for ischemic stroke.
Modernity and the western value-action paradox: contributions from conservation psychology
Authors: Kyle Gerard , Landon Adam
Published: July 2023

We attempt to bridge the value – action paradox inhibiting environmental action by drawing upon work cast within conservation psychology to identify mechanisms by which the processes driving action can be shaped to achieve more sustainable outcomes. The shift toward a more mutualistic orientation with nature suggests the possibility of increasing success of treatments aimed at manipulating the endogenous psychological process (i.e., attitudes, knowledge, efficacy, norms) stemming from value orientation. While empirical evidence illustrates that values can be slow to change, the psychological processes situated higher within the cognitive hierarchy are more susceptible to manipulation. The need for behavioral change is imminent. While developed societies have, for the most part, modernized to the extent basic human needs are amply satisfied, the economic development that has accompanied modernization has coupled economic growth with an unsustainable consumption of natural resources and rising emissions. An increasing number of researchers and activists have called for a transition to a global steady-state economy. We suggest that shifting societal values present an opportunity for modern society to capitalize on humans’ increasing empathy for the natural world and to act in more sustainable ways. Research illustrates that those expressing a stronger affinity toward nature (e.g., mutualists) are more inclined to agree with statements suggesting that environmental protection should be prioritized over economic growth and that climate change is primarily driven by the burning of fossil fuels. Unfortunately, as it presently stands, those most inclined to express this sentiment (i.e., those reporting higher incomes, more years of formal education, and residing in urbanized environments) are also more likely to act in ways that contribute to climate change (e.g., car usage, air travel, household energy use). It is a troubling paradox given they have greater capacity for reducing their ecological footprint. With human values shifting toward a more empathetic orientation toward nature, our review implies that now more than ever, efforts to manipulate elements of the cognitive hierarchy are likely to result in behavioral change that can minimize many anthropogenic drivers of climate change.
Novel pathogenic variant in LMNA gene identified in a six-generation family causing atrial cardiomyopathy and associated right atrial conduction arrhythmias
Authors: Ning Shifeng , Han Min , Qiu Rujie , Hong Xiaoming , Xia Zhao , Liu Li , Liu Chengwei
Published: July 2023

Objective

To characterize the cardiac phenotype associated with the novel pathogenic variant (c.1526del) of LMNA gene, which we identified in a large, six-generation family.

Methods and Results

A family tree was constructed. The clinical data of living and deceased family members were collected. DNA samples from 7 family members were analyzed for LMNA mutations using whole-exome high-throughput sequencing technology. The clinical presentation of pathogenic variant carriers was evaluated. In this six-generation family (n = 67), one member experienced sudden death at the age of 40-years-old. Three pathogenic variant carriers were identified to possess a novel heterozygous deletion mutation in LMNA gene (HGVS: NM_170707.4, c.1526del) located at exon 9 of LMNA chr1:156137145, which creates a premature translational stop signal (p.Pro509Leufs*39) in the LMNA gene and results in an mutant lamin A protein product. The main symptoms of the pathogenic variant carriers were palpitation, fatigue, and syncope, which typically occurred around 20-years-old. AV-conduction block and non-sustained ventricular tachycardia were the first signs of disease and would rapidly progress to atrial standstill around 30-years-old. Significant right atrial enlargement and bicuspid aortic valve malformation was also commonly seen in patients who carried this pathogenic variant.

Conclusion

The pathogenic variant of c.1526del p.P509Lfs*39 was a frameshift deletion located at exon 9 of LMNA chr1:156137145 and causes severe right atrial enlargement, sick sinus syndrome, atrial standstill, ventricular tachycardia, and bicuspid aortic valve malformation. Our findings expand the phenotypic spectrum of novel LMNA gene mutations.
Geriatric nutrition risk index in the prediction of all-cause and cardiovascular mortality in elderly hypertensive population: NHANES 1999–2016
Authors: Huo Xuan , Wu Meiyin , Gao Dongmei , Zhou YueShengzi , Han Xu , Lai Weilin , Wang Mengqi , Hang Yilun
Published: July 2023

Background

Hypertension is a major risk factor for the global burden of disease, and nutrition is associated with an increased risk of mortality from multiple diseases. Few studies have explored the association of nutritional risk with all-cause mortality and cardiovascular mortality in hypertension, and our study aims to fill this knowledge gap.

Method

We included data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2016 on a total of 10,037 elderly patients with hypertension. The nutritional status was evaluated using the Geriatric Nutrition Risk Index (GNRI). Kaplan-Meier survival analysis was performed to analyze the survival rates of different nutritional risk groups. COX proportional risk regression models were used to analyze the predictive effect of GNRI on all-cause mortality and cardiovascular mortality in hypertensive patients. Restricted cubic splines (RCS) were used to explore the nonlinear relationship between GNRI and mortality.

Result

The mean age of the hypertensive patients was 70.7 years. A total of 4255 (42.3%) all-cause mortality and 1207 (17.2%) cardiovascular mortality occurred during a median follow-up period of 106 months. Kaplan-Meier showed a more significant reduction in survival for the moderate to severe malnutrition risk of GNRI. The adjusted COX proportional hazards model showed that the hazard ratios for all-cause mortality and cardiovascular mortality in the moderate to severe malnutrition risk group for GNRI were 2.112 (95% CI, 1.377,3.240) and 2.604 (95% CI, 1.603,4.229), respectively. The RCS showed that increased GNRI was associated with a reduced risk of all-cause mortality and cardiovascular mortality risk reduction.

Conclusion

Malnutrition exposure assessed by GNRI effectively predicts the risk of all-cause mortality and cardiovascular mortality in the elderly with hypertension.
A scoping review of seismic risk communication in Europe
Authors: Musacchio Gemma , Saraò Angela , Falsaperla Susanna , Scolobig Anna
Published: July 2023

Although earthquakes are a threat in many countries and considerable resources have been invested in safety regulations, communities at risk often lack awareness and preparedness. Risk communication is a key tool for building resilient communities, raising awareness, and increasing preparedness. Over the past 2 decades, seismic risk communication has evolved significantly. This has led to a reorientation from a predominantly “one-way”, top-down communication model to the promotion of new models in which people, their needs, and their participation in disaster risk management are central elements. The 2015–2030 Sendai Framework recommendations, recent disaster experiences and research have highlighted that new models can improve communication effectiveness. In this paper, we critically explore this transition by conducting a scoping review (n=109 publications) of seismic risk communication in Europe. We analyse the approaches, messages, tools, and channels used for seismic risk communication and how they have changed over time. The results reveal that the stated goals of seismic risk communication are, in decreasing order, to share information, raise awareness, change behaviours/beliefs, and increase preparedness. Pupils, students, and citizens are the primary recipients of communication activities. Over the years, two trends have emerged. First, “two-way”, transdisciplinary and bottom-up communication models prevailed over the “one-way” model. Second, communication aimed more at promoting proactive behaviours than just informing the public. Face-to-face, hands-on activities, and serious games are key tools to engage with the public. The results also reveal the emerging role of social media to target different audiences/social groups. Strikingly, only one-fifth of the analysed publications explicitly build on or tests risk communication theories. Future research could focus on comparing practices across countries and risks (e.g., earthquakes and floods) and on innovating communication theories and methodologies, especially by incorporating the role of information technologies and social media.
Mutational profiling of Chinese patients with thyroid cancer
Authors: Du Yaying , Zhang Shu , Zhang Gang , Hu Jiaying , Zhao Lianhua , Xiong Yuanyuan , Shen Lu , Chen Rongrong , Ye Ke , Xu Yan
Published: July 2023

Background

The incidence of thyroid cancer in China has rapidly increased in recent decades. As the genetic profiles of thyroid cancer vary dramatically between different geographical regions, a comprehensive genetic landscape of thyroid cancer in the Chinese population is urgently needed.

Methods

We retrospectively included thyroid cancer patients from three Chinese medical centers between February 2015 and August 2020. To dissect the genomic profiling of these patients, we performed targeted next-generation sequencing on their tumor tissues using a 1,021-gene panel.

Results

A total of 458 Chinese patients with thyroid cancer were enrolled, including four malignant histological subtypes arising from follicular epithelial thyroid cells. BRAF driver mutations were identified in 76.0% of patients, followed by RET rearrangements (7.6%) and RAS driver mutations (4.1%). Tumors with more somatic mutations correlated with worse clinical characteristics, including older age at diagnosis, less differentiation of tumor, larger tumor size, lymph node metastasis and distal metastasis. Subclonal BRAF mutations occurred in 20% (6/30) of patients and were frequent in poorly differentiated or anaplastic tumors (33.3% [2/6] vs. 4.2% [1/24], P = 0.09) and those with distal metastasis (50.0% [2/4] vs. 8.7% [2/23], P = 0.09). Tumors with TERT promoter mutations had significantly more somatic mutations (average: 6.5 vs. 1.8, P < 0.001). Moreover, TERT promoter mutations were not associated with lymph node metastasis but significantly associated with older age at diagnosis and poorly differentiated or anaplastic tumors, regardless of their clonal architecture.

Conclusion

Our results shed light on the molecular pathogenesis and clinical characteristics of thyroid cancer in the Chinese population. The number of somatic mutations, TERT promoter mutations, and the clonal architecture of BRAF mutations should be considered in the risk stratification of thyroid cancer.
Molecular and cellular regulation of thermogenic fat
Authors: Wang Cuihua , Wang Xianju , Hu Wenxiang
Published: July 2023

Thermogenic fat, consisting of brown and beige adipocytes, dissipates energy in the form of heat, in contrast to the characteristics of white adipocytes that store energy. Increasing energy expenditure by activating brown adipocytes or inducing beige adipocytes is a potential therapeutic strategy for treating obesity and type 2 diabetes. Thus, a better understanding of the underlying mechanisms of thermogenesis provides novel therapeutic interventions for metabolic diseases. In this review, we summarize the recent advances in the molecular regulation of thermogenesis, focusing on transcription factors, epigenetic regulators, metabolites, and non-coding RNAs. We further discuss the intercellular and inter-organ crosstalk that regulate thermogenesis, considering the heterogeneity and complex tissue microenvironment of thermogenic fat.
Natural antioxidants that act against Alzheimer’s disease through modulation of the NRF2 pathway: a focus on their molecular mechanisms of action
Authors: Sidiropoulou Grammatiki Alexandra , Metaxas Athanasios , Kourti Malamati
Published: July 2023

Characterized by a complex pathophysiology that includes the intraneuronal formation of neurofibrillary tangles and the extracellular deposition of β-amyloid plaques, Alzheimer’s disease (AD) is a terminal neurodegenerative disease that causes dementia in older adults. Oxidative stress in the brain is considered as one of the contributing factors to the pathogenesis of AD, and thus, antioxidants have attracted much interest as potential therapeutic agents against the disorder. Natural antioxidants are typically characterized by low acute and chronic toxicity, which facilitates their potential therapeutic application. One important molecular target for the beneficial effects of natural antioxidants is the nuclear factor erythroid-derived 2-related factor 2 (NFE2L2/NRF2). NRF2 is a key transcription factor that orchestrates the cellular antioxidant response through regulating the expression of oxidative stress-related genes harboring the antioxidant response element (ARE) in their promoters. Indeed, in the case of excessive oxidative damage, NRF2 migrates to the nucleus and binds to ARE, activating the transcription of antioxidant protector genes. There is increasing evidence that NRF2 is implicated in AD pathology through dysfunction and altered localization, which renders it as a potential therapeutic target for AD. Thus, this review summarizes the most recent (2018-2023) advances on the NRF2-modulating activity of natural antioxidants observed in vitro and in AD animal models. This information will help elucidate the molecular mechanisms governing the antioxidant activity of such phytochemicals to highlight their therapeutic potential against common neurodegenerative diseases, such as AD.
Immunogenomic profile at baseline predicts host susceptibility to clinical malaria
Authors: Mbambo Gillian , Dwivedi Ankit , Ifeonu Olukemi O. , Munro James B. , Shrestha Biraj , Bromley Robin E. , Hodges Theresa , Adkins Ricky S. , Kouriba Bourema , Diarra Issa , Niangaly Amadou , Kone Abdoulaye K. , Coulibaly Drissa , Traore Karim , Dolo Amagana , Thera Mahamadou A. , Laurens Matthew B. , Doumbo Ogobara K. , Plowe Christopher V. , Berry Andrea A. , Travassos Mark , Lyke Kirsten E. , Silva Joana C.
Published: July 2023

Introduction

Host gene and protein expression impact susceptibility to clinical malaria, but the balance of immune cell populations, cytokines and genes that contributes to protection, remains incompletely understood. Little is known about the determinants of host susceptibility to clinical malaria at a time when acquired immunity is developing.

Methods

We analyzed peripheral blood mononuclear cells (PBMCs) collected from children who differed in susceptibility to clinical malaria, all from a small town in Mali. PBMCs were collected from children aged 4-6 years at the start, peak and end of the malaria season. We characterized the immune cell composition and cytokine secretion for a subset of 20 children per timepoint (10 children with no symptomatic malaria age-matched to 10 children with >2 symptomatic malarial illnesses), and gene expression patterns for six children (three per cohort) per timepoint.

Results

We observed differences between the two groups of children in the expression of genes related to cell death and inflammation; in particular, inflammatory genes such as CXCL10 and STAT1 and apoptotic genes such as XAF1 were upregulated in susceptible children before the transmission season began. We also noted higher frequency of HLA-DR+ CD4 T cells in protected children during the peak of the malaria season and comparable levels cytokine secretion after stimulation with malaria schizonts across all three time points.

Conclusion

This study highlights the importance of baseline immune signatures in determining disease outcome. Our data suggests that differences in apoptotic and inflammatory gene expression patterns can serve as predictive markers of susceptibility to clinical malaria.
IRF4 is required for migration of CD4+ T cells to the intestine but not for Th2 and Th17 cell maintenance
Authors: Schmidt Constantin , Harberts Aenne , Reimers Daniel , Bertram Tabea , Voß Leonie Caroline , Schmid Joanna , Lory Niels Christian , Spohn Michael , Koch-Nolte Friedrich , Huber Samuel , Raczkowski Friederike , Breloer Minka , Mittrücker Hans-Willi
Published: July 2023

The transcription factor Interferon Regulatory Factor 4 (IRF4) is central in control of T cell activation and differentiation. Deficiency of IRF4 results in severe immune deficiency and affects maturation and function of most if not all T cell subsets. Here we use mouse infection models for Citrobacter rodentium and Strongyloides ratti to analyze the function of IRF4 in T helper (Th) 17 and Th2 cell responses, respectively. IRF4 deficient mice were impaired in the control of both pathogens, failed to mount Th17 and Th2 cell responses and showed impaired recruitment of T helper cells to the intestine, the infection site of both pathogens. Compromised intestinal migration was associated with reduced expression of the intestinal homing receptors α4β7 integrin, CCR9 and GPR15. Identification of IRF4 binding sites in the gene loci of these receptors suggests a direct control of their expression by IRF4. Competitive T cell transfer assays further demonstrated that loss of one functional Irf4 allele already affected intestinal accumulation and Th2 and Th17 cell generation, indicating that lower IRF4 levels are of disadvantage for Th2 and Th17 cell differentiation as well as their migration to the intestine. Conversion of peripheral CD4+ T cells from an Irf4 wildtype to an Irf4 heterozygous or from an Irf4 heterozygous to a homozygous mutant genotype after C. rodentium or S. ratti infection did not reduce their capacity to produce Th17 or Th2 cytokines and only partially affected their persistence in the intestine, revealing that IRF4 is not essential for maintenance of the Th2 and Th17 phenotype and for survival of these T helper cells in the intestine. In conclusion, we demonstrate that the expression levels of IRF4 determine Th2 and Th17 cell differentiation and their intestinal accumulation but that IRF4 expression is not crucial for Th2 and Th17 cell survival.
Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice
Authors: Yang Guang , Tong Yuting , Wang Xingyu , Zhao Chenyi , Ba Zongtao , Ahelijiang Reaila , Liu Xinjuan , Gao Waimao , Zhao Yan , Gu Yining , Yang Jianmei , Xu Ying
Published: July 2023

Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer’s disease (AD), which is associated with the regulation of microglial activation. Preventing microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. Here, the presenilin1/2 conditional double knockout (PS cDKO) mice, a well-established mouse model of AD, were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of lipopolysaccharide (LPS) (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL’s anti-inflammatory potential was closely associated with Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL could inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL prevented LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Taken together, GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.
Comprehensive bioinformatics analysis reveals the crosstalk genes and immune relationship between the systemic lupus erythematosus and venous thromboembolism
Authors: Yu Jingfan , Yang Jian , He Qifan , Zhang Zhixuan , Xu Guoxiong
Published: July 2023

Background

It is well known that patients with systemic lupus erythematosus (SLE) had a high risk of venous thromboembolism (VTE). This study aimed to identify the crosstalk genes between SLE and VTE and explored their clinical value and molecular mechanism initially.

Methods

We downloaded microarray datasets of SLE and VTE from the Gene Expression Omnibus (GEO) dataset. Differential expression analysis was applied to identify the crosstalk genes (CGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on the shared genes. The shared diagnostic biomarkers of the two diseases were further screened from CGs using least absolute shrinkage and selection operator (Lasso) regression. Two risk scores for SLE and VTE were constructed separately to predict the likelihood of illness according to the diagnostic biomarkers using a logical regression algorithm. The immune infiltration levels of SEL and VTE were estimated via the CIBERSORT algorithm and the relationship of CGs with immune cell infiltration was investigated. Finally, we explored potential phenotype subgroups in SLE and VTE based on the expression level of CGs through the consensus clustering method and studied immune cell infiltration in different subtypes.

Result

A total of 171 CGs were obtained by the intersection of differentially expressed genes (DEGs) between SLE and VTE cohorts. The functional enrichment shown these CGs were mainly related to immune pathways. After screening by lasso regression, we found that three hub CGs (RSAD2, HSP90AB1, and FPR2) were the optimal shared diagnostic biomarkers for SLE and VTE. Based on the expression level of RSAD2 and HSP90AB1, two risk prediction models for SLE and VTE were built by multifactor logistic regression and systemically validated in internal and external validation datasets. The immune infiltration results revealed that CGs were highly correlated with multiple infiltrated immunocytes. Consensus clustering was used to respectively regroup SLE and VTE patients into C1 and C2 clusters based on the CGs expression profile. The levels of immune cell infiltration and immune activation were higher in C1 than in C2 subtypes.

Conclusion

In our study, we further screen out diagnostic biomarkers from crosstalk genes SLE and VTE and built two risk scores. Our findings reveal a close relationship between CGs and the immune microenvironment of diseases. This provides clues for further exploring the common mechanism and interaction between the two diseases.
Reduning alleviates sepsis-induced acute lung injury by reducing apoptosis of pulmonary microvascular endothelial cells
Authors: Wang Ziyi , Guo Zhe , Wang Xuesong , Liao Haiyan , Chen Feng , Liu Yuxin , Wang Zhong
Published: July 2023

Introduction

Sepsis-induced acute lung injury (SALI) is a critical illness with high mortality, and pulmonary microvascular endothelial cells (PMECs) barrier dysfunction is a well-documented pathogenesis of SALI. The current study aimed to investigate the underlying mechanism of Reduning (RDN) in the treatment of SALI.

Methods

Network pharmacology and molecular dynamics simulation (MDS) were used to confirm the possibility of key active components of RDN combining with AKT1. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to investigate the effect of RDN in vivo. Immunofluorescence (IF) and co-immunoprecipitation (CoIP) were used to investigate the relationship between mammalian target of rapamycin (mTOR) and Bax in PMECs. ELISA was used to test the level of TNF-α. Flow cytometry was used to detect apoptosis. JC-1 and electron microscopy were used to evaluate mitochondrial damage. The results showed that RDN likely alleviated SALI via targeting AKT1.

Results

In vivo, RDN could evidently decrease the expression levels of apoptosis-related proteins, alleviate mitochondrial damage, reduce lung tissue edema, down-regulate the level of TNF-α in the serum, and improve the mortality of sepsis in mice. In vitro, RDN had a significant effect on reducing the level of apoptosis-related proteins and cell apoptosis rate, while also mitigated mitochondrial damage. Furthermore, RDN could effectively lower the level of Bax in PMECs and increase the level of mTOR both in vivo and in vitro. Notably, mTOR has the ability to directly bind to Bax, and RDN can enhance this binding capability.

Discussion

RDN could attenuate SALI through reducing apoptosis of PMECs, which is a promising therapeutic strategy for SALI prevention.
Prognostic and immunological significance of an M1 macrophage-related gene signature in osteosarcoma
Authors: Mao Xiaoyu , Song Fanglong , Jin Ju , Zou Bin , Dai Peijun , Sun Mingjuan , Xu Weicheng , Wang Lianghua , Kang Yifan
Published: July 2023

As the most abundant infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are pivotal in tumor development and treatment. The present investigation endeavors to explore the potential of M1 macrophage-related genes (MRGs) as biomarkers for assessing risk in individuals with osteosarcoma. RNA-sequence data and clinical data were derived from TCGA and GEO databases. The CIBERSORT method was utilized to discern subtypes of tumor-infiltrating immune cells. Identification of MRGs was achieved through Pearson correlation analysis. A prognostic risk model for MRGs was developed using Cox and LASSO regression analyses. A tripartite gene signature comprising CD37, GABRD, and ARHGAP25 was an independent prognostic indicator and was employed to develop a risk score model. The internal and external validation cohort confirmed the results. The area under the ROC curve (AUC) was determined for survival periods of 1 year, three years, and five years, yielding values of 0.746, 0.839, and 0.850, respectively. The C-index of the risk score was found to be superior to clinicopathological factors. GO/KEGG enrichment showed that the differences between high- and low-risk groups were predominantly associated with immune response pathways. Immune-related analysis related to proportions of immune cells, immune function, and expression levels of immune checkpoint genes all showed differences between the high- and low-risk groups. The qRT-PCR and Western blotting results indicate that CD37 expression was markedly higher in MG63 and U2OS cell lines when compared to normal osteoblast hFOB1.19. In U2OS cell line, GABRD expression levels were significantly upregulated. ARHGAP25 expression levels were elevated in both 143B and U2OS cell lines. In summary, utilizing a macrophage genes signature demonstrates efficacy in predicting both the prognosis and therapy response of OS. Additionally, immune analysis confirms a correlation between the risk score and the tumor microenvironment. Our findings, therefore, provide a cogent account for the disparate prognoses observed among patients and furnish a justification for further inquiry into biomarkers and anti-tumor treatment strategies.
Causal association between inflammatory bowel disease and herpes virus infections: a two-sample bidirectional Mendelian randomization study
Authors: Zou Menglong , Zhang Wei , Shen Lele , Xu Yin , Zhu Ying
Published: July 2023

Background

Previous observational or retrospective studies have suggested an association between inflammatory bowel disease (IBD) and herpes virus infections. Using Mendelian randomization (MR) approach, our objective was to determine whether there was a causal association between IBD and herpes virus infections.

Methods

In genome-wide association study (GWAS) datasets of the International Inflammatory Bowel Disease Genetics Consortium, we obtained genetic instrumental variables for three phenotypes from 34,652 participants (12,882 IBD cases and 21,770 controls), 27,432 participants [6,968 ulcerative colitis (UC) cases and 20,464 controls], and 20,883 participants [5,956 Crohn’s disease (CD) cases and 14,927 controls], respectively. Summary statistics for herpes virus infections (chickenpox, herpes zoster, and mononucleosis) were obtained from the FinnGen database. MR results were expressed as odds ratio (OR) with 95% confidence interval (CI).

Results

Our study found no evidence of a causal effect of genetically predicted IBD on herpes virus infections [P value for inverse variance weighting (IVW): 0.063 to 0.652]. For the subtypes of IBD, UC had a suggestive association with mononucleosis (P value for IVW: 0.023). It appeared that CD was also weakly associated with mononucleosis (P value for IVW: 0.058; P value for Weighted median: 0.036). In addition, we found a suggestive causality for CD on chickenpox (P value for IVW: 0.038). Neither UC (P value for IVW: 0.574) nor CD (P value for IVW: 0.168) has a causal effect on herpes zoster. The results of the bidirectional MR analysis did not indicate that herpes virus infections were associated with IBD, UC or CD (P value for IVW: 0.239 to 0.888).

Conclusion

This study showed a suggestive causality for both CD-chickenpox and UC-mononucleosis, despite no associations reaching a statistical significance value after corrections for multiple testing. There was no evidence of a causal association between IBD and its two subtypes on herpes zoster.
Basophils in pruritic skin diseases
Authors: Wiebe Daniela , Limberg Maren M. , Gray Natalie , Raap Ulrike
Published: July 2023

Basophils are rare cells in the peripheral blood which have the capability to infiltrate into the skin. Invasion of basophils has been detected in pruritic skin diseases, including atopic dermatitis, bullous pemphigoid, chronic spontaneous urticaria and contact dermatitis. In the skin, basophils are important players of the inflammatory immune response, as they release Th2 cytokines, including interleukin (IL)-4 and IL-13, subsequently inducing the early activation of T-cells. Further, basophils release a multitude of mediators, such as histamine and IL-31, which both play an important role in the initiation of the pruritic responseviaactivation of sensory nerves. Chronic pruritus significantly affects the quality of life and the working capability of patients, though its mechanisms are not fully elucidated yet. Since basophils and neurons share many receptors and channels, bidirectional interaction mechanisms, which drive the sensation of itch, are highlighted in this review.