bluuebunny/crossref_metadata_2025 huggingface dataset:
THE EFFECT OF PROMOTION, PRICE, AND CUSTOMER RATING ONLINE ON THE BUYING DECISION OF TOKOPEDIA E-COMMERCE: A CASE STUDY IN PADANG
Authors: Afrinaldi Muhamad , Wiratha Andre
Published: September 2024

This study aims to analyze the impact of promotions, pricing, and online customer ratings on purchasing decisions in the Tokopedia e-commerce platform in Padang City. Data were collected through a questionnaire that was tested for validity and reliability. Regression analysis results indicate that promotions and online customer ratings have a significant positive influence on purchasing decisions, while pricing does not have a substantial impact. These findings provide insights for business practitioners in designing effective marketing strategies in the digital era. It is recommended that sellers continuously optimize promotional strategies, set competitive prices, and manage customer reviews effectively to enhance purchasing decisions. Promotional activities are considered highly important in boosting purchasing decisions, whereas high prices may reduce consumer interest.
O uso do canto coral como intervenção musicoterapêutica para idosos institucionalizados: uma revisão de literatura
Authors: Cola Giraud Milena , De Melo Ferreira Michelle , Ludovico Moreira Rafael
Published: September 2024

Introdução. Falar sobre pessoas idosas na contemporaneidade é uma tarefa difícil, uma vez que esta população é cada vez mais duradoura, sendo o envelhecimento cada vez mais presente. Como alternativa para o envelhecimento possuímos as Instituições de Longa Permanência para Idosos. Neste processo de institucionalização, o idoso sofre inúmeras transformações que podem trazer consequências como dificuldades em se relacionar em sociedade, além de comprometer sua qualidade de vida e saúde. Visando contribuir com essa adaptação das transformações e mudanças na vida dos idosos, apontamos a Musicoterapia como tratamento que auxilia na melhora e diminuição dos efeitos advindos deste processo de institucionalização, assim como de qualquer outra doença ou problema apresentado por eles. Objetivo: O objetivo deste trabalho é estudar sobre os benefícios do canto coral para idosos institucionalizados através do levantamento bibliográfico. Método. Foi feito um levantamento bibliográfico com publicações dos últimos dez anos nas seguintes bases de dados: Pubmed, Scielo, Lilacs e Google Scholar, nos idiomas português, inglês e espanhol Resultados. Foi encontrado um artigo, o qual possuía em sua pesquisa outros três artigos que possuíam relevância a este estudo. Conclusão. Diante dos estudos expostos, conclui-se ser importante que as intervenções musicoterapêuticas sejam dirigidas por um profissional devidamente qualificado, de forma a deter os efeitos iatrogênicos, e que uma intervenção musicoterapêutica bem estruturada conduzida por um profissional qualificado pode gerar inúmeros benefícios como: redução de comportamento agitado, melhoras em sintomas psicológicos e comportamentais advindo de quadros demenciais ou de processo de envelhecimento,  além de auxiliar na diminuição do uso de medicamentos.
O curso de música no ensino superior
Authors: Vicente Rodrigo Aparecido , Pinguello Laís
Published: September 2024

A inclusão e o ensino de música junto a pessoas surdas são temas que vêm sendo debatidos e têm ganhado cada vez mais espaço nas universidades brasileiras. Contudo, ainda há limitações na organização de projetos políticos e de educação pública que tencionam dar visibilidade a essa parcela da população e possibilitar as condições necessárias a uma formação efetiva. Este artigo, de caráter qualitativo exploratório, aborda a disponibilidade de ferramentas e a presença de disciplinas voltadas à inclusão e o ensino de música junto a pessoas surdas em nível superior. Para isso, foi realizada uma pesquisa documental, fazendo um levantamento da grade curricular de cursos de licenciatura em música das universidades públicas das regiões Sul, Sudeste e Centro-Oeste do Brasil e uma busca acerca de alguns recursos voltados para o processo de ensino-aprendizagem de música para pessoas surdas. Como resultado, foram encontrados glossários em LIBRAS desenvolvidos para o ensino de música, softwares que transformam estímulos sonoros em estímulos visuais e dispositivos que ampliam as sensações vibratórias do som absorvidas pelo corpo. Todavia, constatou-se também uma disparidade no ensino da LIBRAS e na oferta de disciplinas que envolvam o tema inclusão entre os cursos de licenciatura em música, o que vem a impactar na formação dos futuros professores, pondo em questão o desenvolvimento e o acesso a um ensino de música realmente inclusivo.
A contribuição da música no desenvolvimento da interação social de sujeitos com transtorno do espectro autista
Authors: Ferri Álvaro Nery , Darroz Luiz Marcelo , Rosa Cleci Teresinha Werner da
Published: September 2024

Este trabalho apresenta os resultados de uma pesquisa-intervenção, de caráter qualitativo, que buscou identificar em que medida a metodologia musical de Carl Orff pode contribuir para a interação social, conforme preconizado por Vygotsky, no caso de sujeitos com Transtorno do Espectro Autista (TEA), visto que a dificuldade de interagir socialmente está entre as principais características presentes nesse espectro. Para a coleta de dados, foram utilizados os registros feitos pelo pesquisador no diário de bordo, além de fotos e gravações de vídeo dos encontros. Os dados foram examinados a partir da Análise de Conteúdo. Os resultados indicaram que a metodologia musical desenvolvida por Carl Orff auxilia no desenvolvimento da interação social de sujeitos com TEA. Tal conclusão teve como base a constatação de que o conceito de música elementar elaborado pelo autor, considerando a observação, a imitação e a apropriação, possibilita distintas experiências e formas de aprendizagem aos sujeitos com esse espectro e, consequentemente, favorece a interação social em grupo.
Collagen II enrichment through scAAV6-RNAi-mediated inhibition of matrix-metalloproteinases 3 and 13 in degenerative nucleus-pulposus cells degenerative disc disease and biological treatment strategies
Authors: Mern Demissew Shenegelegn , Thomé Claudius
Published: September 2024

Intervertebral disc (IVD) degeneration damaging the extracellular matrix (ECM) of IVDs is the main cause of spine-associated disorders. Degenerative disc disease (DDD) is a multifaceted disorder, where environmental factors, inflammatory cytokines and catabolic enzymes act together. DDD starts typically due to imbalance between ECM biosynthesis and degradation within IVDs, especially through unbalanced degradation of aggrecan and collagen II in nucleus pulposus (NP). Current treatment approaches are primarily based on conservative or surgical therapies, which are insufficient for biological regeneration. The disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs) are the key proteolytic enzymes for degradation of aggrecan and collagens. Previously, high expression levels of ADAMTS4, ADAMTS5, MMP3 and MMP13, which are accompanied with low levels of aggrecan and collagen II, were demonstrated in degenerative human NP cells. Moreover, self-complementary adeno-associated virus type 6 (scAAV6) mediated inhibitions of ADAMTS4 and ADAMTS5 by RNA-interference (RNAi) could specifically enhance aggrecan level. Thus, MMPs are apparently the main degrading enzymes of collagen II in NP. Furthermore, scAAV6-mediated inhibitions of MMP3 and MMP13 have not yet been investigated. Therefore, we attempted to enhance the level of collagen II in degenerative NP cells by scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13. MRI was used to determine preoperative grading of IVD degeneration in patients. After isolation and culturing of NP cells, cells were transduced with scAAV6-shRNAs targeting MMP3 or MMP13; and analysed by fluorescence microscopy, FACS, MTT assay, RT-qPCR, ELISA and western blotting. scAAV6-shRNRs have no impact on cell viability and proliferation, despite high transduction efficiencies (98.6%) and transduction units (1383 TU/Cell). Combined knockdown of MMP3 (92.8%) and MMP13 (90.9%) resulted in highest enhancement of collagen II (143.2%), whereby treatment effects were significant over 56 days (p < 0.001). Conclusively, scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13 help to progress less immunogenic and enduring biological treatments in DDD.
Development and validation of a nomogram for predicting rapid relapse in triple-negative breast cancer patients treated with neoadjuvant chemotherapy
Authors: Ma Tao , Liu Xin-Yu , Cai Shuang-Long , Zhang Jin
Published: September 2024

Background

Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. This study aimed to develop and validate a nomogram based on clinicopathological characteristics to predict rapid relapse in TNBC patients treated with neoadjuvant chemotherapy (NAC) first.

Methods

The clinicopathological data of 504 TNBC patients treated with NAC first in Tianjin Medical University Cancer Hospital were analyzed retrospectively, with 109 rapid relapsed patients, and 395 non-rapid relapsed patients, respectively. Based on clinicopathologic characteristics, and follow-up data were analyzed. The independent predictors of clinicopathological characteristics were identified by logistic regression analysis and then used to build a nomogram. The concordance index (C-index), the area under the curve (AUC) of receiver operating characteristic (ROC), and calibration plots were used to evaluate the performance of the model.

Results

Univariate and multivariate logistic regression analyses showed that age at diagnosis (age≥50 years, OR = 0.325,95% CI:0.137–0.771), Nodal staging (N3 staging, OR = 13.669,95% CI:3.693–50.592),sTIL expression levels (sTIL intermediate expression, OR = 0.272,95% CI:0.109–0.678; sTIL high expression, OR = 0.169,95% CI:0.048–0.594), and NAC response (ORR, OR = 0.059,95% CI:0.024–0.143) were independent predictors of rapid relapse in TNBC patients treated with NAC firstly. Among these independent predictors, age ≥ 50 years, sTIL intermediate expression, sTIL high expression, and ORR in NAC were independent protective factors for rapid relapse in TNBC NAC patients. N3 staging was an independent risk factor for rapid relapse in TNBC NAC patients. The ROC curve, calibration curve, and decision curve analysis were used to validate the model. The C-Index of the training sets and validation sets were 0.938 and 0.910, respectively. The Brier scores of the training sets and validation sets were 0.076 and 0.097, respectively.

Conclusion

This study developed and verified a nomogram for predicting rapid relapse in TNBC NAC patients, and the predictive model had high discrimination and accuracy.
KIT-13, a novel plasmalogen derivative, attenuates neuroinflammation and amplifies cognition
Authors: Hossain Md Shamim , Mawatari Shiro , Honsho Masanori , Okauchi Tatsuo , Fujino Takehiko
Published: September 2024

Plasmalogens (Pls) are specialized phospholipids integral to brain health, whose decline due to aging and stress contributes to cognitive impairment and neuroinflammation. This study explores the potential of a novel Pls derivative, KIT-13 (1-O-octadecyl-2-arachidonoyl-sn-glycerol-3-phosphoethanolamine), in mitigating neuroinflammation and enhancing cognition. When administered to mice, KIT-13 exhibited potent memory enhancement attributed to upregulated brain-derived neurotrophic factor (BDNF), a key player in cognitive processes. In vitro experiments with neuronal cells revealed KIT-13’s ability to induce robust cellular signaling, surpassing natural plasmalogens. KIT-13 also promoted neurogenesis and inhibited apoptosis of neuronal-like cells, highlighting its potential in fostering neuronal growth and plasticity. Additionally, KIT-13 treatments reduced pro-inflammatory cytokine expression and attenuated glial activation in the brain. KIT-13’s superior efficacy over natural Pls positions it as a promising therapeutic candidate for neurodegenerative conditions such as Alzheimer’s disease, characterized by cognitive decline and neuroinflammation. This study presents KIT-13 as an innovative approach for addressing cognitive impairment and neuroinflammatory pathologies.
Additive engineering for efficient wide-bandgap perovskite solar cells with low open-circuit voltage losses
Authors: Yu Xixi , He Huxue , Hui Yunuo , Wang Hua , Zhu Xing , Li Shaoyuan , Zhu Tao
Published: September 2024

High-performance wide-bandgap (WBG) perovskite solar cells are used as top cells in perovskite/silicon or perovskite/perovskite tandem solar cells, which possess the potential to overcome the Shockley-Queisser limitation of single-junction perovskite solar cells (PSCs). However, WBG perovskites still suffer from severe nonradiative recombination and large open-circuit voltage (Voc) losses, which restrict the improvement of PSC performance. Herein, we introduce 3,3′-diethyl-oxacarbo-cyanine iodide (DiOC2(3)) and multifunctional groups (C=N, C=C, C-O-C, C-N) into perovskite precursor solutions to simultaneously passivate deep level defects and reduce recombination centers. The multifunctional groups in DiOC2(3) coordinate with free Pb2+ at symmetric sites, passivating Pb vacancy defects, effectively suppressing nonradiative recombination, and maintaining considerable stability. The results reveal that the power conversion efficiency (PCE) of the 1.68 eV WBG perovskite solar cell with an inverted structure increases from 18.51% to 21.50%, and the Voc loss is only 0.487 V. The unpackaged device maintains 95% of its initial PCE after 500 h, in an N2 environment at 25°C.
Unlocking the power of short-chain fatty acids in ameliorating intestinal mucosal immunity: a new porcine nutritional approach
Authors: Liu Haoyang , Lu Hongde , Wang Yuxuan , Yu Chenyun , He Zhiyuan , Dong Hong
Published: September 2024

Short-chain fatty acids (SCFAs), a subset of organic fatty acids with carbon chains ranging from one to six atoms in length, encompass acetate, propionate, and butyrate. These compounds are the endproducts of dietary fiber fermentation, primarily catalyzed by the glycolysis and pentose phosphate pathways within the gut microbiota. SCFAs act as pivotal energy substrates and signaling molecules in the realm of animal nutrition, exerting a profound influence on the intestinal, immune system, and intestinal barrier functions. Specifically, they contibute to 60-70% of the total energy requirements in ruminants and 10-25% in monogastric animals. SCFAs have demonstrated the capability to effectively modulate intestinal pH, optimize the absorption of mineral elements, and impede pathogen invasion. Moreover, they enhance the expression of proteins associated with intestinal tight junctions and stimulate mucus production, thereby refining intestinal tissue morphology and preserving the integrity of the intestinal structure. Notably, SCFAs also exert anti-inflammatory properties, mitigating inflammation within the intestinal epithelium and strengthening the intestinal barrier’s defensive capabilities. The present review endeavors to synthesize recent findings regarding the role of SCFAs as crucial signaling intermediaries between the metabolic activities of gut microbiota and the status of porcine cells. It also provides a comprehensive overview of the current literature on SCFAs’ impact on immune responses within the porcine intestinal mucosa.
AI-based cluster analysis enables outcomes prediction among patients with increased LVM
Authors: Loutati Ranel , Kolben Yotam , Luria David , Amir Offer , Biton Yitschak
Published: September 2024

Background

The traditional classification of left ventricular hypertrophy (LVH), which relies on left ventricular geometry, fails to correlate with outcomes among patients with increased LV mass (LVM).

Objectives

To identify unique clinical phenotypes of increased LVM patients using unsupervised cluster analysis, and to explore their association with clinical outcomes.

Methods

Among the UK Biobank participants, increased LVM was defined as LVM index ≥72 g/m2 for men, and LVM index ≥55 g/m2 for women. Baseline demographic, clinical, and laboratory data were collected from the database. Using Ward's minimum variance method, patients were clustered based on 27 variables. The primary outcome was a composite of all-cause mortality with heart failure (HF) admissions, ventricular arrhythmia, and atrial fibrillation (AF). Cox proportional hazard model and Kaplan-Meier survival analysis were applied.

Results

Increased LVM was found in 4,255 individuals, with an average age of 64 ± 7 years. Of these patients, 2,447 (58%) were women. Through cluster analysis, four distinct subgroups were identified. Over a median follow-up period of 5 years (IQR: 4-6), 100 patients (2%) died, 118 (2.8%) were admissioned due to HF, 29 (0.7%) were admissioned due to VA, and 208 (5%) were admissioned due to AF. Univariate Cox analysis demonstrated significantly elevated risks of major events for patients in the 2nd (HR = 1.6; 95% CI 1.2–2.16; p < .001), 3rd (HR = 2.04; 95% CI 1.49–2.78; p < .001), and 4th (HR = 2.64; 95% CI 1.92–3.62; p < .001) clusters compared to the 1st cluster. Further exploration of each cluster revealed unique clinical phenotypes: Cluster 2 comprised mostly overweight women with a high prevalence of chronic lung disease; Cluster 3 consisted mostly of men with a heightened burden of comorbidities; and Cluster 4, mostly men, exhibited the most abnormal cardiac measures.

Conclusions

Unsupervised cluster analysis identified four outcomes-correlated clusters among patients with increased LVM. This phenotypic classification holds promise in offering valuable insights regarding clinical course and outcomes of patients with increased LVM.
Case Report: Ectopic pulmonary embolism as a complication of bronchial artery embolization
Authors: Liu Min , Liu Jixiang , Chen Shen , Gao Xiaoyan , Zhong Jinnan , Sun Lu , Li Fajiu , Li Chenghong
Published: September 2024

Bronchial artery embolization (BAE) is currently the first-line treatment for massive hemoptysis. Previous studies have proven its safety and efficacy, with mild, transient, and reversible complications. This case described a patient with congenital multiple bronchopulmonary fistulas who underwent BAE due to massive hemoptysis. However, due to an overlooked and misdiagnosed atypical fistula, the patient experienced an ectopic pulmonary embolism and subsequently secondary pulmonary infarction. He eventually exhibited a full postoperative recovery following percutaneous catheter-directed embolectomy. This case revealed a type of occult fistula masked by multiple bronchial artery branches, which may be a potential risk factor for an ectopic pulmonary embolism during BAE. We propose that it is crucial to identify abnormal anastomosis, especially atypical fistula, and select appropriate embolization materials during BAE.
The causal effects of inflammatory and autoimmune skin diseases on thyroid diseases: evidence from Mendelian randomization study
Authors: You Ruixuan , Duan Jiayue , Zhou Yong , Yu Jiangfan , Zou Puyu , Wei Yi , Chai Ke , Zeng Zhuotong , Xiao Yangfan , Yuan Lingqing , Xiao Rong
Published: September 2024

Background

To clarify the controversy between inflammatory or autoimmune skin diseases and thyroid diseases, we performed two-sample Mendelian randomization (MR) analyses.

Participants

Genetic data on factors associated with atopic dermatitis (AD, n=40,835), seborrheic dermatitis (SD, n=339,277), acne (n=363,927), rosacea (n=299,421), urticaria (n=374,758), psoriasis (n=373,338), psoriasis vulgaris (n=369,830), systemic lupus erythematosus (SLE, n=14,267), vitiligo (n=353,348), alopecia areata (AA, n=361,822), pemphigus (n=375,929), bullous pemphigoid (BP, n=376,274), systemic sclerosis (SSc, n=376,864), localized scleroderma (LS, n=353,449), hypothyroidism (n=314,995 or n=337,159), and hyperthyroidism (n=281,683 or n=337,159) were derived from genome-wide association summary statistics of European ancestry.

Main measures

The inverse variance weighted method was employed to obtain the causal estimates of inflammatory or autoimmune skin diseases on the risk of thyroid diseases, complemented by MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO).

Key results

AD, SLE, SD, and psoriasis vulgaris were associated with an increased risk of hypothyroidism, whereas BP was associated with a lower risk of hypothyroidism (all with p < 0.05). The multivariable MR analyses showed that AD (OR = 1.053; 95%CI: 1.015-1.092; p = 0.006), SLE (OR = 1.093; 95%CI: 1.059-1.127; p < 0.001), and SD (OR = 1.006; 95%CI: 1.002-1.010; p = 0.006) independently and predominately contributed to the genetic causal effect on hypothyroidism after adjusting for smoking. The results showed no causal effects of inflammatory or autoimmune skin diseases on hyperthyroidism.

Conclusion

The findings showed a causal effect of AD, SLE, SD on hypothyroidism, but further investigations should be conducted to explore the pathogenic mechanisms underlying these relationships.
Enabling Conditions for Consumer-Centric Business Models in the United Kingdom Energy Market
Authors: Hardy Jeffrey , Mazur Christoph
Published: September 2024

To achieve ambitious United Kingdom decarbonization targets, consumers will need to engage with energy services more so than they have done to date. This engagement could be active or delegated, where in the latter consumers pass responsibility for engagement to a third party in return for ceding some control over decisions. To date, insight into the barriers to consumer adoption of future business models has been limited. To address this gap this study explored benefits, risks and enabling conditions using two extreme consumer-centric business models, third Party Control and Shared Economy. The approach yielded information from stakeholders on what would have to be true for one of the business models to dominate the market. The results show substantial agreement across the expert groups on five key issues that will need to be addressed in the near-term to enable energy business model innovation in the United Kingdom market. These are: 1) Create space to enable business model innovation; 2) Ensure smart devices and data are interoperable and secure; 3) Improve the service standards of energy businesses; 4) Ensure business models work for consumers in all situations; and 5) Implement targeted carbon regulation.
Ion Transport in Solvated Sodium-Ion Conducting Gel Polymer Electrolytes
Authors: Kuray Preeya , Mei Wenwen , Sheffield Sarah E. , Sengeh Joseph , Pulido Carlos Rolando Fernandez , Capparelli Clara , Hickey Robert J. , Hickner Michael A.
Published: September 2024

Single ion conducting gel polymer electrolytes (GPEs) are characterized as having a certain amount of ionic liquid or solvent incorporated into a single ion-conducting polymer matrix and may afford the advantages of high conductivity and low electrolyte polarization under battery operation. Single ion conducting polymers often suffer from low conductivity due to their reliance on polymer segmental motion to achieve sufficient ion mobility. However, by incorporating specific solvents into a single ion conducting matrix, mobility of the polymer can be enhanced while still maintaining the advantages of single ion conduction. Although many of the solvents used to swell GPEs are mixtures of flammable organic solvents (such as dimethyl carbonate), there are many potential non-reactive, low vapor pressure solvents that could effectively solvate alkali-ion based GPEs and plasticize the polymer matrix to enhance ion conductivity. Adipate-based solvents are a group of non-volatile plasticizers with low viscosities and low vapor pressures at room temperature derived from adipic acid. The ester groups in these solvents may effectively solvate alkali ions such as Na+, leading to higher conductivity, while circumventing issues of flammability found in current alkali-ion conducting electrolytes. This study investigates the properties of sodium-ion conducting GPEs that have been swollen with varying adipate-based solvents and the subsequent dielectric response from the solvent addition. Dielectric relaxation spectroscopy was used to characterize the Na+ conductivity, static dielectric constant, ion-conducting content, and mobility of the membranes before and after the non-volatile solvent uptake. Understanding this relationship will pave the path toward safer, more efficient solid-state polymer electrolytes for battery applications.
A study on the spatial correlation network structure and its influencing factors of coupling coordination between FDI flow network and carbon transfer network in the belt and road initiative countries
Authors: Huang Yong , You Di , Yu Haozhen , Yang Chengye , Mao Jiawen
Published: September 2024

Clarifying the spatial correlation characteristics and influencing factors of coupling coordination between Foreign Direct Investment (FDI) flow networks and carbon transfer networks in countries along the Belt and Road Initiative is of utmost importance for the formulation of regional carbon governance strategies and the establishment of a high-quality Green Silk Road. This study used a comprehensive approach combining social network analysis and coupling coordination model to measure the coupling coordination degree of FDI flow networks and carbon transfer networks of 67 Belt and Road countries from 2010 to 2016. In addition, a modified gravity model is used to characterize the spatial correlation network structure of coupling coordination between the two networks, and the QAP regression analysis method is applied to investigate the factors influencing the spatial association network. The results are as follows: 1) The spatial correlation network of coupling coordination between the two networks has good accessibility and relatively high overall network stability. 2) Countries such as Qatar and the United Arab Emirates occupy central positions in the network, while Bahrain and Jordan are positioned on the periphery of the network. 3) The spatial correlation network can be divided into three sectors: net outflow, net inflow, and bidirectional overflow sectors. 4) Spatial adjacency, bilateral investment treaties, economic development, and institutional quality have significant positive effects on the spatial association network, while the industrial structure and the level of infrastructure development have a significant negative impact. This study proposes an indicator system for the coupling coordination between FDI flow networks and carbon transfer networks. The aim is to investigate the coupling coordination relationship between FDI flow networks and carbon emission transfer networks in countries along the Belt and Road Initiative, providing important guidance for the formulation of regional cooperative carbon emission reduction strategies in other regions.
Case report: Second report of neuromuscular syndrome caused by biallelic variants in ASCC3
Authors: Li Wang , Li Zhongliang , Fu Junhui , Xu Kaili , Mei Daoqi , Wang Xiaona , Li Taisong , Du Xilong
Published: September 2024

Introduction

Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) has been implicated in the pathogenesis of neurodevelopmental disorders and neuromuscular diseases (MIM: 620700). This paper analyzes the clinical manifestations of three patients with developmental delay caused by ASCC3 genetic variation. Additionally, we discuss the previously reported clinical features of these patients along with our own findings, thereby enhancing our understanding of these genetic disorders and providing valuable insights into diagnosis, treatment, and potential interventions for affected individuals.

Methods

In this study, we utilized trio-whole-exome sequencing (Trio-WES) and trio-copy number variations sequencing (Trio-CNV-seq) to analyze three unique families diagnosed with developmental delay caused by variation in ASCC3. Additionally, we retrospectively examined eleven previously reported ASCC3 genetic variations exhibiting similar clinical features.

Results

Proband I (family 1) and Proband III (family 3) exhibited global developmental delays, characterized by intellectual disability, motor impairment, language retardation, lower muscle strength, and reduced muscle tone in their extremities. Proband II (family 2) presented poor response and dysphagia during feeding within 7 days after birth, clinical examination displayed short limbs, long trunk proportions, and clenched fists frequently observed alongside high muscle tone in his limbs -all indicative signs of developmental delay. Trio-WES revealed compound heterozygous variants in ASCC3 inherited from their parents. Proband I carried c. [489 dup]; [1897C>T], proband II carried c. [2314C>T]; [5002T>A], and proband III carried c. [5113G>T]; [718delG] variations, respectively.

Conclusion

This study present the first report of Chinese children carrying compound heterozygous genetic variants in ASCC3 with LOF variants, elucidating the relationship between these variants and various aspects of intellectual disability. This novel finding expands the existing spectrum of ASCC3 variations.
Multi-omics landscape of Interferon-stimulated gene OASL reveals a potential biomarker in pan-cancer: from prognosis to tumor microenvironment
Authors: Liu Yi , Yang Runyu , Zhang Mengyao , Yang Bingyu , Du Yue , Feng Hui , Wang Wenjuan , Xue Busheng , Niu Fan , He Pengcheng
Published: September 2024

Background

OASL (Oligoadenylate Synthetase-Like), an interferon-induced protein in the OAS family, plays a significant role in anti-viral response. Studies have demonstrated its association with prognosis of certain tumors. However, the mechanism through which OASL affects tumors is unclear. A systemic pan-cancer study of OASL needs to be illustrated.

Methods

Analysis of OASL expression across 33 tumors was conducted utilizing TCGA, GTEx and CPTAC databases. COX and Log-Rank regressions were employed to calculate the prognosis. We validated the impact of OASL on apoptosis, migration, and invasion in pancreatic cancer cell lines. Moreover, we employed seven algorithms in bulk data to investigate the association of OASL expression and immune cell infiltration within tumor immune microenvironment (TIME) and ultimately validated at single-cell transcriptome level.

Results

We discovered elevated expression of OASL and its genetic heterogeneity in certain tumors, which link closely to prognosis. Validation experiments were conducted in PAAD and confirmed these findings. Additionally, OASL regulates immune checkpoint ligand such as programmed death ligand 1 (PD-L1), through IFN-γ/STAT1 and IL-6/JAK/STAT3 pathways in tumor cells. Meanwhile, OASL affects macrophages infiltration in TIME. By these mechanisms OASL could cause dysfunction of cytotoxic T lymphocytes (CTLs) in tumors.

Discussion

Multi-omics analysis reveals OASL as a prognostic and immunological biomarker in pan-cancer.
Harnessing the potential of the NALT and BALT as targets for immunomodulation using engineering strategies to enhance mucosal uptake
Authors: Seefeld Madison L. , Templeton Erin L. , Lehtinen Justin M. , Sinclair Noah , Yadav Daman , Hartwell Brittany L.
Published: September 2024

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.
The role of cytokines in the pathogenesis of SAPHO syndrome
Authors: Yang Yi , Chen Qianzhu , Zhong Weiyang
Published: September 2024

SAPHO syndrome is a complex inflammatory disorder affecting the skin and bones, characterized by osteomyelitis, acne, and pustulosis. Cytokines play a pivotal role in the pathogenesis of SAPHO syndrome, especially in inflammatory responses and immune regulation. This article reviews the cytokines involved in the pathogenesis of SAPHO syndrome, such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-6, IL-10, and transforming growth factor-β (TGF-β), and discusses their potential as intervention points for treatment. These findings elucidate the intricate immune regulatory network of SAPHO syndrome and provide a theoretical foundation for the development of new targeted therapeutic strategies.
Exploiting branched-chain amino acid metabolism and NOTCH3 expression to predict and target colorectal cancer progression
Authors: Shen Kuan , Zhu Chuming , Wu Jianjun , Yan Jiang , Li Pengyu , Cao Shuqing , Zhou Xinyi , Yao Guozhong
Published: September 2024

Background

The interplay between colon adenocarcinoma (COAD) and branched-chain amino acid (BCAA) metabolism is not fully understood, presenting a crucial area for investigation.

Methods

We developed a prognostic model based on BCAA metabolism using the least absolute shrinkage and selection operator (LASSO) regression algorithm. We employed qRT-PCR and Western blot analyses to examine NOTCH3 expression in COAD tissues versus adjacent non-cancerous tissues and various cell lines. We also investigated the impact of NOTCH3 on COAD cell proliferation, invasion, and migration through in vitro and in vivo experiments.

Results

Our BCAA metabolism-related signature (BRS) distinguished between different immune features, tumor mutation burdens, responses to immunotherapy, and drug sensitivity among COAD patients. NOTCH3 was found to be overexpressed in COAD, promoting tumor growth as verified through various assays. The model effectively predicted COAD prognosis and patient responses to treatments, underscoring the potential of BCAA pathways as therapeutic targets.

Conclusion

The BRS is instrumental in predicting the prognosis and therapeutic response in COAD, with NOTCH3 playing a significant role in the proliferation, invasion and migration of COAD. These findings suggest that targeting BCAA metabolism and NOTCH3 could advance COAD treatment strategies.
Antibodies as key mediators of protection against Mycobacterium tuberculosis
Authors: Wang Qixin , Nag Deepika , Baldwin Susan L. , Coler Rhea N. , McNamara Ryan P.
Published: September 2024

Tuberculosis (TB) is caused by infection with the bacterial pathogen Mycobacterium tuberculosis (M.tb) in the respiratory tract. There was an estimated 10.6 million people newly diagnosed with TB, and there were approximately 1.3 million deaths caused by TB in 2022. Although the global prevalence of TB has remained high for decades and is an annual leading cause of death attributed to infectious diseases, only one vaccine, Bacillus Calmette–Guérin (BCG), has been approved so far to prevent/attenuate TB disease. Correlates of protection or immunological mechanisms that are needed to control M.tb remain unknown. The protective role of antibodies after BCG vaccination has also remained largely unclear; however, recent studies have provided evidence for their involvement in protection against disease, as biomarkers for the state of infection, and as potential predictors of outcomes. Interestingly, the antibodies generated post-vaccination with BCG are linked to the activation of innate immune cascades, providing further evidence that antibody effector functions are critical for protection against respiratory pathogens such as M.tb. In this review, we aim to provide current knowledge of antibody application in TB diagnosis, prevention, and treatment. Particularly, this review will focus on 1) The role of antibodies in preventing M.tb infections through preventing Mtb adherence to epithelium, antibody-mediated phagocytosis, and antibody-mediated cellular cytotoxicity; 2) The M.tb-directed antibody response generated after vaccination and how humoral profiles with different glycosylation patterns of these antibodies are linked with protection against the disease state; and 3) How antibody-mediated immunity against M.tb can be further explored as early diagnosis biomarkers and different detection methods to combat the global M.tb burden. Broadening the paradigm of differentiated antibody profiling and antibody-based detection during TB disease progression offers new directions for diagnosis, treatment, and preventative strategies. This approach involves linking the aforementioned humoral responses with the disease state, progression, and clearance.
Causal associations between gut microbiota and premature rupture of membranes: a two-sample Mendelian randomization study
Authors: Zhang Lei , Li Qian , Huang Jiafeng , Zou Qin , Zou Hua , Zhang Xinyuan , Su Yan , Li Chunli
Published: September 2024

Background

Previous study has indicated a potential link between gut microbiota and maternal pregnancy outcomes. However, the causal relationship between gut microbiota and premature rupture of membranes (PROM) remains a topic of ongoing debate.

Methods

A two-sample Mendelian Randomization (MR) study was used to investigate the relationship between gut microbiota and PROM. Genetic data on gut microbiota was obtained from the MiBioGen consortium’s largest genome-wide association study (GWAS) (n=14,306). Genetic data on PROM (3011 cases and 104247 controls) were sourced from publicly available GWAS data from the Finnish National Biobank FinnGen consortium. Various methods including Inverse variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were utilized to assess the causal relationship by calculating the odd ratio (OR) value and confidence interval (CI). Sensitivity analyses for quality control were performed using MR-Egger intercept tests, Cochran’s Q tests, and leave-one-out analyses.

Results

The IVW method revealed that class Mollicutes (IVW, OR=0.773, 95%CI: 0.61-0.981, pval = 0.034), genus Marvinbryantia (IVW, OR=00.736, 95%CI: 0.555-0.977, pval = 0.034), genus Ruminooccaceae UCG003 (IVW, OR=0.734, 95%CI: 0.568-0.947, pval = 0.017) and phylum Tenericutes (IVW, OR=0.773, 95%CI: 0.566-1.067, pval = 0.034) were associated with a reduced risk of PROM, while genus Collinsella (IVW, OR=1.444, 95%CI: 1.028-2.026, pval = 0.034), genus Intestinibacter (IVW, OR=1.304, 95%CI: 1.047-1.623, pval = 0.018) and genus Turicibacter (IVW, OR=1.282, 95%CI: 1.02-1.611, pval = 0.033) increased the risk of PROM. Based on the other four supplementary methods, six gut microbiota may have a potential effect on PROM. Due to the presence of pleiotropy (pval=0.045), genus Lachnoclostridium should be ruled out. No evidence of horizontal pleiotropy or heterogeneity was found in other microbiota (pval >0.05).

Conclusions

In this study, we have discovered a causal relationship between the presence of specific probiotics and pathogens in the host and the risk of PROM. The identification of specific gut microbiota associated with PROM through MR studies offers a novel approach to diagnosing and treating this condition, thereby providing a new strategy for clinically preventing PROM.
Identification of ribosome biogenesis genes and subgroups in ischaemic stroke
Authors: Wang Xi , Zhang Xiao-Yu , Liao Nan-Qing , He Ze-Hua , Chen Qing-Feng
Published: September 2024

Background

Ischaemic stroke is a leading cause of death and severe disability worldwide. Given the importance of protein synthesis in the inflammatory response and neuronal repair and regeneration after stroke, and that proteins are acquired by ribosomal translation of mRNA, it has been theorised that ribosome biogenesis may have an impact on promoting and facilitating recovery after stroke. However, the relationship between stroke and ribosome biogenesis has not been investigated.

Methods

In the present study, a ribosome biogenesis gene signature (RSG) was developed using Cox and least absolute shrinkage and selection operator (LASSO) analysis. We classified ischaemic stroke patients into high-risk and low-risk groups using the obtained relevant genes, and further elucidated the immune infiltration of the disease using ssGSEA, which clarified the close relationship between ischaemic stroke and immune subgroups. The concentration of related proteins in the serum of stroke patients was determined by ELISA, and the patients were divided into groups to evaluate the effect of the ribosome biogenesis gene on patients. Through bioinformatics analysis, we identified potential IS-RSGs and explored future therapeutic targets, thereby facilitating the development of more effective therapeutic strategies and novel drugs against potential therapeutic targets in ischaemic stroke.

Results

We obtained a set of 12 ribosome biogenesis-related genes (EXOSC5, MRPS11, MRPS7, RNASEL, RPF1, RPS28, C1QBP, GAR1, GRWD1, PELP1, UTP, ERI3), which play a key role in assessing the prognostic risk of ischaemic stroke. Importantly, risk grouping using ribosome biogenesis-related genes was also closely associated with important signaling pathways in stroke. ELISA detected the expression of C1QBP, RPS28 and RNASEL proteins in stroke patients, and the proportion of neutrophils was significantly increased in the high-risk group.

Conclusions

The present study demonstrates the involvement of ribosomal biogenesis genes in the pathogenesis of ischaemic stroke, providing novel insights into the underlying pathogenic mechanisms and potential therapeutic strategies for ischaemic stroke.
The anti-inflammatory and tolerogenic potential of small spleen peptides
Authors: Wixler Viktor , Zaytsev Igor Z. , Boergeling Yvonne , Ludwig Stephan
Published: September 2024

Maintaining peripheral immune tolerance and preventing harmful autoimmune reactions is a fundamental task of the immune system. However, these essential functions are significantly compromised during autoimmune disorders, creating a major challenge in treating these conditions. In this context, we provide an overview of research on small spleen polypeptides (SSPs) that naturally regulate peripheral immune tolerance. Alongside outlining the observed effects of SSPs, we summarize here the findings on the cellular and molecular mechanisms that underlie their regulatory impact. Specifically, SSPs have demonstrated remarkable effectiveness in halting the progression of developing or established autoimmune disorders like psoriasis or arthritis in animal models. They primarily target dendritic cells (DCs), swiftly prompting the production of extracellular ATP, which is then degraded and sensed by adenosine receptors. This process triggers the mTOR signaling cascade, similar to powerful immune triggers, but instead of a rapid and intense reaction, it leads to a moderate yet significant activation of the mTOR signaling cascade. This induces a tolerogenic state in dendritic cells, ultimately leading to the generation of Foxp3+ immunosuppressor Treg cells. In addition, SSPs may indirectly attenuate the autoimmune response by reducing extracellular ATP synthesis in non-immune cells, such as endothelial cells, when exposed to elevated levels of proinflammatory cytokines. SSPs thus have the potential to contribute to the restoration of peripheral immune tolerance and may offer valuable therapeutic benefits in treating autoimmune diseases.
Case report: Deep sequencing and long-read genome sequencing refine prior genetic analyses in families with apparent gonadal mosaicism in PIK3CD-related activated PI3K delta syndrome
Authors: Orellana Halyn , Yan Jia , Paul Alex , Tokita Mari , Ding Yan , Ghosh Rajarshi , Lewis Katie L. , Davis Joie , Jamal Leila , Jodarski Colleen , Similuk Morgan , Saucier Nermina , Zhu Zhanyang , Wang Yihe , Wu Sitao , Ruggieri Jason ,   NIAID Centralized Sequencing Program Working Group, Su Helen C. , Uzel Gulbu , Nahas Shareef , Cooper Megan , Walkiewicz Magdalena A.
Published: September 2024

Gonadal and gonosomal mosaicism describe phenomena in which a seemingly healthy individual carries a genetic variant in a subset of their gonadal tissue or gonadal and somatic tissue(s), respectively, with risk of transmitting the variant to their offspring. In families with one or more affected offspring, occurrence of the same apparently de novo variants can be an indicator of mosaicism in either parent. Panel-based deep sequencing has the capacity to detect low-level mosaic variants with coverage exceeding the typical limit of detection provided by current, readily available sequencing techniques. In this study, we report three families with more than one affected offspring with either confirmed or apparent parental gonosomal or gonadal mosaicism for PIK3CD pathogenic variants. Data from targeted deep sequencing was suggestive of low-level maternal gonosomal mosaicism in Family 1. Through this approach we did not detect pathogenic variants in PIK3CD from parental samples in Family 2 and Family 3. We conclude that mosaicism was likely confined to the maternal gonads in Family 2. Subsequent long-read genome sequencing in Family 3 showed that the paternal chromosome harbored the pathogenic variant in PIK3CD in both affected children, consistent with paternal gonadal mosaicism. Detection of parental mosaic variants enables accurate risk assessment, informs reproductive decision-making, and provides helpful context to inform clinical management in families with PIK3CD pathogenic variants.