bluuebunny/crossref_metadata_2025 huggingface dataset:
ANÁLISE QUALITATIVA DA LOCALIZAÇÃO DA ETE EM ITUMBIARA – GO
Authors: Reginaldo Pereira Leonardo , Guerra Ferreira Campos Ana Flávia , Coutinho Maciel Mendes Gabriel , Ridan Pires de Melo Suiaine
Published: July 2024

Uma das áreas contempladas pelo saneamento básico é a coleta e, posteriormente, o  tratamento de esgoto, o qual na maioria dos municípios brasileiros é feito em estações de tratamento de esgoto, chamada de ETE. Um dos tipos de tratamento adotado nas estações é o tratamento anaeróbio, que apresenta uma característica importante: a emissão de gases odorantes, como, por exemplo, o gás sulfídrico, o que acontece na cidade de Itumbiara, em Goiás.  Esses odores podem ser percebidos até um determinado raio de influência a partir da estação, causando incômodo para a população. O crescimento da população nas proximidades da estação e a direção de propagação do vento são fatores que podem favorecer a susceptibilidade ao efeito do gás sulfídrico nos habitantes. Posto isto, esse artigo teve por objetivo realizar uma abordagem qualitativa tendo como foco o local da ETE, analisando a presença de áreas urbanizadas e os impactos causados pelo gás sulfídrico na circunvizinhança, baseando-se em um raio de influência. Na metodologia, foi utilizado um software para elaboração de mapas e obtenção de imagens de satélite, além de literaturas para obtenção do raio de influência e de fonte específica para adotar a direção do vento. Como resultados, obteve-se que há uma expansão urbana que direciona-se para o entorno da ETE, além de que os ventos predominantes impactam na propagação dos odores para locais onde há presença de habitantes. Conclui-se então que existem construções dentro do raio de influência da ETE, que estão suscetíveis à atuação do gás sulfídrico.
Development of SYK NanoBRET cellular target engagement assays for gain–of–function variants
Authors: Capener Jacob L. , Vasta James D. , Katis Vittorio L. , Michaud Ani , Beck Michael T. , Daglish Sabrina C. D. , Cohen-Kedar Sarit , Shaham Barda Efrat , Howell Stefanie , Dotan Iris , Robers Matthew B. , Axtman Alison D. , Bashore Frances M.
Published: July 2024

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that is activated by phosphorylation events downstream of FcR, B-cell and T-cell receptors, integrins, and C-type lectin receptors. When the tandem Src homology 2 (SH2) domains of SYK bind to phosphorylated immunoreceptor tyrosine-based activation motifs (pITAMs) contained within these immunoreceptors, or when SYK is phosphorylated in interdomain regions A and B, SYK is activated. SYK gain-of-function (GoF) variants were previously identified in six patients that had higher levels of phosphorylated SYK and phosphorylated downstream proteins JNK and ERK. Furthermore, the increased SYK activation resulted in the clinical manifestation of immune dysregulation, organ inflammation, and a predisposition for lymphoma. The knowledge that the SYK GoF variants have enhanced activity was leveraged to develop a SYK NanoBRET cellular target engagement assay in intact live cells with constructs for the SYK GoF variants. Herein, we developed a potent SYK-targeted NanoBRET tracer using a SYK donated chemical probe, MRL-SYKi, that enabled a NanoBRET cellular target engagement assay for SYK GoF variants, SYK(S550Y), SYK(S550F), and SYK(P342T). We determined that ATP-competitive SYK inhibitors bind potently to these SYK variants in intact live cells. Additionally, we demonstrated that MRL-SYKi can effectively reduce the catalytic activity of SYK variants, and the phosphorylation levels of SYK(S550Y) in an epithelial cell line (SW480) stably expressing SYK(S550Y).
The intratumoral microbiota: a new horizon in cancer immunology
Authors: Liu Wei , Li Yuming , Wu Ping , Guo Xinyue , Xu Yifei , Jin Lianhai , Zhao Donghai
Published: July 2024

Over the past decade, advancements in high-throughput sequencing technologies have led to a qualitative leap in our understanding of the role of the microbiota in human diseases, particularly in oncology. Despite the low biomass of the intratumoral microbiota, it remains a crucial component of the tumor immune microenvironment, displaying significant heterogeneity across different tumor tissues and individual patients. Although immunotherapy has emerged a major strategy for treating tumors, patient responses to these treatments vary widely. Increasing evidence suggests that interactions between the intratumoral microbiota and the immune system can modulate host tumor immune responses, thereby influencing the effectiveness of immunotherapy. Therefore, it is critical to gain a deep understanding of how the intratumoral microbiota shapes and regulates the tumor immune microenvironment. Here, we summarize the latest advancements on the role of the intratumoral microbiota in cancer immunity, exploring the potential mechanisms through which immune functions are influenced by intratumoral microbiota within and outside the gut barrier. We also discuss the impact of the intratumoral microbiota on the response to cancer immunotherapy and its clinical applications, highlighting future research directions and challenges in this field. We anticipate that the valuable insights into the interactions between cancer immunity and the intratumoral microbiota provided in this review will foster the development of microbiota-based tumor therapies.
Standardization of an antimicrobial resistance surveillance network through data management
Authors: Kim Hyunji , Park Jeong Su , Kim Dokyun , Kim Hee Jung , Shin Jeong Hwan , Kim Young Ah , Uh Young , Kim Soo Hyun , Shin Jong Hee , Jeong Seok Hoon , Park Kyoung Un
Published: July 2024

Introduction

The rapid spread of COVID-19 worldwide within 2 months demonstrated the vulnerability of the world’s population to infectious diseases. In 2015, the Global Antimicrobial Resistance and Use Surveillance System (GLASS) was launched to combat antimicrobial resistance (AMR). However, there has been no comprehensive assessment of the decade-long global battle against AMR based on GLASS data.

Methods

South Korea established Kor-GLASS (Korean-GLASS) to proactively monitor data quality and enable international collaborations. A unique feature of Kor-GLASS is the quality control center (QCC), which uses network hubs and ensures standardized, high-quality data through interlaboratory proficiency testing (IPT) and external quality assessment (EQA). In addition, the QCC multifaceted endeavors for integrated data quality management.

Results

Since 2020, high-quality AMR data have indicated fluctuating antibiotic resistance rates in South Korea. This trend does not align with the decrease in antibiotic usage seen in humans but coincides with non-human antibiotic sales, indicating a need for greater monitoring of non-human antibiotic resistance. Comprehensive and robust management taking account of the intricate interplay among humans, animals, and the environment is essential. Kor-GLASS has been expanded into a “One Health” multiagency collaborative initiative.

Discussion

Although a standardized solution is not suitable for all countries, it must align with the local context and international standards. A centralized top-down management structure such as that of the QCC is essential to ensure continuous data quality coordination. Sustained efforts and surveillance systems are crucial for monitoring and managing AMR and safeguarding human health.
Provision of digital devices and internet connectivity to improve synchronous telemedicine access in the U.S.: a systematic scoping review
Authors: Bell Joshua , Gottlieb Laura M. , Lyles Courtney R. , Nguyen Oanh Kieu , Ackerman Sara L. , De Marchis Emilia H.
Published: July 2024

Introduction

The COVID-19 pandemic led to a dramatic increase in telemedicine use for direct patient care. Inequities in device/internet access can limit the extent to which patients can engage with telemedicine care and exacerbate health disparities. In this review, we examined existing literature on interventions designed to improve patient telemedicine access by providing digital devices including tablets, smartphones, and computers and/or internet connectivity.

Methods

In this systematic scoping review, we searched four databases for peer-reviewed studies published 1/1/2000–10/19/2021 that described healthcare interventions that provided patients with devices and/or internet connectivity and reported outcomes related to telemedicine access and/or usage. Data extraction elements included: study population, setting, intervention design, details on device/connectivity provision, and outcomes evaluated.

Results

Twelve articles reflecting seven unique interventions met inclusion criteria. Ten articles examined telemedicine utilization (83%) and reported improved patient show rates/utilization. Seven articles examined patient satisfaction with the interventions (58%) and reported positive experiences. Fewer articles examined health outcomes (17%; 2/12) though these also demonstrated positive results. Across included studies, study quality was low. There were no controlled trials, and the most rigorously designed studies (n = 4) involved pre/post-intervention assessments.

Discussion

Findings from this review indicate that providing material technology supports to patients can facilitate telemedicine access, is acceptable to patients and clinicians, and can contribute to improved health outcomes. The low number and quality of existing studies limits the strength of this evidence. Future research should explore interventions that can increase equitable access to telemedicine services.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=183442, identifier, PROSPERO: CRD42020183442.
Petrogenesis and tectonic implications of Early Paleozoic granitoids in the Baoshan deposit, Guangxi, South China
Authors: Lyu Puliang , Liu Fang , Chen Ling , Song Zhiguang , Ma Wenen , Hou Yanlin
Published: July 2024

The Early Paleozoic tectonic setting and geological processes of the South China Block have long been a subject of debate. This study presented zircon U-Pb geochronology and Hf isotope, and whole-rock geochemical analyses for the Early Paleozoic granitoids in the Baoshan deposit of the Dayaoshan Uplift. LA–ICP–MS zircon U‒Pb results suggest that the diorites, granite porphyries, granodiorites and its mafic microgranular enclaves in the Baoshan deposit formed at 449–430 Ma. Their formation ages are consistent with those of granite, MMEs and mafic rocks found in the Dayaoshan region. The granite porphyries, granodiorites, diorites and their MMEs in the Baoshan deposit have high Eu/Eu* ratios, low Zr + Nb + Y + Ce contents, 10,000×Ga/Al values, and A/CNK ratios (0.74–1.08), belonging to metaluminous to weakly peraluminous calc-alkaline I-type granitoids. Based on zircon Hf isotopic compositions (εHf(t) from −5.5 to +3.1), it is unlikely that these rocks were solely originated from a crustal source, and mantle-derived magma also played a significant role in the formation of these intrusive rocks. It is inferred that the granitoids in the Baoshan deposit were probably formed through the underplating of mantle-derived magmas during a transitional collision to extension tectonic setting, which led to the remelting of Mesoproterozoic crust.
Secondary school students’ perspectives on supports for overcoming school attendance problems: a qualitative case study in Germany
Authors: Enderle Chiara , Kreitz-Sandberg Susanne , Backlund Åsa , Isaksson Joakim , Fredriksson Ulf , Ricking Heinrich
Published: July 2024

Introduction

School attendance problems (SAPs) affect both the education and development of young learners. There is a need to better understand what supports are needed to overcome and prevent SAPs from students’ perspectives. The aim of the current study is to explore students’ perspectives on what challenges they faced, and what they perceived as helpful in overcoming attendance challenges on their pathways towards completing their education.

Method

We conducted interviews with students (n = 9) in a local comprehensive school (Stadtteilschule) in the city-state Hamburg in Germany. Students were in their final year before obtaining a certificate that qualifies them for possible admission to post-secondary education. Data was analyzed using qualitative content analysis.

Results

Findings show that students experienced complex challenges to school attendance that were associated with emotional distress, negative school experiences, and reduced well-being. Our findings point to common protective mechanisms in students’ perceptions of what helped them overcome SAPs. The key drivers of school attendance are located within students and their social contexts, including personal resilience, supportive relationships at school, and the social environment.

Discussion

Based on students’ views, we present a model that illustrates the interconnectedness of perceived challenges and supports in the function of risk and protective factors moving across ecological systems in the development of SAPs. We highlight how these areas can guide prevention and intervention to support students in successfully completing their education and transitioning into multiple post-secondary pathways.
The value of the platelet/high-density lipoprotein cholesterol ratio in predicting depression and its cardiovascular disease mortality: a population-based observational study
Authors: Zhang Huifeng , Xu Ying , Xu Yaying
Published: July 2024

Background

Cardiovascular disease (CVD) and depression have a bidirectional association, with inflammation and metabolic factors being common important triggers for both conditions. However, as a novel inflammatory and metabolic marker, platelet-to-HDL-C ratio (PHR) has not been established in relation to depression and cardiovascular disease.

Materials and methods

Participants aged 20 years and older were included in the 2005–2018 NHANES database. PHR was calculated as the ratio of platelet count (1000 cells/μL) to HDL-C (mmol/L). The Patient Health Questionnaire (PHQ-9) was used to diagnose depression, with a cutoff value of 10. Weighted logistic regression analysis and restricted cubic spline (RCS) analysis were employed to examine the association between PHR and depression-related features. Additionally, weighted COX regression and RCS were used to analyze the association of PHR with CVD mortality in patients with depression. Receiver operating characteristic curves were used to assess whether PHR had an advantage over HDL-C in predicting depression. Finally, the mediating role of PHR in the latest cardiovascular health indicator Life’s Essential 8 and depression was explored.

Results

A total of 26,970 eligible participants were included, including 2,308 individuals with depression, representing approximately 160 million U.S. adults when weighted. After full adjustment, we estimated that the odds ratio (OR) of depression associated with a per standard deviation (SD) increase in PHR was 1.06 (95% CI: 1.01–1.12, P=0.03). The restricted cubic spline (RCS) analysis indicated a linear association (Nonlinear P=0.113). When PHR was divided into four groups based on quartiles and included in the model after full adjustment for depression risk factors, participants in quartile 2, quartile 3, and quartile 4 of PHR showed a trend of increasing risk of depression compared to the lowest quartile group (P trend=0.01). In addition, weighted COX regression and RCS revealed that a per SD increase in PHR was associated with a higher risk of CVD mortality among patients with depression (HR: 1.38, 95% CI: 1.05–1.81, P=0.02, Nonlinear P=0.400). Subgroup analyses showed that current alcohol consumption enhanced the association between PHR and depression (P for interaction=0.017). Furthermore, the areas under the ROC curves (AUC) were 0.556 (95% CI, 0.544–0.568; P < 0.001) for PHR and 0.536 (95% CI, 0.524–0.549; P < 0.001) for HDL-C (PDeLong = 0.025). Finally, mediation analysis indicated that PHR was an intermediate mechanism between LE8 and depression (mediation proportion=5.02%, P=0.02).

Conclusion

In U.S. adults, an increase in PHR linearly increases the risk of depression and CVD mortality among individuals with depression. Additionally, PHR has a better predictive advantage for depression compared to HDL-C. Furthermore, PHR significantly mediates the association between LE8 scores and depression.
Genetically predicted small dense low-density lipoprotein cholesterol and ischemic stroke subtype: multivariable Mendelian randomization study
Authors: Yu Xiao , Shen Guangxun , Zhang Yan , Cui Cancan , Zha Yining , Li Pingan , Li Lihong , Wang Xu , Nan Guangxian
Published: July 2024

Purpose

Small dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design.

Methods

We identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis.

Results

In univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117–1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106–1.597, P = 0.002).

Conclusions

Findings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.
The effect of hyperuricemia and its interaction with hypertension towards chronic kidney disease in patients with type 2 diabetes: evidence from a cross- sectional study in Eastern China
Authors: Chen Xiang-yu , Lu Feng , Zhang Jie , Xu Chun-xiao , Du Xiao-fu , Liang Ming-bin , Chen Li-jin , Zhong Jie-ming
Published: July 2024

Objectives

This study aimed to explore the synergistic interaction effect between hyperuricemia and hypertension towards chronic kidney disease in patients with type 2 diabetes.

Methods

This research originates from a cross-sectional study performed in Zhejiang Province, Eastern China, between March and November 2018. The correlation between serum uric acid levels and the risk of chronic kidney disease was assessed using a restricted cubic spline model. An unconditional multivariable logistic regression model, along with an interaction table, was utilized to explore the potential interaction effect of hyperuricemia and hypertension towards chronic kidney disease.

Results

1,756 patients with type 2 diabetes were included in this study, the prevalence of chronic kidney disease (CKD) was 27.62% in this population. A U-shaped non-linear pattern emerged correlating serum uric acid (SUA) levels and CKD risk, indicating that both low and high SUA levels were linked to an increased CKD risk. This risk achieved its lowest point (nadir) at SUA approximately equals to 285μmol/L (p for trend <0.05). Once adjustments for age, gender, education level, abnormal fasting plasma glucose (FPG), abnormal hemoglobin A1c (HbA1c), abnormal total cholesterol (TC), abnormal high-density lipoprotein cholesterol (HDL-C), alcohol consumption and duration of diabetes were factored in, it was found that patients with both hyperuricemia and hypertension demonstrated a 5.42-fold (95% CI: 3.72–7.90) increased CKD risk compared to the reference group. The additive interaction between hyperuricemia and hypertension was statistically significant, as manifested by the following values: a relative excess risk due to interaction (RERI) of 2.57 (95% CI: 0.71–4.71), an attributable proportion due to interaction (AP) of 0.47 (95% CI: 0.14–0.64), and a synergy index (SI) of 2.39 (95% CI: 1.24–4.58). In contrast, there was no significant interaction effect in multiplicative scale.

Conclusion

Hyperuricemia and hypertension may contribute additively to CKD, beyond their isolated impacts. Evaluating the risk of CKD in type 2 diabetes patients necessitates considering this potential interaction.
The identification and expression analysis of walnut Acyl-ACP thioesterases
Authors: Wang Hui , Shi Jianqing , Guo Wanhui , Sun Xiaohui , Niu Shuhui , Chen Li , Liu Shenghong , Ma Lei
Published: July 2024

Walnuts (Juglans regia L.), renowned for their nutritional potency, are a rich source of unsaturated fatty acids. Their regular intake plays a pivotal role in health maintenance and recuperation from a myriad of ailments. Fatty acyl-acyl carrier protein thioesterases, which orchestrate the hydrolysis of acyl-ACP thioester bonds, thereby yielding fatty acids of varying chain lengths, are instrumental in augmenting plant fatty acid content and modulating the balance between saturated and unsaturated fatty acids. Despite some investigative efforts into the synthesis and metabolic pathways of fatty acids in walnuts, our comprehension of Fat in walnuts remains rudimentary. This research undertook a comprehensive characterization of the JrFat family, predicated on the complete genome sequence of walnuts, leading to the identification of 8 JrFat genes and an exploration of their protein physicochemical properties. Utilizing Arabidopsis and soybean Fat genes as outgroups, JrFat genes can be categorized into 5 distinct subgroups, three of which encompass a pair of homologous gene pairs. These genes have demonstrated remarkable conservation throughout the evolutionary process, with highly analogous conserved base sequences. The promoter region of JrFats genes predominantly harbors light response and plant hormone response regulatory elements, with no discernible disparity in promoter elements among different JrFats. Predictive analyses indicate that JrFats proteins engage extensively with walnut fatty acid synthesis and metabolism-associated proteins. qRT-PCR analysis reveals an initial surge in the expression of JrFats during the development of walnut kernels, which either stabilizes or diminishes following the hard core period. Homologous gene pairs exhibit analogous expression patterns, and the expression trajectory of JrFats aligns with the dynamic accumulation of fatty acids in kernels. The expression of JrFatA2 exhibits a strong correlation with the content of Alpha-linolenic acid, while the expression of JrFatB2 is inversely correlated with the content of two saturated fatty acids. Collectively, these findings enrich our understanding of fatty acid synthesis and metabolism in walnuts and furnish gene resources for enhancing the content and ratio of fatty acids in walnuts.
Transcriptome analysis reveals the pathogenesis of spontaneous tibial dyschondroplasia in broilers
Authors: Shi Kai , Wu Yongfu , Jiang Xusheng , Liu Xiangping , Du Yuesong , Feng Chungang , Li Dongfeng
Published: July 2024

Tibial dyschondroplasia (TD) is a severe bone disease that affects fast-growing broiler chickens and causes economic loss. Despite previous studies, the regulatory mechanism of TD remains unclear and is thought to be primarily based on thiram induction, which may differ from that of naturally occurring diseases. To better understand TD, a digital X-ray machine was used in the present study to determine its incidence in four hundred yellow-feathered broiler chickens. The results showed that the incidence of TD was 22% after 6 weeks and gradually decreased after 8 and 10 weeks. The body weight of broilers with TD decreased significantly compared to that of NTD broilers. In addition, the length and density of the tibia were reduced after eight and 10 weeks, and the density of the tibia was reduced after 6 weeks compared with the NTD chickens. This study also examined tibial quality parameters from TD (n = 12) and NTD broilers (n = 12) and found that bone mineral content, bone mineral density, bone ash content, calcium content, and phosphorus content were significantly reduced in TD broilers. Transcriptome analysis revealed 849 differentially expressed genes (DEGs) in the growth plate between TD (n = 6) and NTD groups (n = 6). These genes were enriched in ECM-receptor interaction, cytokine-cytokine receptor interaction, calcium signaling pathway, and TGF-β signaling. Genes encoding the alpha chain of type XII collagen, that is, COL1A1, COL5A1, and COL8A1) were identified as critical in the regulatory network of TD. Gene set enrichment analysis (GSEA) revealed that the pathways of cartilage development, circulatory system development, and nervous system development were changed in the growth plates of TD birds. In the blood transcriptome, 12 DEGs were found in TD (n = 4) and NTD chickens (n = 4), and GSEA revealed that the pathways from TD broilers’ blood related to the phagosome, linoleic acid metabolism, monoatomic ion homeostasis, and calcium ion transport were downregulated. This study provides a comprehensive understanding of TD, including its effects on tibial quality, tibial changes, and the circulatory system, along with identifying important genes that may lead to the development of TD.
The distribution and maturation of tertiary lymphoid structures can predict clinical outcomes of patients with gastric adenocarcinoma
Authors: Sun Hui , Liu Yuxi , Cheng Wanjing , Xiong Rong , Gu Wenchao , Zhang Xiaoyan , Wang Xin , Wang Xu , Tan Cong , Weng Weiwei , Zhang Meng , Ni Shujuan , Huang Dan , Xu Midie , Sheng Weiqi , Wang Lei
Published: July 2024

Introduction

Tertiary lymphoid structures (TLSs) are analogues of secondary lymphoid organs that contain various immune cells. The spatial distribution, maturation and composition of TLSs have differential effects on prognosis, and the roles of TLSs in gastric adenocarcinoma (GA) have not been revealed.

Methods

Thus, we evaluated the prognostic value of TLSs in GA through analysis of bulk RNA sequencing(RNA-seq) data from public databases and validated our findings in tumour samples from the Fudan University Shanghai Cancer Center (FUSCC) cohort. The spatial distribution,maturation, and composition of TLSs in GA were analysed by reviewing H&E-stained sections and by multiplex immunofluorescence (mIF) staining.

Results

We found that TLSs, especially TLSs with germinal centres (GCs) and TLSs located in the invasive margin (IM), were correlated with prolonged overall survival (OS). Second, analysis of public RNA-seq data showed that high dendritic cell (DC) scores were a favourable prognostic factor in GA patients with high scores for both TLSs and GCs. In the FUSCC cohort, DC-LAMP+ DCs weresignificantly enriched in IM-TLSs with GCs, suggesting a potential correlation between the tumour immune activation milieu and the DC abundance. Third, compared to that in TLSs without GCs, the proportion of FOXP3+CD8+ Treg cells was significantly decreased in IM-TLSs with GCs, and the percentage of PD1+CD20+ B cells was significantly increased in TLSs with GCs.

Discussion

Our results demonstrate that the spatial arrangement and maturation of TLSs significantly affect prognosis and indicate that TLSs could be a new additional factor for histopathological evaluation.
Case report: Effective treatment of rituximab-resistant minimal change disease with obinutuzumab in an adult
Authors: Wang Qiang , Lin Lin , Zhen Junhui , Jiang Bei , Liu Guangyi
Published: July 2024

Background

Minimal change disease (MCD) is a common cause of adult nephrotic syndrome. Most adults with MCD achieve complete remission (CR) after initial steroid therapy. However, approximately 30% of adults who respond to steroids experience frequent relapses, becoming steroid-dependent and potentially developing refractory MCD. Treating refractory MCD in adults poses a significant challenge.

Main body

A 37-year-old woman presented to the nephrology department with a 6-year history of MCD. The diagnosis of MCD was confirmed via renal biopsy. She initially achieved CR with steroid treatment but experienced relapse during steroid tapering. Subsequent CR was achieved with a regimen of steroids and tacrolimus although multiple relapses occurred. Rituximab led to another CR, but its maintenance lasted only 6 months. The response to subsequent rituximab treatments was unsatisfactory. Ultimately, obinutuzumab was selected, resulting in the induction and maintenance of CR for 12 months.

Conclusions

This case demonstrates the successful treatment of frequently relapsed, steroid-dependent, and rituximab-resistant MCD with obinutuzumab. Obinutuzumab is a promising therapeutic option for rituximab-resistant MCD.
Ceramide metabolism alterations contribute to Tumor Necrosis Factor-induced melanoma dedifferentiation and predict resistance to immune checkpoint inhibitors in advanced melanoma patients
Authors: Dufau Carine , Genais Matthieu , Mucher Elodie , Jung Benjamin , Garcia Virginie , Montfort Anne , Tosolini Marie , Clarke Christopher J. , Medin Jeffrey A. , Levade Thierry , Delord Jean-Pierre , Meyer Nicolas , Pancaldi Vera , Andrieu-Abadie Nathalie , Ségui Bruno
Published: July 2024

Introduction

Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation. Interestingly, accumulating evidence suggests that TNF may play a role in melanoma progression and resistance to immunotherapies. Additionally, TNF has been identified as a potent regulator of sphingolipid metabolism, which could contribute to melanoma aggressiveness and the process of melanoma dedifferentiation.

Methods

We conducted RNA sequencing and mass spectrometry analyses to investigate TNF-induced dedifferentiation in two melanoma cell lines. In vitro experiments were performed to manipulate sphingolipid metabolism using genetic or pharmacologic alterations in combination with TNF treatment, aiming to elucidate the potential involvement of this metabolism in TNF-induced dedifferentiation. Lastly, to evaluate the clinical significance of our findings, we performed unsupervised analysis of plasma sphingolipid levels in 48 patients receiving treatment with immune checkpoint inhibitors, either alone or in combination with anti-TNF therapy.

Results

Herein, we demonstrate that TNF-induced melanoma cell dedifferentiation is associated with a global modulation of sphingolipid metabolism. Specifically, TNF decreases the expression and activity of acid ceramidase (AC), encoded by the ASAH1 gene, while increasing the expression of glucosylceramide synthase (GCS), encoded by the UGCG gene. Remarkably, knockdown of AC alone via RNA interference is enough to induce melanoma cell dedifferentiation. Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation. Lastly, analysis of plasma samples from patients treated with immune checkpoint inhibitors, with or without anti-TNF therapy, revealed significant predictive sphingolipids. Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy.

Discussion

Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy.
Single-cell RNA sequencing reveals that MYBL2 in malignant epithelial cells is involved in the development and progression of ovarian cancer
Authors: Shao Wenwen , Lin Zhiheng , Xiahou Zhikai , Zhao Fu , Xu Jue , Liu Xinqi , Cai Pingping
Published: July 2024

Background

Ovarian carcinoma (OC) is a prevalent gynecological malignancy associated with high recurrence rates and mortality, often diagnosed at advanced stages. Despite advances in immunotherapy, immune exhaustion remains a significant challenge in achieving optimal tumor control. However, the exploration of intratumoral heterogeneity of malignant epithelial cells and the ovarian cancer tumor microenvironment is still limited, hindering our comprehensive understanding of the disease.

Materials and methods

Utilizing single-cell RNA sequencing (scRNA-seq), we comprehensively investigated the cellular composition across six ovarian cancer patients with omental metastasis. Our focus centered on analysis of the malignant epithelial cells. Employing CytoTRACE and slingshot pseudotime analyses, we identified critical subpopulations and explored associated transcription factors (TFs) influencing ovarian cancer progression. Furthermore, by integrating clinical factors from a large cohort of bulk RNA sequencing data, we have established a novel prognostic model to investigate the impact of the tumor immune microenvironment on ovarian cancer patients. Furthermore, we have investigated the condition of immunological exhaustion.

Results

Our study identified a distinct and highly proliferative subgroup of malignant epithelial cells, known as C2 TOP2A+ TCs. This subgroup primarily consisted of patients who hadn’t received neoadjuvant chemotherapy. Ovarian cancer patients with elevated TOP2A expression exhibited heightened sensitivity to neoadjuvant chemotherapy (NACT). Moreover, the transcription factor MYBL2 in this subgroup played a critical role in ovarian cancer development. Additionally, we developed an independent prognostic indicator, the TOP2A TCs Risk Score (TTRS), which revealed a correlation between the High TTRS Group and unfavorable outcomes. Furthermore, immune infiltration and drug sensitivity analyses demonstrated increased responsiveness to Paclitaxel, Cisplatin, and Gemcitabine in the Low TTRS Group.

Conclusion

This research deepens our understanding of malignant epithelial cells in ovarian cancer and enhances our knowledge of the ovarian cancer immune microenvironment and immune exhaustion. We have revealed the heightened susceptibility of the C2 TOP2A+ TCs subgroup to neoadjuvant chemotherapy and emphasized the role of MYBL2 within the C2 subgroup in promoting the occurrence and progression of ovarian cancer. These insights provide valuable guidance for the management of ovarian cancer treatment.
Connotation analysis and path discussion of China’s land-sea coordination policy: based on the interregional externality theory
Authors: Li Yanping , Wang Yuping , Liu Dahai , Hou Yuting
Published: July 2024

As two spatial geographic units that are both independent of each other and closely linked, the land and sea have complex spatial interactions. Therefore, China implements the land-sea coordination policy (LSC) needs to be approached from a more macroscopic, systematic and comprehensive perspective. Based on the interregional externality theory, this study takes the land-sea coordination policy of China as an example, and focuses on the interaction process and manifestation between land and sea, and then explores the connotation and realization path of LSC. Firstly, we delineated the spatial unit and analyzed the land-sea interactions (LSI) using Vensim software. Secondly, the characteristics and manifestations of LSI are summarized from the perspective of interregional externalities. Finally, this study elucidates the foundational concept of implementing LSC and further propose actionable pathways for promoting land and sea development in a coordinated way, aimed at offering supportive decision-making insights for achieving LSC within the broader framework of China’s territorial spatial planning. Initiating LSC implementation involves strategies such as source control, process management, and interaction interface optimization. Deepening LSC effectiveness entails strengthening positive interregional externalities while mitigating negative interregional externalities.
Diagnostic test performance of the Mentzer index in evaluating Saudi children with microcytosis
Authors: AlQarni Amani M. , Althumairi Arwa , Alkaltham Nourah K. , AlJishi Samaa , Hakami Amani Mohammed , Abdalla Leena Mohamed Osman Ali , Alawi Zahra Sayed Jalal , Alreedy Abdullah H.
Published: July 2024

Background

Anemia is a global public health concern, affecting both developing and industrialized countries at a rate of 39.8%. It is defined by low hemoglobin concentration, and anemia varies in severity based on age: <11 g/dL (6–59 months), <11.5 g/dL (5–11 years), and < 12 g/dL (12–14 years).

Aim

This study evaluates the Mentzer index’s reliability in differentiating iron deficiency anemia from the thalassemia trait.

Methods

A total of 434 children (≤16 years) with hemoglobin electrophoresis previously screened for microcytosis (MCV <80 FL) and an iron profile were included. Children with other hematological conditions were excluded.

Results

Out of 434 children, 181 were diagnosed with thalassemia, and 345 had iron deficiency anemia. The Mentzer index showed 74% sensitivity and 63% specificity for the beta-thalassemia trait, with 61% sensitivity and 36% specificity for iron deficiency anemia. The beta-thalassemia trait group had the highest negative predictive value (98%), while iron deficiency anemia had the highest positive predictive value (79%).

Conclusion

Our study, which is consistent with previous literature, suggests that the Mentzer index is not highly reliable in distinguishing iron deficiency anemia from the thalassemia trait among children in Saudi Arabia.
The one-year incidence of stroke in patients with atrial fibrillation in Jordan and its associated factors
Authors: Al-Shatanawi Tariq N. , Alkouri Osama , Khader Yousef , ALSalamat Husam , Qaladi Omar Aawadh , Jarrah Mohamad , Ababneh Anas , Al-Awaisheh Raed , Zamil Taqialdeen , Hammoudeh Ayman
Published: July 2024

Background

An elevated risk of stroke is linked to atrial fibrillation (AF). Effective care and prevention measures for individuals with AF require an understanding of the factors impacting the incidence of stroke in this population. Evidence regarding the incidence of stroke among patients with AF is insufficient in Jordan. This study aimed to determine the incidence of stroke and its associated factors among patients with AF in Jordan.

Methods

The Jordan Atrial Fibrillation Registry JoFib was used to identify a total of 2020 AF patients meeting the study inclusion and exclusion criteria. Demographics, clinical characteristics, and the CHA2DS2-VASc score-based evaluation of stroke risk were extracted from the registry.

Results

This study encompassed 2020 participants diagnosed with AF, with 925 (45.8%) being men and 1,095 (54.2%) women. The one-year stroke incidence among the 2020 AF patients was 3.4%. Notably, stroke incidence significantly increased with age (p = 0.04) and was associated with the history of stroke (7.4% vs. 2.7%), hypertension (3.9% vs. 1.9%), and diabetes (5.1% vs. 2.1%). In the multivariate analysis, diabetes (OR = 2.6, 95% CI: 1.5–4.4, p = 0.001) and history of stroke (OR = 2.6, 95% CI: 1.5–4.6, p = 0.001) were significantly associated with stroke incidence.

Conclusion

This study emphasizes Jordan’s high stroke rate among AF patients. Diabetes and prior stroke history are associated with increased odds of stroke, like all stroke patients. These results highlight the necessity for specialized management strategies among AF patients and highlight the significance of thorough risk assessment and focused interventions to reduce stroke risk in AF patients.
Hibernating ribosomes as drug targets?
Authors: Ekemezie Chinenye L. , Melnikov Sergey V.
Published: July 2024

When ribosome-targeting antibiotics attack actively growing bacteria, they occupy ribosomal active centers, causing the ribosomes to stall or make errors that either halt cellular growth or cause bacterial death. However, emerging research indicates that bacterial ribosomes spend a considerable amount of time in an inactive state known as ribosome hibernation, in which they dissociate from their substrates and bind to specialized proteins called ribosome hibernation factors. Since 60% of microbial biomass exists in a dormant state at any given time, these hibernation factors are likely the most common partners of ribosomes in bacterial cells. Furthermore, some hibernation factors occupy ribosomal drug-binding sites – leading to the question of how ribosome hibernation influences antibiotic efficacy, and vice versa. In this review, we summarize the current state of knowledge on physical and functional interactions between hibernation factors and ribosome-targeting antibiotics and explore the possibility of using antibiotics to target not only active but also hibernating ribosomes. Because ribosome hibernation empowers bacteria to withstand harsh conditions such as starvation, stress, and host immunity, this line of research holds promise for medicine, agriculture, and biotechnology: by learning to regulate ribosome hibernation, we could enhance our capacity to manage the survival of microorganisms in dormancy.
Protective effects of a probiotic-fermented germinated grain complex on neurotransmitters and sleep quality in sleep-deprived mice
Authors: Cheng Jiahua , Wu Qiqi , Sun Rui , Li Wujuan , Wang Zhuoling , Zhou Min , Yang Tian , Wang Jing , Lyu Yuhong , Yue Changwu
Published: July 2024

Objective

To explore the effects of probiotic fermentation products of germinated grains on cognitive and sleep improvement in mice with sleep deprivation induced by chlorophenylalanine (PCPA), and to provide theoretical and experimental basis for the development of natural products to alleviate insomnia.

Methods

ELISA and high-performance liquid chromatography (HPLC) were used to determine the contents of γ-aminobutyric acid and L-theanine in fermentation products. Open Field Test was used to analyze the changes of emotional behavior between groups before and after intervention. ELISA was used to analyze the changes of hypothalamic serotonin, GABA, glutamate, and serum interleukin 6. 16S rRNA sequencing was used to analyze the changes of intestinal flora before and after the intervention of compound fermentation products. LC–MS/MS was used to analyze the changes of intestinal SCFAs before and after the intervention.

Results

The content of GABA and L-theanine in 7 L fermentation products was 12.555 μmol/L (1.295 mg/L) and 0.471 mg/mL by ELISA. Compared with the PCPA-induced Model group, the sleep duration of the KEY group was statistically significant (p < 0.0001). Compared with the PCPA-induced Model group, the number of crossing the central lattice in the KEY group was significantly increased, and the number of grooming was significantly reduced (all p < 0.05), suggesting that the anxiety behavior of the mice was improved. In addition, this study found that the compound fermentation products could significantly increase the content of neurotransmitters such as 5-HT, GABA and Glu in the hypothalamus of mice, reduce the content of inflammatory factors such as IL-6, IL-1β and TNF-α in serum, regulate the structure of intestinal flora and increase the content of short-chain fatty acids.

Conclusion

Probiotic fermentation products of germinated grains can significantly improve sleep deprivation in PCPA mice, which may be related to regulating the levels of neurotransmitters and inflammatory factors, improving the structure of intestinal flora, and increasing the content of short-chain fatty acids. This study provides new candidates and research directions for the development of natural drugs to alleviate insomnia.
Rescue and characterization of PCV4 infectious clones: pathogenesis and immune response in piglets
Authors: Chen Lan , Deng Li-Shuang , Xu Tong , Lai Si-Yuan , Ai Yan-Ru , Zhu Ling , Xu Zhi-Wen
Published: July 2024

Porcine circovirus 4 (PCV4) was first identified in 2019, categorized within the genus Circovirus in the family Circoviridae. To date, the virus has not been isolated from clinical samples. Meanwhile, many aspects of the biology and pathogenic mechanisms of PCV4 infection remain unknown. In this study, PCV4 was successfully rescued from an infectious clone. We utilized a PCV4 virus stock derived from this infectious clone to intranasally inoculate 4-week-old specific-pathogen-free piglets to evaluate PCV4 pathogenesis. The rescued PCV4 was capable of replicating in both PK-15 cells and piglets, with the virus detectable in nearly all collected samples from the challenge groups. Pathological lesions and PCV4-specific antigens were observed in various tissues and organs, including the lungs, kidneys, lymph nodes, spleen, and liver, in the inoculated piglets. Additionally, the levels of pro-inflammatory cytokines in the serum of the PCV4-inoculated group were significantly elevated compared to the control group, indicating that the induced inflammatory response may contribute to tissue damage associated with PCV4 infection. These findings offer new insights into the pathogenesis and inflammatory responses associated with PCV4-related diseases.
Effect of chiral silver nanoparticles on prolyl-oligopeptidase binding and activity
Authors: Batista Carin C. S. , Toledo Victor H. , Ramos Marcos P. C. , Oliveira Vitor , Acuña Javier , Icimoto Marcelo Y. , Nantes Iseli L.
Published: July 2024

Introduction: Silver nanoparticles have a diversity of applications both in biological and technological areas. More recently, studies conducted in the Nano/Bio interface have demonstrated that chiral nanocrystals grew in chiral templates, and nanostructures functionalized with chiral molecules present specific properties. These properties apply to advanced materials, energy, medicine, and pharmacology.

Methodology: The present study synthesized silver nanoparticles on silver seeds using D- and L-histidine as templates and borohydride as a reducing agent.

Results and Discussion: The nanoparticles were characterized by UV-visible spectroscopy and presented surface plasmon resonance (SPR) bands around 415 nm. CD spectra showed signals in the region of the SPR band, indicating the growth of nanocrystals with chiral distortion. Synthesized silver nanoparticles were also characterized by high-resolution transmission electron microscopy (HRTEM), which evidenced the presence of histidine corona. The silver nanoparticles were functionalized with prolyl-oligopeptidase (POP), a prolinespecific endopeptidase expressed in the brain. This enzyme cleaves neuroactive peptides involved in memory, learning, and neurodegeneration. The enzyme POP was expressed with a His-tag to provide competitive binding affinity to silver nanoparticles covered by D- and L-histidine. Considering the biological importance, POP was chosen as a model for studying the functionalization of chiral silver nanoparticles regarding the chiral discrimination for binding affinity and stabilization.