bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of machine learning models for venous thromboembolism risk assessment at admission: a retrospective study
Authors: Sheng Wenbo , Wang Xiaoli , Xu Wenxiang , Hao Zedong , Ma Handong , Zhang Shaodian
Published: August 2023

Introduction

Venous thromboembolism (VTE) risk assessment at admission is of great importance for early screening and timely prophylaxis and management during hospitalization. The purpose of this study is to develop and validate novel risk assessment models at admission based on machine learning (ML) methods.

Methods

In this retrospective study, a total of 3078 individuals were included with their Caprini variables within 24 hours at admission. Then several ML models were built, including logistic regression (LR), random forest (RF), and extreme gradient boosting (XGB). The prediction performance of ML models and the Caprini risk score (CRS) was then validated and compared through a series of evaluation metrics.

Results

The values of AUROC and AUPRC were 0.798 and 0.303 for LR, 0.804 and 0.360 for RF, and 0.796 and 0.352 for XGB, respectively, which outperformed CRS significantly (0.714 and 0.180, P < 0.001). When prediction scores were stratified into three risk levels for application, RF could obtain more reasonable results than CRS, including smaller false positive alerts and larger lower-risk proportions. The boosting results of stratification were further verified by the net-reclassification-improvement (NRI) analysis.

Discussion

This study indicated that machine learning models could improve VTE risk prediction at admission compared with CRS. Among the ML models, RF was found to have superior performance and great potential in clinical practice.
Authentication, access, and monitoring system for critical areas with the use of artificial intelligence integrated into perimeter security in a data center
Authors: Villegas-Ch William , García-Ortiz Joselin
Published: August 2023

Perimeter security in data centers helps protect systems and the data they store by preventing unauthorized access and protecting critical resources from potential threats. According to the report of the information security company SonicWall, in 2021, there was a 66% increase in the number of ransomware attacks. In addition, the message from the same company indicates that the total number of cyber threats detected in 2021 increased by 24% compared to 2019. Among these attacks, the infrastructure of data centers was compromised; for this reason, organizations include elements Physical such as security cameras, movement detection systems, authentication systems, etc., as an additional measure that contributes to perimeter security. This work proposes using artificial intelligence in the perimeter security of data centers. It allows the automation and optimization of security processes, which translates into greater efficiency and reliability in the operations that prevent intrusions through authentication, permit verification, and monitoring critical areas. It is crucial to ensure that AI-based perimeter security systems are designed to protect and respect user privacy. In addition, it is essential to regularly monitor the effectiveness and integrity of these systems to ensure that they function correctly and meet security standards.
School attendance problems and absenteeism as early warning signals: review and implications for health-based protocols and school-based practices
Authors: Kearney Christopher A. , Dupont Randolph , Fensken Michael , Gonzálvez Carolina
Published: August 2023

School attendance has been historically linked to healthy states of functioning, whereas school attendance problems/absenteeism have been historically linked to unhealthy states of functioning. Indeed, school attendance and its problems are deeply embedded within multiple domains of functioning at both analytic and systemic levels. This article utilizes complex systems theory and the concept of early warning signals to illustrate how changes in school attendance could indicate instability and perhaps sudden transitions to unhealthy states of functioning for students, families, schools, and communities. The article reviews how school attendance problems/absenteeism intersect with functioning at analytic (academic, social–emotional, mental health, physical health, family) and systemic (school and community) levels. The article also includes recommendations for how viewing changes in school attendance as early warning signals could improve health-based protocols (enhancing access to care; integrating systems of care) and school-based practices (developing multi-tiered systems of support models and community asset maps; modifying educational and policy perspectives). A primary theme involves more streamlined efforts to identify movement from healthy to unhealthy states among individuals to assign proactive and personalized treatment avenues (health-based protocols) and among systems to enact needed intervention supports and reforms (school-based practices).
The landscape of implantation and placentation: deciphering the function of dynamic RNA methylation at the maternal-fetal interface
Authors: Wu Shengyu , Xie Han , Su Yao , Jia Xinrui , Mi Yabing , Jia Yuanhui , Ying Hao
Published: August 2023

The maternal-fetal interface is defined as the interface between maternal tissue and sections of the fetus in close contact. RNA methylation modifications are the most frequent kind of RNA alterations. It is effective throughout both normal and pathological implantation and placentation during pregnancy. By influencing early embryo development, embryo implantation, endometrium receptivity, immune microenvironment, as well as some implantation and placentation-related disorders like miscarriage and preeclampsia, it is essential for the establishment of the maternal-fetal interface. Our review focuses on the role of dynamic RNA methylation at the maternal-fetal interface, which has received little attention thus far. It has given the mechanistic underpinnings for both normal and abnormal implantation and placentation and could eventually provide an entirely novel approach to treating related complications.
Association of angiotensin II and receptors in peri-implantation endometrium with microvessel density and pregnancy outcomes of women with recurrent implantation failure after embryo transfer
Authors: Qi Ruofan , Zhang Tao , Zhang Yingying , Chung Jacqueline Pui Wah , Yang Wen-Jui , Wang Chi Chiu
Published: August 2023

Purpose

Investigate whether local angiotensin II (AngII) and its AngII type 1 and 2 receptors (AT1R, AT2R) in the endometrium are different and correlate with microvessel density in women with reproductive failure and pregnancy outcomes.

Methods

Endometrium during the window of implantation from 40 women with recurrent miscarriage (RM) and 40 with recurrent implantation failure (RIF) were compared with 27 fertile women. Peri-implantation endometrium from 54 women prior to euploid embryo transfer were collected and compared in women with successful pregnancy and unsuccessful pregnancy.

Results

Compared with fertile women, expression of AT2R was significantly lower, while AT1R/AT2R expression ratio was significantly higher in the stroma of the RIF group. Endometrium arteriole MVD was significantly lower and negatively correlated with the AT1R/AT2R expression ratio in the stroma of the RIF group. No significant differences and correlations were found in the RM group. Compared with the pregnancy group, expression of AT1R and AT2R were significantly lower in all compartments, but only AT1R/AT2R ratio was significantly higher in the stroma of the non-pregnancy group. Similarly, endometrium arteriole MVD was also significantly lower and negatively correlated with the AT1R/AT2R ratio in the stroma of the non-pregnancy group.

Conclusion

Local renin-angiotensin system is dysregulated in peri-implantation endometrium and associated with abnormal angiogenesis in RIF and poor implantation outcome after embryo transfer.
Role of bone marrow adipocytes in bone metastasis development and progression: a systematic review
Authors: Salamanna F. , Contartese D. , Errani C. , Sartori M. , Borsari V. , Giavaresi G.
Published: August 2023

Purpose

Bone marrow adipocytes (BMAs) are the most plentiful cells in the bone marrow and function as an endocrine organ by producing fatty acids, cytokines, and adipokines. Consequently, BMAs can interact with tumor cells, influencing both tumor growth and the onset and progression of bone metastasis. This review aims to systematically evaluate the role of BMAs in the development and progression of bone metastasis.

Methods

A comprehensive search was conducted on PubMed, Web of Science, and Scopus electronic databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards, to identify studies published from March 2013 to June 2023. Two independent reviewers assessed and screened the literature, extracted the data, and evaluated the quality of the studies. The body of evidence was evaluated and graded using the ROBINS-I tool for non-randomized studies of interventions and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool for in vivo studies. The results were synthesized using descriptive methods.

Results

The search yielded a total of 463 studies, of which 17 studies were included in the final analysis, including 15 preclinical studies and two non-randomized clinical studies. Analysis of preclinical studies revealed that BMAs play a significant role in bone metastasis, particularly in prostate cancer followed by breast and malignant melanoma cancers. BMAs primarily influence cancer cells by inducing a glycolytic phenotype and releasing or upregulating soluble factors, chemokines, cytokines, adipokines, tumor-derived fatty acid-binding protein (FABP), and members of the nuclear receptor superfamily, such as chemokine (C-C motif) ligand 7 (CCL7), C-X-C Motif Chemokine Ligand (CXCL)1, CXCL2, interleukin (IL)-1β, IL-6, FABP4, and peroxisome proliferator-activated receptor γ (PPARγ). These factors also contribute to adipocyte lipolysis and regulate a pro-inflammatory phenotype in BMAs. However, the number of clinical studies is limited, and definitive conclusions cannot be drawn.

Conclusion

The preclinical studies reviewed indicate that BMAs may play a crucial role in bone metastasis in prostate, breast, and malignant melanoma cancers. Nevertheless, further preclinical and clinical studies are needed to better understand the complex role and relationship between BMAs and cancer cells in the bone microenvironment. Targeting BMAs in combination with standard treatments holds promise as a potential therapeutic strategy for bone metastasis.
Pharmaceutical efficacy of novel human-origin Faecalibacterium prausnitzii strains on high-fat-diet-induced obesity and associated metabolic disorders in mice
Authors: Yang Meng , Wang Jing-Hua , Shin Joo-Hyun , Lee Dokyung , Lee Sang-Nam , Seo Jae-Gu , Shin Ji-Hee , Nam Young-Do , Kim Hojun , Sun Xiaomin
Published: August 2023

Introduction

Obesity and related metabolic issues are a growing global health concern. Recently, the discovery of new probiotics with anti-obesity properties has gained interest.

Methods

In this study, four Faecalibacte-rium prausnitzii strains were isolated from healthy human feces and evaluated on a high-fat diet-induced mouse model for 12 weeks.

Results

The F. prausnitzii strains reduced body weight gain, liver and fat weights, and calorie intake while improving lipid and glucose metabolism in the liver and adipose tissue, as evidenced by regulating lipid metabolism-associated gene expression, including ACC1, FAS, SREBP1c, leptin, and adiponectin. Moreover, the F. prausnitzii strains inhibited low-grade inflammation, restored gut integrity, and ameliorated hepatic function and insulin resistance. Interestingly, the F. prausnitzii strains modulated gut and neural hormone secretion and reduced appetite by affecting the gut-brain axis. Supplementation with F. prausnitzii strains noticeably changed the gut microbiota composition.

Discussion

In summary, the novel isolated F. prausnitzii strains have therapeutic effects on obesity and associated metabolic disorders through modulation of the gut-brain axis. Additionally, the effectiveness of different strains might not be achieved through identical mechanisms. Therefore, the present findings provide a reliable clue for developing novel therapeutic probiotics against obesity and associated metabolic disorders.
Analysis of risk factors for non-alcoholic fatty liver disease in hospitalized children with obesity before the late puberty stage
Authors: Zhou Lishan , Zhang Linli , Zhang Lingling , Yi Wei , Yu Xue , Mei Hong , Xiao Haiyan , Wang Yuji , Qin Huan , Xiong Xiaoli , Yan Suqi , Dong Hui , Chen Peng , Chen Xiaohong
Published: August 2023

Objective

This study aimed to determine the clinical characteristics of obese pediatric non-alcoholic fatty liver disease (NAFLD) in central China and verify the applicability of some known risk factors for pediatric NAFLD before late puberty.

Methods

This was a retrospective case–control study. A total of 1,029 inpatients at Wuhan Children’s Hospital before the late puberty stage were enrolled in the study, including 815 children with obesity (non-NAFLD group) and 214 children with obesity and NAFLD (NAFLD group) diagnosed by liver ultrasound. Subgroup analyses were performed according to sex and puberty. The anthropometric indices and laboratory test data of these 1,029 children were sorted. After intergroup comparison, a logistic regression model was used to determine the risk factors for pediatric NAFLD. Significant risk factors for NAFLD were further tested using receiver operating characteristic (ROC) curves to evaluate their ability to predict an early diagnosis of NAFLD.

Results

The NAFLD group had a mean age of 11.03 ± 1.66, with 11.18 ± 1.66 and 10.27 ± 1.45 years for male and female children, respectively (p < 0.05 and p < 0.01, respectively). Even subdivided by both sex and puberty, raised body mass index (BMI), homeostatic model-insulin resistance, triglycerides, alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (γ-GT) were still found in the non-NAFLD and NAFLD groups (p < 0.05 and p < 0.01, respectively). The results of logistic regression analysis showed that BMI (odds ratio [OR], 1.468;95% confidence interval [CI], 1.356-1.590; p<0.001) and ALT (OR, 1.073;95%CI, 1.060-1.087; P<0.001) were two most independent risk factors for NAFLD. The maximal OR for BMI was 1.721 (95% CI, 1.336–2.217). In the female group, the maximal OR of ALT was found to be 1.104 (95% CI, 1.061–1.148). Age and thyroid-stimulating hormone (TSH) and γ-GT levels were also risk factors, but they appeared only in some groups. The results of the ROC analysis showed that ALT was a better predictor of pediatric NAFLD than BMI. The maximum area under the ROC curve in six of the nine groups belongs to ALT.

Conclusions

BMI, ALT, and age are risk factors for NAFLD in children with obesity before late puberty. BMI had the greatest exposure risk for NAFLD, and ALT had the highest predictive value for the diagnosis of NAFLD. At the stratified level, for exposure risk, age was specific to the male sex, TSH was specific to the early puberty stage, and γ-GT was specific to the female sex plus the prepuberty stage. On a stratified level, for the female sex, even with age stratification, BMI rather than ALT has a better ability for the diagnosis of NAFLD.
Early prediction of body composition parameters on metabolically unhealthy in the Chinese population via advanced machine learning
Authors: Deng Xiujuan , Qiu Lin , Sun Xin , Li Hui , Chen Zejiao , Huang Min , Hu Fangxing , Zhang Zhenyi
Published: August 2023

Background

Metabolic syndrome (Mets) is considered a global epidemic of the 21st century, predisposing to cardiometabolic diseases. This study aims to describe and compare the body composition profiles between metabolic healthy (MH) and metabolic unhealthy (MU) phenotype in normal and obesity population in China, and to explore the predictive ability of body composition indices to distinguish MU by generating machine learning algorithms.

Methods

A cross-sectional study was conducted and the subjects who came to the hospital to receive a health examination were enrolled. Body composition was assessed using bioelectrical impedance analyser. A model generator with a gradient-boosting tree algorithm (LightGBM) combined with the SHapley Additive exPlanations method was adapted to train and interpret the model. Receiver-operating characteristic curves were used to analyze the predictive value.

Results

We found the significant difference in body composition parameters between the metabolic healthy normal weight (MHNW), metabolic healthy obesity (MHO), metabolic unhealthy normal weight (MUNW) and metabolic unhealthy obesity (MUO) individuals, especially among the MHNW, MUNW and MUO phenotype. MHNW phenotype had significantly lower whole fat mass (FM), trunk FM and trunk free fat mass (FFM), and had significantly lower visceral fat areas compared to MUNW and MUO phenotype, respectively. The bioimpedance phase angle, waist-hip ratio (WHR) and free fat mass index (FFMI) were found to be remarkably lower in MHNW than in MUNW and MUO groups, and lower in MHO than in MUO group. For predictive analysis, the LightGBM-based model identified 32 status-predicting features for MUNW with MHNW group as the reference, MUO with MHO as the reference and MUO with MHNW as the reference, achieved high discriminative power, with area under the curve (AUC) values of 0.842 [0.658, 1.000] for MUNW vs. MHNW, 0.746 [0.599, 0.893] for MUO vs. MHO and 0.968 [0.968, 1.000] for MUO and MHNW, respectively. A 2-variable model was developed for more practical clinical applications. WHR > 0.92 and FFMI > 18.5 kg/m2 predict the increased risk of MU.

Conclusion

Body composition measurement and validation of this model could be a valuable approach for the early management and prevention of MU, whether in obese or normal population.
Carbon footprint generated by individual port websites. The missing idea in the concept of green ports
Authors: Bielenia Małgorzata , Podolska Anna
Published: August 2023

One of the objectives of European Union policy, as well as the assumptions of cooperation as part of United Nations, is to ensure sustainable development. The gradual decarbonisation of the economy is a significant element in this case. This is particularly important in transport, including maritime transport. That is why the concept of Green Ports is so important. It contains various infrastructure solutions that maximize the benefits of maritime transport while minimizing environmental damage. However, the term Green Ports is defined in the literature it is difficult to have a clear definition, a formula that defines the term and there is still a place for scientific research in this area. The purpose of the research is to analyze the assumptions of the Green Ports concept in economic terms, but also in legal terms. The authors want to focus on Internet infrastructure as a link in reducing the carbon footprint in maritime transport. For this purpose, they studied the carbon footprint generated by the websites of selected seaports (seaports considered by the Transport and Environment report (https://www.transportenvironment.org/discover/port-carbon-emissions-ranking/) the most polluting European ports and ports considered by the Leading Maritime Cities 2022 report to be the most technologically advanced (DNV, Menon Economics, 2022 https://www.dnv.com/maritime/publications/leading-maritime-cities-of-the-world-2022.html). Both at the United Nations and at the level of organizations of a regional nature (such as the European Union), the use of new technologies is closely linked to economic development or social progress. For example, access to the Internet has been recognized by the United Nations General Assembly as a human right. This is because it has been recognized that the Internet provides an opportunity to realize other rights, such as freedom of expression, the right to information, and education. However, there are also risks associated with the use of new technologies, if only in terms of the right to privacy, intellectual property, security or a clean environment. According to the authors, far less attention is paid to the risks than to the benefits. That’s why it’s worth building awareness to prevent harm rather than repair it. An important aspect of the research is to show that websites consume large amounts of energy. In addition, they have a negative impact on the environment, influencing the production of a significant amount of carbon dioxide. The main finding from the empirical part is that there is a certain relationship between the generation of CO2 by the ports and the “cleanliness” of their websites.
Prussian blue nanoparticles–mediated sensing and removal of 137Cs
Authors: Pandey Prem C. , Yadav Hari Prakash , Tiwari Atul Kumar , Sawant Shilpa N. , Sinharoy Prithwish , Banerjee Dayamoy , Narayan Roger J.
Published: August 2023

Prussian blue nanoparticles (PBNPs) with controlled nano-geometry were synthesized from a single precursor (potassium hexacyanoferrate) in the presence of three different reagents, namely, polyethylenimine (PEI), tetrahydrofuran (THF)/H2O2, and 2-(3,4-epoxycyclohexyl)-ethyl-trimethoxysilane (EETMS)/cyclohexanone, which enabled the controlled nucleation and stabilization of PBNPs of variable plasmonic activities for selective sensing and removal of cesium radionuclides. The results of this study show the sensing and removal of cesium ions based on the nano-geometry, magnetic behavior, and fluorescence quenching ability of PBNPs as a function of the cesium ion concentration for the first time. A similar process was used to synthetically incorporate PBNPs in mesoporous silica with potential use for the selective adsorption of 137Cs, followed by the detection of radioactivity. The distribution coefficient (Kd) for adsorption of the cesium nuclide 137Cs was calculated to be 3.2 × 104 mL/g−1, displaying both Langmuir and Freundlich adsorption isotherms. The plasmonic activity of PBNPs has enabled fluorometric sensing of cesium ions; regulating the spatial control between the functional PBNPs and fluorescence probe molecules is a promising approach for PBNP-enhanced fluorescence and fluorescence resonance energy transfer–based cesium ion sensing. Similarly, PBNPs display superparamagnetic behavior; these magnetic properties were observed to be linearly dependent on the cesium ion concentration.
Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion
Authors: González-Castrillón Luz María , Wurmser Maud , Öhlund Daniel , Wilson Sara Ivy
Published: August 2023

Background: High nerve density in tumors and metastasis via nerves (perineural invasion—PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve–tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve–tumor crosstalk and to determine common molecular features between PNI-associated cancers.

Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%–16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin–Eph, semaphorin–neuropilin/plexin, and slit–robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival.

Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers.
Multivariate analysis and genetic dissection of staygreen and stem reserve mobilisation under combined drought and heat stress in wheat (Triticum aestivum L.)
Authors: Taria Sukumar , Arora Ajay , Krishna Hari , Manjunath Karthik Kumar , Meena Shashi , Kumar Sudhir , Singh Biswabiplab , Krishna Pavithra , Malakondaiah Animireddy China , Das Ritwika , Alam Badre , Kumar Sushil , Singh Pradeep Kumar
Published: August 2023

Introduction: Abiotic stresses significantly reduce crop yield by adversely affecting many physio-biochemical processes. Several physiological traits have been targeted and improved for yield enhancement in limiting environmental conditions. Amongst them, staygreen and stem reserve mobilisation are two important mutually exclusive traits contributing to grain filling under drought and heat stress in wheat. Henceforth, the present study was carried out to identify the QTLs governing these traits and to identify the superiors’ lines through multi-trait genotype-ideotype distance index (MGIDI)

Methods: A mapping population consisting of 166 recombinant inbred lines (RILs) developed from a cross between HD3086 and HI1500 was utilized in this study. The experiment was laid down in alpha lattice design in four environmental conditions viz. Control, drought, heat and combined stress (heat and drought). Genotyping of parents and RILs was carried out with 35 K Axiom® array (Wheat breeder array).

Results and Discussion: Medium to high heritability with a moderate to high correlation between traits was observed. Principal component analysis (PCA) was performed to derive latent variables in the original set of traits and the relationship of these traits with latent variables.From this study, 14 QTLs were identified, out of which 11, 2, and 1 for soil plant analysis development (SPAD) value, leaf senescence rate (LSR), and stem reserve mobilisation efficiency (SRE) respectively. Quantitative trait loci (QTLs) for SPAD value harbored various genes like Dirigent protein 6-like, Protein FATTY ACID EXPORT 3, glucan synthase-3 and Ubiquitin carboxyl-terminal hydrolase, whereas QTLs for LSR were found to contain various genes like aspartyl protease family protein, potassium transporter, inositol-tetrakisphosphate 1-kinase, and DNA polymerase epsilon subunit D-like. Furthermore, the chromosomal region for SRE was found to be associated with serine-threonine protein kinase. Serine-threonine protein kinases are involved in many signaling networks such as ABA mediated ROS signaling and acclimation to environmental stimuli. After the validation of QTLs in multilocation trials, these QTLs can be used for marker-assisted selection (MAS) in breeding programs.
Menarche, Menstruation, Menopause and Mental Health (4M): a consortium facilitating interdisciplinary research at the intersection of menstrual and mental health
Authors: Sharp Gemma C. , De Giorgio Luana
Published: August 2023

Menstrual and mental health form a close relationship that is under-appreciated in scientific research, clinical practice and social policy. This association is extremely complex, involving interactions between biology, psychology and social, political and structural influences on health and wellbeing. Research in these areas has traditionally been siloed: focusing on menstrual or mental health in isolation, or the interrelation from a limited one-dimensional perspective. We recognised the need for a more holistic and comprehensive approach that considers the complex interweaving nature of menstrual and mental health. In 2021, we established the Menarche, Menstruation, Menopause and Mental Health (4M) consortium as a tool to address this gap and to facilitate interdisciplinary research. This paper provides a comprehensive source of information about 4M for researchers and stakeholders who may be interested in joining or working with the consortium.
Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid
Authors: Iovino Margaud , Colonval Megan , Wilkin Chloé , L’homme Laurent , Lassence Cédric , Campas Manon , Peulen Olivier , de Tullio Pascal , Piette Jacques , Legrand-Poels Sylvie
Published: August 2023

In obesity, adipose tissue infiltrating macrophages acquire a unique pro-inflammatory polarization, thereby playing a key role in the development of chronic inflammation and Type 2 diabetes. Increased saturated fatty acids (SFAs) levels have been proposed to drive this specific polarization. Accordingly, we investigated the immunometabolic reprogramming in SFA-treated human macrophages. As expected, RNA sequencing highlighted a pro-inflammatory profile but also metabolic signatures including glycolysis and hypoxia as well as a strong unfolded protein response. Glycolysis upregulation was confirmed in SFA-treated macrophages by measuring glycolytic gene expression, glucose uptake, lactate production and extracellular acidification rate. Like in LPS-stimulated macrophages, glycolysis activation in SFA-treated macrophages was dependent on HIF-1α activation and fueled the production of pro-inflammatory cytokines. SFAs and LPS both induced IRE1α endoribonuclease activity, as demonstrated by XBP1 mRNA splicing, but with different kinetics matching HIF-1α activation and the glycolytic gene expression. Interestingly, the knockdown of IRE1α and/or the pharmacological inhibition of its RNase activity prevented HIF-1α activation and significantly decreased glycolysis upregulation. Surprisingly, XBP1s appeared to be dispensable, as demonstrated by the lack of inhibiting effect of XBP1s knockdown on glycolytic genes expression, glucose uptake, lactate production and HIF-1α activation. These experiments demonstrate for the first time a key role of IRE1α in HIF-1α-mediated glycolysis upregulation in macrophages stimulated with pro-inflammatory triggers like LPS or SFAs through XBP1s-independent mechanism. IRE1 could mediate this novel function by targeting other transcripts (mRNA or pre-miRNA) through a mechanism called regulated IRE1-dependent decay or RIDD. Deciphering the underlying mechanisms of this novel IRE1 function might lead to novel therapeutic targets to curtail sterile obesity- or infection-linked inflammation.
Dendritic cell-based vaccine prepared with recombinant Lactococcus lactis enhances antigen cross-presentation and antitumor efficacy through ROS production
Authors: Zhang Tingting , Wei Xianxian , Li Yijie , Huang Shuai , Wu Yulin , Cai Shanshan , Aipire Adila , Li Jinyao
Published: August 2023

Introduction

Lactococcus lactis (L.L) is safe and can be used as vehicle. In this study, the immunoregulatory effect of L.L on dendritic cell (DC) activation and mechanism were investigated. The immune responses and antigen cross-presentation mechanism of DC-based vaccine prepared with OVA recombinant L.L were explored.

Methods

Confocal microscopy and flow cytometry were used to analyze the mechanism of L.L promoting DC maturation, phagosome membrane rupture and antigen presentation. The antitumor effect of DC vaccine prepared with L.L-OVA was assessed in the B16-OVA tumor mouse model.

Results

L.L significantly promoted DC maturation, which was partially dependent on TLR2 and downstream MAPK and NF-κB signaling pathways. L.L was internalized into DCs by endocytosis and did not co-localized with lysosome. OVA recombinant L.L enhanced antigen cross-presentation of DCs through the phagosome-to-cytosol pathway in a reactive oxygen species (ROS)- and proteasome-dependent manner. In mouse experiments, L.L increased the migration of DCs to draining lymph node and DC vaccine prepared with OVA recombinant L.L induced strong antigen-specific Th1 and cytotoxic T lymphocyte responses, which significantly inhibited B16-OVA tumor growth.

Conclusion

This study demonstrated that recombinant L.L as an antigen delivery system prepared DC vaccine can enhance the antigen cross-presentation and antitumor efficacy.
Highly rearranged gene orders and rapid evolutionary rates in the mitochondrial genomes of Apodida (Echinodermata: Holothuroidea)
Authors: Sun Shao’e , Ni Gang , Wang Wansheng , Sha Zhongli , Xiao Ning , Xiaoqi Zeng
Published: August 2023

Mitochondrial genome (mitogenome) is a frequently-used tool for phylogenetic and evolutionary studies among metazoans, however, it was still poorly represented in some invertebrate groups, including holothurians. Apodida is one of the most ancient orders of Holothuroidea, with unique characteristics in lacking tube feet and the respiratory tree. Here, we sequenced six mitogenomes from the holothurian order Apodida (Synaptidae and Chiridotidae) and compared them with other available holothurian mitogenomes. The apodan mitogenomes present positive GC skews and negative AT skews, a pattern diametrically opposite to that found in the mitogenomes of other holothurians. The amino acid genetic distances of the 13 protein-coding genes (PCGs) were the highest between Apodida and other holothurians. The mitochondrial gene orders within Apodida were extensively rearranged at the species level, and also were unique from the arrangement patterns of other holothurians. Phylogenetic relationships based on two different criteria: (i) nucleotides sequences with all codon positions (PCG123) and (ii) Neutral Transitions Excluded model (NTE) confirmed the monophyly and basal position of the order Apodida with a long branch. The NTE phylogeny generated a low variation of branch length, but it did not ameliorate the long branch length of Apodida. The divergence time estimation suggested that the Apodida originated in the Middle Carboniferous, implying that they survived the extinction event that occurred in the boundary of the Permian and Triassic. The NTE dataset revealed younger age than that generated by PCG123 dataset. Apodida is accompanied by a faster evolutionary rate than other holothurians (0.0069 vs 0.0043 subs/s/my). The absence of tube feet and the respiratory tree may play an important role in the dramatic evolutionary changes of apodan mitogenomes.
A global unstructured, coupled, high-resolution hindcast of waves and storm surge
Authors: Mentaschi Lorenzo , Vousdoukas Michalis I. , García-Sánchez Guillermo , Fernández-Montblanc Tomás , Roland Aron , Voukouvalas Evangelos , Federico Ivan , Abdolali Ali , Zhang Yinglong J. , Feyen Luc
Published: August 2023

Accurate information on waves and storm surges is essential to understand coastal hazards that are expected to increase in view of global warming and rising sea levels. Despite the recent advancement in development and application of large-scale coastal models, nearshore processes are still not sufficiently resolved due to coarse resolutions, transferring errors to coastal risk assessments and other large-scale applications. Here we developed a 73-year hindcast of waves and storm surges on an unstructured mesh of >650,000 nodes with an unprecedented resolution of 2-4 km at the global coast. Our modelling system is based on the circulation model SCHISM that is fully coupled with the WWM-V (WindWaveModel) and is forced by surface winds, pressure, and ice coverage from the ERA5 reanalysis. Results are compared with observations from satellite altimeters, tidal gauges and buoys, and show good skill for both Sea Surface Height (SSH) and Significant Wave Height (Hs), and a much-improved ability to reproduce the nearshore dynamics compared with previous, lower-resolution studies. Besides SSH, the modelling system also produces a range of other wave-related fields at each node of the mesh with a time step of 3 hours, including the spectral parameters of the first three largest energy peaks. This dataset offers the potential for more accurate global-scale applications on coastal hazard and risk.
Association of C-type lectin-like receptor 2 and galectin-1 with portal vein system thrombosis in HBV-related liver cirrhosis
Authors: Zhang Yiyan , Zhang Xintong , Xu Xiangbo , Guo Xiaozhong , Xu Shixue , Ma Shaoze , Chen Jihong , Qi Xingshun
Published: August 2023

Background and aims

Hepatitis B virus (HBV) infection is the most common cause of liver cirrhosis. Portal venous system thrombosis (PVST) is a major complication of liver cirrhosis. Recently, it has been shown that C-type lectin-like receptor 2 (CLEC-2) and galectin-1 participate in the activation and aggregation of platelets, thereby promoting the development of thrombosis. This cross-sectional study aims to evaluate the association of serum CLEC-2 and galectin-1 levels with PVST in patients with HBV-related liver cirrhosis.

Methods

Overall, 65 patients with HBV-related liver cirrhosis were included, of whom 23 had PVST and 42 did not have. Serum CLEC-2 and galectin-1 levels were measured using enzyme-linked immunosorbent assay kits. PVST was assessed by contrast-enhanced computed tomography and/or magnetic resonance imaging scans. Subgroup analyses were conducted according to the degree and location of PVST.

Results

Patients with PVST had significantly higher serum CLEC-2 (p = 0.006) and galectin-1 (p = 0.009) levels than those without. Patients with partial/complete PVST or fibrotic cord (p = 0.007; p = 0.002), but not those with mural PVST (p = 0.199; p = 0.797), had significantly higher serum CLEC-2 and galectin-1 levels than those without PVST. Patients with superior mesenteric vein thrombosis had significantly higher serum CLEC-2 (p = 0.013) and galectin-1 (p = 0.025) levels than those without PVST. Patients with main portal vein thrombosis had higher serum CLEC-2 (p = 0.020) and galectin-1 (p = 0.066) levels than those without PVST, but the difference in serum galectin-1 level was not significant between them.

Conclusion

Serum CLEC-2 and galectin-1 levels may be associated with the presence of PVST in HBV-related cirrhotic patients, but this association should be dependent upon the degree of PVST.
Doctor-patient interactions in the age of AI: navigating innovation and expertise
Authors: Hryciw Brett N. , Fortin Zanna , Ghossein Jamie , Kyeremanteng Kwadwo
Published: August 2023

The integration of artificial intelligence (AI) in healthcare has the capacity to transform medical practice. Despite its revolutionary potential, the influence of AI may affect the physician-patient interaction and presents ethical challenges that will need to be carefully considered. This article discusses how patients may interact with this technology, considers how emerging technologies may alter the dynamics of the physician-patient relationship, and reviews some of the limitations that continue to exist. We identify potential challenges that may arise with the integration of AI into medical settings and propose solutions to help mitigate these issues.
Impact of temperature on the temporal dynamics of microcystin in Microcystis aeruginosa PCC7806
Authors: Roy Souvik , Guljamow Arthur , Dittmann Elke
Published: August 2023

Cyanobacterial blooms pose a serious threat to water quality and human health due to the production of the potent hepatotoxin microcystin. In microcystin-producing strains of the widespread genus Microcystis, the toxin is largely constitutively produced, but there are fluctuations between the cellular and extracellular pool and between free microcystin and protein-bound microcystin. Here we addressed the question of how different temperatures affect the growth and temporal dynamics of secondary metabolite production in the strain Microcystis aeruginosa PCC7806 and its microcystin-deficient ΔmcyB mutant. While the wild-type strain showed pronounced growth advantages at 20°C, 30°C, and 35°C, respectively, the ΔmcyB mutant was superior at 25°C. We further show that short-term incubations at 25°C–35°C result in lower amounts of freely soluble microcystin than incubations at 20°C and that microcystin congener ratios differ at the different temperatures. Subsequent assessment of the protein-bound microcystin pool by dot blot analysis and subcellular localization of microcystin using immunofluorescence microscopy showed re-localization of microcystin into the protein-bound pool combined with an enhanced condensation at the cytoplasmic membrane at temperatures above 25°C. This temperature threshold also applies to the condensate formation of the carbon-fixing enzyme RubisCO thereby likely contributing to reciprocal growth advantages of wild type and ΔmcyB mutant at 20°C and 25°C. We discuss these findings in the context of the environmental success of Microcystis at higher temperatures.
Allosteric activation of RhlB by RNase E induces partial duplex opening in substrate RNA
Authors: Zetzsche Heidi , Raschke Laura , Fürtig Boris
Published: August 2023

The E. coli DEAD-Box helicase RhlB is responsible for ATP-dependent unwinding of structured mRNA to facilitate RNA degradation by the protein complex degradosome. The allosteric interaction with complex partner RNase E is necessary to stimulate both, RhlB’s ATPase and RNA unwinding activity to levels comparable with other DEAD-Box helicases. However, the structural changes of the helicase RhlB induced by binding of RNase E have not been characterized and how those lead to increased reaction rates has remained unclear. We investigated the origin of this activation for RNA substrates with different topologies. Using NMR spectroscopy and an RNA centered approach, we could show that RNase E binding increases the affinity of RhlB towards a subset of RNA substrates, which leads to increased ATP turnover rates. Most strikingly, our studies revealed that in presence of RNase E (694-790) RhlB induces a conformational change in an RNA duplex with 5’- overhang even in absence of ATP, leading to partial duplex opening. Those results indicate a unique and novel activation mode of RhlB among DEAD-Box helicases, as ATP binding is thought to be an essential prerequisite for RNA unwinding.
The differing effects of a dual acting regulator on SIRT1
Authors: Hur Yujin , Huynh Johnson , Leong Emily , Dosanjh Reena , Charvat Annemarie F. , Vu My H. , Alam Zain , Lee Yue Tong , Cabreros Christiane C. , Carroll Emma C. , Hura Greg L. , Wang Ningkun
Published: August 2023

SIRT1 is an NAD+-dependent protein deacetylase that has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism, and neurodegeneration. There is great interest in understanding the regulation of SIRT1 to better understand SIRT1-related diseases and to better design therapeutic approaches that target SIRT1. There are many known protein and small molecule activators and inhibitors of SIRT1. One well-studied SIRT1 regulator, resveratrol, has historically been regarded as a SIRT1 activator, however, recent studies have shown that it can also act as an inhibitor depending on the identity of the peptide substrate. The inhibitory nature of resveratrol has yet to be studied in detail. Understanding the mechanism behind this dual behavior is crucial for assessing the potential side effects of STAC-based therapeutics. Here, we investigate the detailed mechanism of substrate-dependent SIRT1 regulation by resveratrol. We demonstrate that resveratrol alters the substrate recognition of SIRT1 by affecting the KM values without significantly impacting the catalytic rate (kcat). Furthermore, resveratrol destabilizes SIRT1 and extends its conformation, but the conformational changes differ between the activation and inhibition scenarios. We propose that resveratrol renders SIRT1 more flexible in the activation scenario, leading to increased activity, while in the inhibition scenario, it unravels the SIRT1 structure, compromising substrate recognition. Our findings highlight the importance of substrate identity in resveratrol-mediated SIRT1 regulation and provide insights into the allosteric control of SIRT1. This knowledge can guide the development of targeted therapeutics for diseases associated with dysregulated SIRT1 activity.
Associations between cognition, anxiety, depression, and residual dizziness in elderly people with BPPV
Authors: Sun Jin , Ma Xiaobao , Yang Ying , He Kuan , Wang Wei , Shen Jiali , Wang Lu , Chen Xiangping , Jin Yulian , Yang Jun , Chen Jianyong
Published: August 2023

Objective

To investigate the associations between cognition, anxiety, depression, and residual dizziness after successful repositioning maneuvers in the elderly with benign paroxysmal positional vertigo (BPPV).

Methods

We enrolled 40 elderly patients with BPPV in our outpatient department. We used the Dizziness Handicap Inventory (DHI), Visual Analog Scale (VAS), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder Questionnaire-7 (GAD-7) to assess the degree of dizziness, anxiety, and depression of participants before repositioning therapy, respectively. At the 1-week follow-up after BPPV treatment, each participant will be reassessed and divided into a group with residual dizziness (RD) and a group without residual dizziness (NRD) based on the follow-up DHI score. The Mini-Mental State Examination (MMSE) evaluated the cognitive function of the participants.

Results

The age, gender, duration of BPPV, and involved semicircular canals in the two groups did not show a significant difference. The RD group scored significantly higher on the DHI (p = 0.006), GAD-7 (p < 0.001), and PHQ-9 (p = 0.002) before the repositioning treatment than the NRD group. The two groups had no significant difference in MMSE score (p = 0.381). Anxiety and depression scores before repositioning treatment significantly and positively correlated with follow-up DHI scores (r = 0.678 and 0.522, respectively), but the MMSE score did not significantly relate to it. The univariate linear regression showed that the DHI (p < 0.001), GAD-7 (p < 0.001), and PHQ-9 (p = 0.002) scores before treatment could predict residual dizziness. The multivariate linear regression showed that GAD-7 before treatment was the only significant predictor of residual dizziness (p < 0.001).

Conclusion

The level of dizziness, anxiety, and depression before treatment can predict residual dizziness after successful repositioning maneuvers in the elderly with BPPV. Anxiety may be the strongest predictor of residual dizziness after successful repositioning treatment in elderly BPPV patients.