bluuebunny/crossref_metadata_2025 huggingface dataset:
A systematic review and meta-analysis of the impact of resveratrol on oral cancer: potential therapeutic implications
Authors: Alam Mohammad Khursheed , Alqhtani Nasser Raqe , Alnufaiy Banna , Alqahtani Abdullah Saad , Elsahn Nesrine A. , Russo Diana , Di Blasio Marco , Cicciù Marco , Minervini Giuseppe
Published: April 2024

The present study aimed to investigate the impact of resveratrol on oral neoplastic parameters through a systematic review and meta-analysis. Resveratrol, a naturally occurring polyphenol, has shown promising potential as a therapeutic agent in various cancer types, including oral neoplasms. Understanding the collective findings from existing studies can shed light on the efficacy and mechanisms of resveratrol in oral cancer management. The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed to identify relevant studies from various databases, registers, websites, and citation searches. The inclusion criteria encompassed in-vivo studies investigating the impact of resveratrol on oral neoplastic parameters in animal models. After screening and assessment, a total of five eligible studies were included in the meta-analysis. The meta-analysis of the selected studies revealed that resveratrol treatment exhibited a potential impact on reducing oral neoplastic proliferation and promoting neoplastic apoptosis. The combined analysis showed a statistically significant decrease in neoplastic parameters with an overall effect size (ES) of 0.85 (95% CI: [0.74, 0.98]). Subgroup analyses were conducted to explore potential variations among different cellular types and exposure compounds, providing further insights into the efficacy of resveratrol in specific contexts. This systematic review and meta-analysis support the potential of resveratrol as a promising therapeutic agent in oral cancer management. The findings indicate that resveratrol may effectively modulate neoplastic proliferation and apoptosis in various cellular types within animal models of oral cancer. However, further well-controlled studies and clinical trials are warranted to validate these observations and elucidate the underlying mechanisms of resveratrol's actions. Resveratrol holds promise as a complementary therapeutic approach in the prevention and treatment of oral neoplastic conditions.
Cognitive enrichment through art: a randomized controlled trial on the effect of music or visual arts group practice on cognitive and brain development of young children
Authors: James C. E. , Tingaud M. , Laera G. , Guedj C. , Zuber S. , Diambrini Palazzi R. , Vukovic S. , Richiardi J. , Kliegel M. , Marie D.
Published: April 2024

Background

The optimal stimulation for brain development in the early academic years remains unclear. Current research suggests that musical training has a more profound impact on children's executive functions (EF) compared to other art forms. What is crucially lacking is a large-scale, long-term genuine randomized controlled trial (RCT) in cognitive neuroscience, comparing musical instrumental training (MIP) to another art form, and a control group (CG). This study aims to fill this gap by using machine learning to develop a multivariate model that tracks the interconnected brain and EF development during the academic years, with or without music or other art training.

Methods

The study plans to enroll 150 children aged 6-8 years and randomly assign them to three groups: Orchestra in Class (OC), Visual Arts (VA), and a control group (CG). Anticipating a 30% attrition rate, each group aims to retain at least 35 participants. The research consists of three analytical stages: 1) baseline analysis correlating EF, brain data, age, gender, and socioeconomic status, 2) comparison between groups and over time of EF brain and behavioral development and their interactions, including hypothesis testing, and 3) exploratory analysis combining behavioral and brain data. The intervention includes intensive art classes once a week, and incremental home training over two years, with the CG receiving six annual cultural outings.

Discussion

This study examines the potential benefits of intensive group arts education, especially contrasting music with visual arts, on EF development in children. It will investigate how artistic enrichment potentially influences the presumed typical transition from a more unified to a more multifaceted EF structure around age eight, comparing these findings against a minimally enriched active control group. This research could significantly influence the incorporation of intensive art interventions in standard curricula.

Trial registration

The project was accepted after peer-review by the Swiss National Science Foundation (SNSF no. 100014_214977) on March 29, 2023. The study protocol received approval from the Cantonal Commission for Ethics in Human Research of Geneva (CCER, BASEC-ID 2023-01016), which is part of Swiss ethics, on October 25, 2023. The study is registered at clinicaltrials.gov (NCT05912270).
In vitro assessment of the anthelmintic activity of copper oxide and zinc oxide nanoparticles on egg and adult stages of Fasciola hepatica: evidence on oxidative stress biomarkers, and DNA damage
Authors: Ravvaz Amirhassan , Malekifard Farnaz , Esmaeilnejad Bijan
Published: April 2024

Objectives

Fasciolosis is of significant economic and public health importance worldwide. The lack of a successful vaccine and emerging resistance in flukes to the drug of choice, triclabendazole, has initiated the search for alternative approaches. In recent years, metallic nanoparticles have been extensively investigated for their anthelmintic effects. This study investigates the in vitro anthelmintic activity of copper oxide and zinc oxide nanoparticles against Fasciola hepatica.

Methods

The in vitro study was based on egg hatchability test (EHA), adult motility inhibition tests, DNA damage, ROS levels, as well as several biomarkers of oxidative stress, including glutathione peroxidase (GSH) and glutathione S-transferase (GST), superoxide dismutase (SOD) and malondialdehyde (MDA). For this purpose, different concentrations of copper oxide nanoparticles (CuO-NPs) and Zinc oxide nanoparticles (ZnO-NPs) (1, 4, 8, 12, and 16 ppm) were used to evaluate the anthelmintic effect on different life stages, including egg and adults of Fasciola hepatica, over 24 h.

Results

In vitro treatment of F. hepatica worms with both CuO-NPs and ZnO-NPs could significantly increase ROS production and oxidative stress induction (decreased SOD, GST and GSH and increased MDA) compared to control group.

Conclusions

Based on the results, it seems that CuO-NPs and ZnO-NPs may be effective in the control and treatment of F. hepatica infection. Further research is needed to investigate their potential for in vivo use in the treatment of parasitic infections.
Enhancing endometrial receptivity: the roles of human chorionic gonadotropin in autophagy and apoptosis regulation in endometrial stromal cells
Authors: Wang Bin , Gao Mingxia , Yao Ying , Shen Haofei , Li Hongwei , Sun Jingjing , Wang Liyan , Zhang Xuehong
Published: April 2024

Inadequate endometrial receptivity often results in embryo implantation failure and miscarriage. Human chorionic gonadotropin (hCG) is a key signaling molecule secreted during early embryonic development, which regulates embryonic maternal interface signaling and promotes embryo implantation. This study aimed to examine the impact of hCG on endometrial receptivity and its underlying mechanisms. An exploratory study was designed, and endometrial samples were obtained from women diagnosed with simple tubal infertility or male factor infertile (n = 12) and recurrent implantation failure (RIF, n = 10). Using reverse transcription-quantitative PCR and western blotting, luteinizing hormone (LH)/hCG receptor (LHCGR) levels and autophagy were detected in the endometrial tissues. Subsequently, primary endometrial stromal cells (ESCs) were isolated from these control groups and treated with hCG to examine the presence of LHCGR and markers of endometrial receptivity (HOXA10, ITGB3, FOXO1, LIF, and L-selectin ligand) and autophagy-related factors (Beclin1, LC3, and P62). The findings revealed that the expressions of receptivity factors, LHCGR, and LC3 were reduced in the endometrial tissues of women with RIF compared with the control group, whereas the expression of P62 was elevated. The administration of hCG to ESCs specifically activated LHCGR, stimulating an increase in the endometrial production of HOXA10, ITGB3, FOXO1, LIF and L-selectin ligands. Furthermore, when ESCs were exposed to 0.1 IU/mL hCG for 72 h, the autophagy factors Beclin1 and LC3 increased within the cells and P62 decreased. Moreover, the apoptotic factor Bax increased and Bcl-2 declined. However, when small interfering RNA was used to knock down LHCGR, hCG was less capable of controlling endometrial receptivity and autophagy molecules in ESCs. In addition, hCG stimulation enhanced the phosphorylation of ERK1/2 and mTOR proteins. These results suggest that women with RIF exhibit lower levels of LHCGR and compromised autophagy function in their endometrial tissues. Thus, hCG/LHCGR could potentially improve endometrial receptivity by modulating autophagy and apoptosis.
Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma
Authors: Zhang Long , Xiong Yajun , Zhang Jie , Feng Yuying , Xu Aiguo
Published: April 2024

Background

Lung adenocarcinoma (LUAD) is the predominant histological subtype of lung cancer and the leading cause of cancer-related mortality. Identifying effective drug targets is crucial for advancing LUAD treatment strategies.

Methods

This study employed proteome-wide Mendelian randomization (MR) and colocalization analyses. We collected data on 1394 plasma proteins from a protein quantitative trait loci (pQTL) study involving 4907 individuals. Genetic associations with LUAD were derived from the Transdisciplinary Research in Cancer of the Lung (TRICL) study, including 11,245 cases and 54,619 controls. We integrated pQTL and LUAD genome-wide association studies (GWASs) data to identify candidate proteins. MR utilizes single nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of exposure on outcome, while Bayesian colocalization analysis determines the probability of shared causal genetic variants between traits. Our study applied these methods to assess causality between plasma proteins and LUAD. Furthermore, we employed a two-step MR to quantify the proportion of risk factors mediated by proteins on LUAD. Finally, protein–protein interaction (PPI) analysis elucidated potential links between proteins and current LUAD medications.

Results

We identified nine plasma proteins significantly associated with LUAD. Increased levels of ALAD, FLT1, ICAM5, and VWC2 exhibited protective effects, with odds ratios of 0.79 (95% CI 0.72–0.87), 0.39 (95% CI 0.28–0.55), 0.91 (95% CI 0.72–0.87), and 0.85 (95% CI 0.79–0.92), respectively. Conversely, MDGA2 (OR, 1.13; 95% CI 1.08–1.19), NTM (OR, 1.12; 95% CI 1.09–1.16), PMM2 (OR, 1.35; 95% CI 1.18–1.53), RNASET2 (OR, 1.15; 95% CI 1.08–1.21), and TFPI (OR, 4.58; 95% CI 3.02–6.94) increased LUAD risk. Notably, none of the nine proteins showed evidence of reverse causality. Bayesian colocalization indicated that RNASET2, TFPI, and VWC2 shared the same variant with LUAD. Furthermore, NTM and FLT1 demonstrated interactions with targets of current LUAD medications. Additionally, FLT1 and TFPI are currently under evaluation as therapeutic targets, while NTM, RNASET2, and VWC2 are potentially druggable. These findings shed light on LUAD pathogenesis, highlighting the tumor-promoting effects of RNASET2, TFPI, and NTM, along with the protective effects of VWC2 and FLT1, providing a significant biological foundation for future LUAD therapeutic targets.

Conclusions

Our proteome-wide MR analysis highlighted RNASET2, TFPI, VWC2, NTM, and FLT1 as potential drug targets for further clinical investigation in LUAD. However, the specific mechanisms by which these proteins influence LUAD remain elusive. Targeting these proteins in drug development holds the potential for successful clinical trials, providing a pathway to prioritize and reduce costs in LUAD therapeutics.
Exploring the effects of the dietary fiber compound mediated by a longevity dietary pattern on antioxidation, characteristic bacterial genera, and metabolites based on fecal metabolomics
Authors: Shi Fengcui , Liu Qingli , Yue Dayong , Zhang Yanan , Wei Xueying , Wang Ying , Ma WenJian
Published: April 2024

Background

Age-related dysbiosis of the microbiota has been linked to various negative health outcomes. This study aims to investigate the effects of a newly discovered dietary fiber compound (DFC) on aging, intestinal microbiota, and related metabolic processes. The DFC was identified through in vitro fermentation screening experiments, and its dosage and composition were determined based on a longevity dietary pattern.

Methods

Aged SPF C57BL/6 J mice (65 weeks old) and young mice (8 weeks old) were divided into three groups: a subgroup without dietary fiber (NDF), a low DFC dose subgroup (LDF, 10% DFC), and a high DFC dose subgroup (HDF, 20% DFC). The total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD) activity, malondialdehyde (MDA) content, and glutathione peroxidase (GSH-Px) activity in liver and serum samples of the mice were measured according to the manufacturer’s protocol. The expression levels of characteristic bacterial genera and fecal metabolite concentrations in mice were determined using quantitative real-time PCR (qPCR) and nuclear magnetic resonance hydrogen spectroscopy (1H NMR). Metabolomics analysis was further conducted to identify biological functions and potential pathways related to aging.

Results

After an 8-weeks dietary intervention, DFC supplementation significantly attenuated age-related weight loss, organ degeneration, and oxidative stress. And promoted the growth of Lactobacillus and Bifidobacterium and inhibited the growth of Escherichia coli (E. coli) and Bacteroides (p < 0.05) in the intestinal tracts of aged mice. Metabolomic analysis identified glycolipid and amino acid metabolic pathway biomarkers associated with aging that were differentially regulated by DFC consumption. Correlation analysis between the identified microbial flora and the biomarkers revealed potential mechanistic links between altered microbial composition and metabolic activity with aging markers.

Conclusions

In conclusion, this study revealed an important mechanism by which DFC consumption impacts healthspan and longevity, shedding light on optimizing dietary fiber or developing fiber-based interventions to improve human health.
Single-cell analysis of mesenchymal cells in permeable neural vasculature reveals novel diverse subpopulations of fibroblasts
Authors: Bastedo William E. , Scott R. Wilder , Arostegui Martin , Underhill T. Michael
Published: April 2024

Background

In the choroid plexus and pituitary gland, vasculature is known to have a permeable, fenestrated phenotype which allows for the free passage of molecules in contrast to the blood brain barrier observed in the rest of the CNS. The endothelium of these compartments, along with secretory, neural-lineage cells (choroid epithelium and pituitary endocrine cells) have been studied in detail, but less attention has been given to the perivascular mesenchymal cells of these compartments.

Methods

The Hic1CreERT2 Rosa26LSL−TdTomato mouse model was used in conjunction with a PdgfraH2B−EGFP mouse model to examine mesenchymal cells, which can be subdivided into Pdgfra+ fibroblasts and Pdgfra− pericytes within the choroid plexus (CP) and pituitary gland (PG), by histological, immunofluorescence staining and single-cell RNA-sequencing analyses.

Results

We found that both CP and PG possess substantial populations of distinct Hic1+ mesenchymal cells, including an abundance of Pdgfra+ fibroblasts. Within the pituitary, we identified distinct subpopulations of Hic1+ fibroblasts in the glandular anterior pituitary and the neurosecretory posterior pituitary. We also identified multiple distinct markers of CP, PG, and the meningeal mesenchymal compartment, including alkaline phosphatase, indole-n-methyltransferase and CD34.

Conclusions

Novel, distinct subpopulations of mesenchymal cells can be found in permeable vascular interfaces, including the CP, PG, and meninges, and make distinct contributions to both organs through the production of structural proteins, enzymes, transporters, and trophic molecules.
Revisiting echocardiographic features of prosthetic heart valves: the necessity of correct differentiation of mono-leaflet vs. bileaflet mechanical heart valves in a case report
Authors: Larti Farnoosh , Geraiely Babak , Asli Samaneh Hasanpour , Moghadam Arman Soltani
Published: April 2024

Background

Mechanical heart valve replacement is a standard treatment for severe valvular disorders. The use of mono-leaflet valves has decreased recently. Recognizing the echocardiographic features of mono-leaflet and bileaflet valves is crucial for accurate complication diagnosis and proper management.

Case Presentation

A 65-year-old female with mono-leaflet mitral and bileaflet tricuspid valves underwent an echocardiographic assessment. This simple educational case provides a unique opportunity to compare the echocardiographic features of these valves within a single patient.

Conclusion

There is a crucial need for clinicians, particularly those in training, to differentiate between mono-leaflet and bileaflet mechanical heart valves adeptly. With mono-leaflet valves decreasing in prevalence, proficiency in recognizing the echocardiographic nuances of each type is imperative. Failure to do so may result in misdiagnoses and inappropriate management. This underscores the significance of continuous education and vigilance in echocardiographic assessments to ensure optimal patient care.
GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression
Authors: Yan Chaolong , Yang Zijiang , Chen Pin , Yeh Yuyang , Sun Chongjing , Xie Tao , Huang Wei , Zhang Xiaobiao
Published: April 2024

Background

Lactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, the precise mechanisms underlying how lactate influences the communication between tumor cells and tumor-associated macrophages (TAMs), the most abundant immune cells in glioma, remain poorly understood. This study aims to elucidate the impact of tumor-derived lactate on TAMs and investigate the regulatory pathways governing TAM-mediated tumor-promotion in glioma.

Methods

Bioinformatic analysis was conducted using datasets from TCGA and CGGA. Single-cell RNA-seq datasets were analyzed by using UCSC Cell Browser and Single Cell Portal. Cell proliferation and mobility were evaluated through CCK8, colony formation, wound healing, and transwell assays. Western blot and immunofluorescence staining were applied to assess protein expression and cell distribution. RT-PCR and ELISA were employed to identify the potential secretory factors. Mechanistic pathways were explored by western blotting, ELISA, shRNA knockdown, and specific inhibitors and activators. The effects of pathway blockades were further assessed using subcutaneous and intracranial xenograft tumor models in vivo.

Results

Elevated expressions of LDHA and MCT1 were observed in glioma and exhibited a positive correlation with M2-type TAM infiltration. Lactate derived from glioma cells induced TAMs towards M2-subtype polarization, subsequently promoting glioma cells proliferation, migration, invasion, and mesenchymal transition. GPR65, highly expressed on TAMs, sensed lactate-stimulation in the TME, fueling glioma cells malignant progression through the secretion of HMGB1. GPR65 on TAMs triggered HMGB1 release in response to lactate stimulation via the cAMP/PKA/CREB signaling pathway. Disrupting this feedback loop by GPR65-knockdown or HMGB1 inhibition mitigated glioma progression in vivo.

Conclusion

These findings unveil the intricate interplay between TAMs and tumor cells mediated by lactate and HMGB1, driving tumor progression in glioma. GPR65, selectively highly expressed on TAMs in glioma, sensed lactate stimulation and fostered HMGB1 secretion via the cAMP/PKA/CREB signaling pathway. Blocking this feedback loop presents a promising therapeutic strategy for GBM.
The mechanisms of MicroRNA 21 in premature ovarian insufficiency mice with mesenchymal stem cells transplantation
Authors: Yin Na , Luo Chao , Wei Lun , Yang Guangzhao , Bo Le , Mao Caiping
Published: April 2024

Umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation has been deeply explored for premature ovarian insufficiency (POI) disease. However, the associated mechanism remains to be researched. To explore whether and how the microRNA 21 (miR-21) functions in POI mice with UCMSCs transplantation, the autoimmune-induced POI mice model was built up, transplanted with or without UCMSCs transfect with the LV-hsa-miR-21-5p/LV-hsa-miR-21-5p-inhibition, with the transfection efficiency analyzed by QRT-PCR. Mice hormone secretion and the anti-Zona pellucida antibody (AZPAb) levels were analyzed, the ovarian morphological changes and folliculogenesis were observed, and the ovarian apoptosis cells were detected to evaluate ovarian function. The expression and localization of the PTEN/Akt/FOXO3a signal pathway-related cytokines were analyzed in mice ovaries.

Additionally, the spleen levels of CD8 + CD28-T cells were tested and qualified with its significant secretory factor, interleukin 10 (IL-10). We found that with the LV-hsa-miR-21-5p-inhibition-UCMSCs transplantation, the mice ovarian function can be hardly recovered than mice with LV-NC-UCMSCs transplantation, and the PTEN/Akt/FOXO3a signal pathway was activated. The expression levels of the CD8 + CD28-T cells were decreased, with the decreased levels of the IL-10 expression. In contrast, in mice with the LV-hsa-miR-21-5p-UCMSCs transplantation, the injured ovarian function can be reversed, and the PTEN/AKT/FOXO3a signal pathway was detected activated, with the increased levels of the CD8 + CD28-T cells, and the increased serum levels of IL-10. In conclusion, miR-21 improves the ovarian function recovery of POI mice with UCMSCs transplantation, and the mechanisms may be through suppressing the PTEN/AKT/FOXO3a signal pathway and up-regulating the circulating of the CD8 + CD28-T cells.
Alternative consent methods used in the multinational, pragmatic, randomised clinical trial SafeBoosC-III
Authors: Vestager Maria Linander , Hansen Mathias Lühr , Greisen Gorm ,   the SafeBoosC-III trial group, Pellicer Adelina , Chathasaigh Caitriona Ni , Lecart Chantal , Knoepfli Claudia , Hagmann Cornelia , Gallo Dario , Ergenekon Ebru , Hatzidaki Eleftheria , Dempsey Eugene , Papathoma Evangelina , Dimitrou Gabriel , Pichler Gerhard , Hahn Gitte Holst , Naulaers Gunnar , Fuchs Hans , Ozkan Hilal , de las Cuevas Isabel , Serrano-Viñuales Itziar , Sirc Jan , de Buyst Julie , Sarafidis Kosmos , Arrusa Luis , Baserga Mariana , Stocker Martin , Cetinkaya Merih , Alsina Miguel , Fumagalli Monica , Vaccarello Olalla Otero , Baud Olivier , Zafra-Rodríguez Pamela , Maton Pierre , Cheng Quoqiang , del Rio Florentino Ruth , Lauterbach Ryszard , Piris-Borregas Salvador , Nesargi Saudamini , Fredly Siv , Marciniak Sylwia , Szczapa Tomasz , Gao Xiaoyang , Xu Xin
Published: April 2024

Background

The process of obtaining prior informed consent for experimental treatment does not fit well into the clinical reality of acute and intensive care. The therapeutic window of interventions is often short, which may reduce the validity of the consent and the rate of enrolled participants, to delay trial completion and reduce the external validity of the results. Deferred consent and ‘opt-out’ are alternative consent methods. The SafeBoosC-III trial was a randomised clinical trial investigating the benefits and harms of cerebral oximetry monitoring in extremely preterm infants during the first 3 days after birth, starting within the first 6 h after birth. Prior, deferred and opt-out consent were all allowed by protocol.

This study aimed to evaluate the use of different consent methods in the SafeBoosC-III trial, Furthermore, we aimed to describe and analyse concerns or complaints that arose during the first 6 months of trial conduct.

Methods

All 70 principal investigators were invited to join this descriptive ancillary study. Each principal investigator received a questionnaire on the use of consent methods in their centre during the SafeBoosC-III trial, including the possibility to describe any concerns related to the consent methods used during the first 6 months of the trial, as raised by the parents or the clinical staff.

Results

Data from 61 centres were available. In 43 centres, only prior informed consent was used: in seven, only deferred consent. No centres used the opt-out method only, but five centres used prior and deferred, five used prior, deferred and opt-out (all possibilities) and one used both deferred and opt-out. Six centres applied to use the opt-out method by their local research ethics committee but were denied using it. One centre applied to use deferred consent but was denied. There were only 23 registered concerns during the execution of the trial.

Conclusions

Consent by opt-out was allowed by the protocol in this multinational trial but only a few investigators opted for it and some research ethics boards did not accept its use. It is likely to need promotion by the clinical research community to unfold its potential.
Trx4, a novel thioredoxin protein, is important for Toxoplasma gondii fitness
Authors: Zhang Zhi-Wei , Wang Meng , Sun Li-Xiu , Elsheikha Hany M. , Lei Cheng-Lin , Wang Jin-Lei , Fu Bao-Quan , Luo Jian-Xun , Zhu Xing-Quan , Li Ting-Ting
Published: April 2024

Background

To successfully replicate within the host cell, Toxoplasma gondii employs several mechanisms to overcome the host cell defenses and mitigate the harmful effects of the free radicals resulting from its own metabolic processes using effectors such as thioredoxin proteins. In this study, we characterize the location and functions of a newly identified thioredoxin in T. gondii, which was named Trx4.

Methods

We characterized the functional role of Trx4 in T. gondii Type I RH and Type II Pru strains by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The enzyme-catalyzed proximity labeling technique, the TurboID system, was employed to identify the proteins in proximity to Trx4.

Results

Trx4 was identified as a dense granule protein of T. gondii predominantly expressed in the parasitophorous vacuole (PV) and was partially co-localized with GRA1 and GRA5. Functional analysis showed that deletion of trx4 markedly influenced the parasite lytic cycle, resulting in impaired host cell invasion capacity in both RH and Pru strains. Mutation of Trx domains in Trx4 in RH strain revealed that two Trx domains were important for the parasite invasion. By utilizing the TurboID system to biotinylate proteins in proximity to Trx4, we identified a substantial number of proteins, some of which are novel, and others are previously characterized, predominantly distributed in the dense granules. In addition, we uncovered three novel proteins co-localized with Trx4. Intriguingly, deletion of trx4 did not affect the localization of these three proteins. Finally, a virulence assay demonstrated that knockout of trx4 resulted in a significant attenuation of virulence and a significant reduction in brain cyst loads in mice.

Conclusions

Trx4 plays an important role in T. gondii invasion and virulence in Type I RH strain and Type II Pru strain. Combining the TurboID system with CRISPR-Cas9 technique revealed many PV-localized proximity proteins associated with Trx4. These findings suggest a versatile role of Trx4 in mediating the processes that occur in this distinctive intracellular membrane-bound vacuolar compartment.

Graphical Abstract
Low-level physical activity predictors among adults living with HIV in Ethiopia’s southern region, focusing on work, transportation, and recreation domains: unmatched case-control study
Authors: Bune Girma Tenkolu
Published: April 2024

Background

Low-level physical activity (LLPA) is crucial for the well-being of adults living with HIV (PLWHs). However, many do not engage in enough physical activity, leading to adverse health outcomes. Identifying the determinants of LLPA can aid in developing effective interventions. Despite this, Ethiopia lacks evidence on this topic. This study aimed to identify predictors of LLPA among PLWHs in the Gedeo zone, located in southern Ethiopia.

Methods

An unmatched case-control study was conducted on PLWHs in the Gedeo zone who visited two hospitals and healthcare institutions between December 29th, 2017 and January 22nd, 2019. Respondents were classified into three categories based on their total physical activity levels: high, moderate, and low. Cases were defined as those meeting the criteria for LLPA, while controls were those who did not fall under the cases category. Data was collected using the WHO Stepwise surveillance tool and analyzed using Epidata v3.1 templates and SPSS v22. Predictor variables with a P-value < 0.25 in bivariable analysis and < 0.05 with a 95% confidence interval in multivariable analysis were selected.

Results

The study involved 633 HIV-positive adults, with a response rate of 92.41%. Most participants were under 34 years old, with an average age of 36.47±(9.055) for cases and 36.38±(8.389) for controls. The multivariable analysis revealed that educational status (AOR = 4.85, P = 0.02, 95%CI (1.28–18.44)), sex (AOR = 0.24, P = 0.04, 95%CI (0.07–0.90)), duration on ART being exposed for 1–4 Years (AOR = 0.12, P < 0.001, 95%CI (0.03–0.44)) and being exposed for 5–9 Years (AOR = 0.03, P < 0.001, 95%CI (0.01–0.16)), and former alcohol use (AOR = 0.11, P < 0.01, 95%CI (0.02–0.56) were significant predictors of LLPA performance.

Conclusions

The study concluded that educational status, sex, ART duration, and past alcohol use are key determinants of LLPA performance among PLWHs in southern Ethiopia. This suggests that policymakers should implement public health campaigns to promote healthy habits, particularly low-level physical activity, among PLWHs.
Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis
Authors: Terron Heather M. , Parikh Sagar J. , Abdul-Hay Samer O. , Sahara Tomoko , Kang Dongcheul , Dickson Dennis W. , Saftig Paul , LaFerla Frank M. , Lane Shelley , Leissring Malcolm A.
Published: April 2024

Background

Cathepsin D (CatD) is a lysosomal protease that degrades both the amyloid-β protein (Aβ) and the microtubule-associated protein, tau, which accumulate pathognomonically in Alzheimer disease (AD), but few studies have examined the role of CatD in the development of Aβ pathology and tauopathy in vivo.

Methods

CatD knockout (KO) mice were crossed to human amyloid precursor protein (hAPP) transgenic mice, and amyloid burden was quantified by ELISA and immunohistochemistry (IHC). Tauopathy in CatD-KO mice, as initially suggested by Gallyas silver staining, was further characterized by extensive IHC and biochemical analyses. Controls included human tau transgenic mice (JNPL3) and another mouse model of a disease (Krabbe A) characterized by pronounced lysosomal dysfunction. Additional experiments examined the effects of CatD inhibition on tau catabolism in vitro and in cultured neuroblastoma cells with inducible expression of human tau.

Results

Deletion of CatD in hAPP transgenic mice triggers large increases in cerebral Aβ, manifesting as intense, exclusively intracellular aggregates; extracellular Aβ deposition, by contrast, is neither triggered by CatD deletion, nor affected in older, haploinsufficient mice. Unexpectedly, CatD-KO mice were found to develop prominent tauopathy by just ∼ 3 weeks of age, accumulating sarkosyl-insoluble, hyperphosphorylated tau exceeding the pathology present in aged JNPL3 mice. CatD-KO mice exhibit pronounced perinuclear Gallyas silver staining reminiscent of mature neurofibrillary tangles in human AD, together with widespread phospho-tau immunoreactivity. Striking increases in sarkosyl-insoluble phospho-tau (∼ 1250%) are present in CatD-KO mice but notably absent from Krabbe A mice collected at an identical antemortem interval. In vitro and in cultured cells, we show that tau catabolism is slowed by blockade of CatD proteolytic activity, including via competitive inhibition by Aβ42.

Conclusions

Our findings support a major role for CatD in the proteostasis of both Aβ and tau in vivo. To our knowledge, the CatD-KO mouse line is the only model to develop detectable Aβ accumulation and profound tauopathy in the absence of overexpression of hAPP or human tau with disease-associated mutations. Given that tauopathy emerges from disruption of CatD, which can itself be potently inhibited by Aβ42, our findings suggest that impaired CatD activity may represent a key mechanism linking amyloid accumulation and tauopathy in AD.
Self-reporting of psychoneurophysical (PNP) symptoms in adults with four chronic diseases: a protocol for a scoping review
Authors: Rio Carielle Joy , Blumhorst Catherine , Kwiat Catherine A. , Nguyen Christopher M. , Livinski Alicia A. , Saligan Leorey N.
Published: April 2024

Background

Patient self-reporting of health-specific information, including symptoms, allows healthcare providers to provide more timely, personalized, and patient-centered care to meet their needs. It is critical to acknowledge that symptom reporting draws from the individual’s unique sociocultural background influencing how one perceives health and illness. This scoping review will explore whether racial groups with 4 chronic diseases (cardiovascular diseases, respiratory diseases, cancers, and diabetes) differ in self-reporting of psychoneurophysical (PNP) symptoms. The PNP symptoms of interest include depressive symptoms, fatigue, anxiety, pain, cognitive impairment, sleep impairment, mood impairment, irritability, and shortness of breath.

Methods

Four databases will be searched by a biomedical librarian: CINAHL Plus (EBSCOhost), Embase (Elsevier), PubMed (NLM), Web of Science: Core Collection (Clarivate Analytics), and limited to publications written in the English language. Two independent reviewers will screen the records’ title, abstract, and then full text and extract the data from included articles using Covidence. A third reviewer will be used for resolving disagreements. Included articles must comprise adult patients with at least one of the specified chronic diseases who self-report at least one of the specified PNP symptoms. Studies that used clinician-administered questionnaires or obtained symptom responses from primary caregiver or patient designee will be excluded. Articles on patient-reported functionality or perceived quality of life will also be excluded from the review. Two reviewers will independently extract data (e.g., demographics, study design, racial group, chronic disease, measure/scale used for self-report) from each included article using Covidence and Microsoft Excel for data cleaning and analyses.

Discussion

This scoping review may potentially identify the relevant and practical implications related to clinical decision-making and health outcomes for patients experiencing the psychoneurophysical symptoms included in this study. The authors will present how the results can be utilized in clinical practice, health policy, and research planning.

Systematic review registration

The protocol was registered on Open Science Framework (OSF) at: https://osf.io/ps7aw
EpiDiP/NanoDiP: a versatile unsupervised machine learning edge computing platform for epigenomic tumour diagnostics
Authors: Hench Jürgen , Hultschig Claus , Brugger Jon , Mariani Luigi , Guzman Raphael , Soleman Jehuda , Leu Severina , Benton Miles , Stec Irenäus Maria , Hench Ivana Bratic , Hoffmann Per , Harter Patrick , Weber Katharina J , Albers Anne , Thomas Christian , Hasselblatt Martin , Schüller Ulrich , Restelli Lisa , Capper David , Hewer Ekkehard , Diebold Joachim , Kolenc Danijela , Schneider Ulf C. , Rushing Elisabeth , della Monica Rosa , Chiariotti Lorenzo , Sill Martin , Schrimpf Daniel , von Deimling Andreas , Sahm Felix , Kölsche Christian , Tolnay Markus , Frank Stephan
Published: April 2024

DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally employ nanopore sequencing as a faster alternative. In addition, methylation-specific parallel sequencing can generate methylation and genomic copy number data. Given these diverse approaches to methylation profiling, to date, there is no single tool that allows (1) classification and interpretation of microarray, nanopore and parallel sequencing data, (2) direct control of nanopore sequencers, and (3) the integration of microarray-based methylation reference data. Furthermore, no software capable of entirely running in routine diagnostic laboratory environments lacking high-performance computing and network infrastructure exists. To overcome these shortcomings, we present EpiDiP/NanoDiP as an open-source DNA methylation and copy number profiling suite, which has been benchmarked against an established supervised machine learning approach using in-house routine diagnostics data obtained between 2019 and 2021. Running locally on portable, cost- and energy-saving system-on-chip as well as gpGPU-augmented edge computing devices, NanoDiP works in offline mode, ensuring data privacy. It does not require the rigid training data annotation of supervised approaches. Furthermore, NanoDiP is the core of our public, free-of-charge EpiDiP web service which enables comparative methylation data analysis against an extensive reference data collection. We envision this versatile platform as a useful resource not only for neuropathologists and surgical pathologists but also for the tumour epigenetics research community. In daily diagnostic routine, analysis of native, unfixed biopsies by NanoDiP delivers molecular tumour classification in an intraoperative time frame.
Examining the reliability of brain age algorithms under varying degrees of participant motion
Authors: Hanson Jamie L. , Adkins Dorthea J. , Bacas Eva , Zhou Peiran
Published: April 2024

Brain age algorithms using data science and machine learning techniques show promise as biomarkers for neurodegenerative disorders and aging. However, head motion during MRI scanning may compromise image quality and influence brain age estimates. We examined the effects of motion on brain age predictions in adult participants with low, high, and no motion MRI scans (Original N = 148; Analytic N = 138). Five popular algorithms were tested: brainageR, DeepBrainNet, XGBoost, ENIGMA, and pyment. Evaluation metrics, intraclass correlations (ICCs), and Bland–Altman analyses assessed reliability across motion conditions. Linear mixed models quantified motion effects. Results demonstrated motion significantly impacted brain age estimates for some algorithms, with ICCs dropping as low as 0.609 and errors increasing up to 11.5 years for high motion scans. DeepBrainNet and pyment showed greatest robustness and reliability (ICCs = 0.956–0.965). XGBoost and brainageR had the largest errors (up to 13.5 RMSE) and bias with motion. Findings indicate motion artifacts influence brain age estimates in significant ways. Furthermore, our results suggest certain algorithms like DeepBrainNet and pyment may be preferable for deployment in populations where motion during MRI acquisition is likely. Further optimization and validation of brain age algorithms is critical to use brain age as a biomarker relevant for clinical outcomes.
Male involvement in maternal and child nutrition in low-income informal settlements, Nairobi, Kenya
Authors: Muthiru Ann W. , Bukachi Salome A.
Published: April 2024

Background

Maternal and child nutrition is a significant public health concern because adequate nutrition is essential for the health, development, and well-being of mothers and children. Men can play a critical role in improving maternal and child health, including through their involvement in the nutrition of the mother and child. However, little has been studied on male involvement in maternal and child nutrition; therefore, this qualitative exploratory study focused on the level of male involvement and factors influencing male involvement in maternal and child nutrition in low-income urban informal settings.

Methods

Qualitative data collection methods were triangulated in the exploratory study to inform the study objectives. In-depth interviews (IDIs) were conducted with 30 men and 20 women based on the inclusion criteria that they have children aged between 6 and 23 months. An additional 10 key informant interviews with stakeholders in nutrition within the study setting were also carried out. Data from the qualitative interviews were captured in audio files with informed consent and permission to record from the study participants. The interviews were transcribed and translated into English transcripts for coding and analysis. Themes were derived from the five levels of the socio-ecological model of human behavior, namely, (i) individual factors; (ii) interpersonal factors; (iii) community factors; (iv) institutional factors guided the analysis.

Results

Findings from the study revealed that personal beliefs and values, the nature of work, mistrust and stigma and discrimination, and the association clinic visits with HIV testing, were some of the factors that influenced male involvement in maternal and child nutrition.

Conclusion

It is important to recognize the potential value of research on the role of men in maternal and child nutrition and to identify ways to overcome the barriers to their involvement. By better understanding the factors that influence male involvement in maternal and child nutrition and the impact of this involvement on maternal and child nutrition, it may be possible to develop more effective interventions to promote the nutritional well-being of mothers and children.
Status epilepticus in patients with brain tumors and metastases: A multicenter cohort study of 208 patients and literature review
Authors: Rickel Johanna K. , Zeeb Daria , Knake Susanne , Urban Hans , Konczalla Jürgen , Weber Katharina J. , Zeiner Pia S. , Pagenstecher Axel , Hattingen Elke , Kemmling André , Fokas Emmanouil , Adeberg Sebastian , Wolff Robert , Sebastian Martin , Rusch Tillmann , Ronellenfitsch Michael W. , Menzler Katja , Habermehl Lena , Möller Leona , Czabanka Marcus , Nimsky Christopher , Timmermann Lars , Grefkes Christian , Steinbach Joachim P. , Rosenow Felix , Kämppi Leena , Strzelczyk Adam
Published: April 2024

Objective

Brain tumors and metastases account for approximately 10% of all status epilepticus (SE) cases. This study described the clinical characteristics, treatment, and short- and long-term outcomes of this population.

Methods

This retrospective, multi-center cohort study analyzed all brain tumor patients treated for SE at the university hospitals of Frankfurt and Marburg between 2011 and 2017.

Results

The 208 patients (mean 61.5 ± 14.7 years of age; 51% male) presented with adult-type diffuse gliomas (55.8%), metastatic entities (25.5%), intracranial extradural tumors (14.4%), or other tumors (4.3%). The radiological criteria for tumor progression were evidenced in 128 (61.5%) patients, while 57 (27.4%) were newly diagnosed with tumor at admission and 113 (54.3%) had refractory SE. The mean hospital length of stay (LOS) was 14.8 days (median 12.0, range 1–57), 171 (82.2%) patients required intensive care (mean LOS 8.9 days, median 5, range 1–46), and 44 (21.2%) were administered mechanical ventilation. All patients exhibited significant functional status decline (modified Rankin Scale) post-SE at discharge (p < 0.001). Mortality at discharge was 17.3% (n = 36), with the greatest occurring in patients with metastatic disease (26.4%, p = 0.031) and those that met the radiological criteria for tumor progression (25%, p < 0.001). Long-term mortality at one year (65.9%) was highest in those diagnosed with adult-type diffuse gliomas (68.1%) and metastatic disease (79.2%). Refractory status epilepticus cases showed lower survival rates than non-refractory SE patients (log-rank p = 0.02) and those with signs of tumor progression (log-rank p = 0.001).

Conclusions

SE occurrence contributed to a decline in functional status in all cases, regardless of tumor type, tumor progression status, and SE refractoriness, while long-term mortality was increased in those with malignant tumor entities, tumor progressions, and refractory SE. SE prevention may preserve functional status and improve survival in individuals with brain tumors.
Parity-time symmetry enabled ultra-efficient nonlinear optical signal processing
Authors: Kim Chanju , Lu Xinda , Kong Deming , Chen Nuo , Chen Yuntian , Oxenløwe Leif Katsuo , Yvind Kresten , Zhang Xinliang , Yang Lan , Pu Minhao , Xu Jing
Published: April 2024

Nonlinear optical signal processing (NOSP) has the potential to significantly improve the throughput, flexibility, and cost-efficiency of optical communication networks by exploiting the intrinsically ultrafast optical nonlinear wave mixing. It can support digital signal processing speeds of up to terabits per second, far exceeding the line rate of the electronic counterpart. In NOSP, high-intensity light fields are used to generate nonlinear optical responses, which can be used to process optical signals. Great efforts have been devoted to developing new materials and structures for NOSP. However, one of the challenges in implementing NOSP is the requirement of high-intensity light fields, which is difficult to generate and maintain. This has been a major roadblock to realize practical NOSP systems for high-speed, high-capacity optical communications. Here, we propose using a parity-time (PT) symmetric microresonator system to significantly enhance the light intensity and support high-speed operation by relieving the bandwidth-efficiency limit imposed on conventional single resonator systems. The design concept is the co-existence of a PT symmetry broken regime for a narrow-linewidth pump wave and near-exceptional point operation for broadband signal and idler waves. This enables us to achieve a new NOSP system with two orders of magnitude improvement in efficiency compared to a single resonator. With a highly nonlinear AlGaAs-on-Insulator platform, we demonstrate an NOSP at a data rate approaching 40 gigabits per second with a record low pump power of one milliwatt. These findings pave the way for the development of fully chip-scale NOSP devices with pump light sources integrated together, potentially leading to a wide range of applications in optical communication networks and classical or quantum computation. The combination of PT symmetry and NOSP may also open up opportunities for amplification, detection, and sensing, where response speed and efficiency are equally important.