bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embryo-restricted responses to maternal IL-17A promote neurodevelopmental disorders in mouse offspring
Authors: Andruszewski David , Uhlfelder David C. , Desiato Genni , Regen Tommy , Schelmbauer Carsten , Blanfeld Michaela , Scherer Lena , Radyushkin Konstantin , Pozzi Davide , Waisman Ari , Mufazalov Ilgiz A. 
Published: October 2024

AbstractPrenatal imprinting to interleukin 17A (IL-17A) triggers behavioral disorders in offspring. However, reported models of maternal immune activation utilizing immunostimulants, lack specificity to elucidate the anatomical compartments of IL-17A’s action and the distinct behavioral disturbances it causes. By combining transgenic IL-17A overexpression with maternal deficiency in its receptor, we established a novel model of prenatal imprinting to maternal IL-17A (acronym: PRIMA-17 model). This model allowed us to study prenatal imprinting established exclusively through embryo-restricted IL-17A responses. We demonstrated a transfer of transgenic IL-17A across the placental barrier, which triggered the development of selected behavioral deficits in mouse offspring. More specifically, embryonic responses to IL-17A resulted in communicative impairment in early-life measured by reduced numbers of nest retrieval calls. In adulthood, IL-17A-imprinted offspring displayed an increase in anxiety-like behavior. We advocate our PRIMA-17 model as a useful tool to study neurological deficits in mice.
Circulating tumour DNA and risk of recurrence in patients with asymptomatic versus symptomatic colorectal cancer
Authors: Øgaard Nadia , Jensen Sarah Østrup , Ørntoft Mai-Britt Worm , Demuth Christina , Rasmussen Mads Heilskov , Henriksen Tenna Vesterman , Nors Jesper , Frydendahl Amanda , Lyskjær Iben , Nesic Marijana , Therkildsen Christina , Kleif Jakob , Gögenur Mikail , Jørgensen Lars Nannestad , Vilandt Jesper , Seidelin Jakob Benedict , Gotschalck Kåre Anderson , Jaensch Claudia , Andersen Berit , Løve Uffe Schou , Thorlacius-Ussing Ole , Andersen Per Vadgaard , Kolbro Thomas , Monti Alessio , Kildsig Jeppe , Bondeven Peter , Schlesinger Nis Hallundbæk , Iversen Lene Hjerrild , Rasmussen Morten , Gögenur Ismail , Bramsen Jesper Bertram , Andersen Claus Lindbjerg 
Published: October 2024

Abstract
Background
Multiple initiatives aim to develop circulating tumour DNA (ctDNA) tests for early cancer detection in asymptomatic individuals. The few studies describing ctDNA-testing in both asymptomatic and symptomatic patients report lower ctDNA detection in the asymptomatic patients. Here, we explore if asymptomatic patients differ from symptomatic patients e.g. by including a ‘low-ctDNA-shedding’ and ‘less-aggressive’ subgroup.

Methods
ctDNA assessment was performed in two independent cohorts of consecutively recruited patients with asymptomatic colorectal cancer (CRC) (Cohort#1: n = 215, Cohort#2: n = 368) and symptomatic CRC (Cohort#1: n = 117, Cohort#2: n = 722).

Results
After adjusting for tumour stage and size, the odds of ctDNA detection was significantly lower in asymptomatic patients compared to symptomatic patients (Cohort#1: OR: 0.4, 95%CI: 0.2–0.8, Cohort#2: OR: 0.7, 95%CI: 0.5–0.9). Further, the recurrence risk was lower in asymptomatic patients (Cohort#1: sHR: 0.6, 95%CI: 0.3–1.2, Cohort#2: sHR: 0.6, 95%CI: 0.4–1.0). Notably, ctDNA-negative asymptomatic patients had the lowest recurrence risk compared to the symptomatic patients (Cohort#1: sHR: 0.2, 95%CI: 0.1–0.6, Cohort#2: sHR: 0.3, 95%CI: 0.2–0.6).

Conclusions
Our study suggests that asymptomatic patients are enriched for a ‘low-ctDNA-shedding-low-recurrence-risk’ subgroup. Such insights are needed to guide ctDNA-based early-detection initiatives and should prompt discussions about de-escalation of therapy and follow-up for ctDNA-negative asymptomatic CRC patients.
The SRC-family serves as a therapeutic target in triple negative breast cancer with acquired resistance to chemotherapy
Authors: Egeland Eivind Valen , Seip Kotryna , Skourti Eleni , Øy Geir Frode , Pettersen Solveig J. , Pandya Abhilash D. , Dahle Maria A. , Haugen Mads H. , Kristian Alexander , Nakken Sigve , Engebraaten Olav , Mælandsmo Gunhild M. , Prasmickaite Lina 
Published: October 2024

Abstract
Background
Resistance to chemotherapy, combined with heterogeneity among resistant tumors, represents a significant challenge in the clinical management of triple negative breast cancer (TNBC). By dissecting molecular pathways associated with treatment resistance, we sought to define patient sub-groups and actionable targets for next-line treatment.

Methods
Bulk RNA sequencing and reverse phase protein array profiling were performed on isogenic patient-derived xenografts (PDX) representing paclitaxel-sensitive and -resistant tumors. Pathways identified as upregulated in the resistant model were further explored as targets in PDX explants. Their clinical relevance was assessed in two distinct patient cohorts (NeoAva and MET500).

Results
Increased activity in signaling pathways involving SRC-family kinases (SFKs)- and MAPK/ERK was found in treatment resistant PDX, with targeted inhibitors being significantly more potent in resistant tumors. Up-regulation of SFKs- and MAPK/ERK-pathways was also detected in a sub-group of chemoresistant patients after neoadjuvant treatment. Furthermore, High SFK expression (of either SRC, FYN and/or YES1) was detected in metastatic lesions of TNBC patients with fast progressing disease (median disease-free interval 27 vs 105 months).

Conclusions
Upregulation of SFK-signaling is found in a subset of chemoresistant tumors and is persistent in metastatic lesions. Based on pre-clinical results, these patients may respond favorably to treatment targeting SFKs.
SLAMF7 (CD319) on activated CD8+ T cells transduces environmental cues to initiate cytotoxic effector cell responses
Authors: Lingel Holger , Fischer Laura , Remstedt Sven , Kuropka Benno , Philipsen Lars , Han Irina , Sander Jan-Erik , Freund Christian , Arra Aditya , Brunner-Weinzierl Monika C. 
Published: October 2024

AbstractCD8+ T-cell responses are meticulously orchestrated processes regulated by intercellular receptor:ligand interactions. These interactions critically control the dynamics of CD8+ T-cell populations that is crucial to overcome threats such as viral infections or cancer. Yet, the mechanisms governing these dynamics remain incompletely elucidated. Here, we identified a hitherto unknown T-cell referred function of the self-ligating surface receptor SLAMF7 (CD319) on CD8+ T cells during initiation of cytotoxic T-cell responses. According to its cytotoxicity related expression on T effector cells, we found that CD8+ T cells could utilize SLAMF7 to transduce environmental cues into cellular interactions and information exchange. Indeed, SLAMF7 facilitated a dose-dependent formation of stable homotypic contacts that ultimately resulted in stable cell-contacts, quorum populations and commitment to expansion and differentiation. Using pull-down assays and network analyses, we identified novel SLAMF7-binding intracellular signaling molecules including the CRK, CRKL, and Nck adaptors, which are involved in T-cell contact formation and may mediate SLAMF7 functions in sensing and adhesion. Hence, providing SLAMF7 signals during antigen recognition of CD8+ T cells enhanced their overall magnitude, particularly in responses towards low-affinity antigens, resulting in a significant boost in their proliferation and cytotoxic capacity. Overall, we have identified and characterized a potent initiator of the cytotoxic T lymphocyte response program and revealed advanced mechanisms to improve CD8+ T-cell response decisions against weak viral or tumor-associated antigens, thereby strengthening our defense against such adversaries.
Inhibition of primary cilia-hedgehog signaling axis triggers autophagic cell death and suppresses malignant progression of VHL wild-type ccRCC
Authors: Tian Shuo , Du Songliang , Wang Chenfeng , Zhang Yu , Wang Hanfeng , Fan Yang , Gao Yu , Gu Liangyou , Huang Qingbo , Wang Baojun , Ma Xin , Zhang Xu , Huang Yan 
Published: October 2024

AbstractPrimary cilia are present on renal tubules and are implicated to play a pivotal role in transducing signals during development; however, the oncogenic role of cilia in clear cell renal cell carcinoma (ccRCC) has not been examined. Here we show that VHL wild-type ccRCC cell lines have a high incidence of primary cilia, and a high frequency of primary cilia is positively correlated with VHL expression and poor prognosis. Besides, the depletion of KIF3A and IFT88, genes required for ciliogenesis, significantly inhibited tumor proliferation and metastasis in vitro and in vivo. Further analysis found that mutations of key genes in hedgehog signaling are enriched in VHL wild ccRCC, its downstream signaling activation depends on ciliogenesis. Moreover, depletion of primary cilia or suppression of hedgehog pathway activation with inhibitor-induced robust autophagic cell death. Collectively, our findings revealed that primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of VHL wild-type ccRCC progression. Targeting the primary cilia-hedgehog pathway may represent an effective therapeutic strategy for VHL wild-type ccRCC.
The pathogenic germline ETV4 P433L mutation identified in multiple primary lung cancer affect tumor stem-like property by Wnt/β-catenin pathway
Authors: Liu Yu , Fang Lingling , Wang Yalong , Fan Tao , Wang Liyu , Xiao Chu , Deng Ziqin , Cai Wenpeng , Zheng Bo , Qiu Junfeng , Li Chunxiang , He Jie 
Published: October 2024

AbstractThe occurrence of multiple primary lung cancer (MPLC) has witnessed a significant surge in recent years within the Chinese population. MPLC is distinguished by its potential genetic susceptibility and notable genetic heterogeneity. Investigating the etiology of MPLC holds substantial clinical importance.The whole genome sequencing (WGS) and genome-wide linkage analysis were performed in a family affected by a dominant form of lung abnormalities. Specifically, five family members were diagnosed with MPLC, while nine members had pulmonary nodules and one normal member. To confirm the potential pathogenic germline mutations sites, Sanger sequencing was performed in an additional 162 MPLC family patients. Furthermore, molecular biology experiments were conducted to investigate the function and the mechanism of the identified pathogenic mutation site in lung cancer A549 and H322, both in vitro and in vivo. Linkage analysis revealed the presence of shared genomic regions among affected family members. Subsequent exome sequencing identified a deleterious variant within these linkage intervals, specifically a heterozygous mutation in ETS-oncogene transcription factors 4 (ETV4). This particular variant was found in affected family members at a rate of 13 out of 15 individuals. Furthermore, ETV4 P433L mutation could be detected in an additional MPLC family patients and mutation frequency was 3.7% (6 out of 162). The ETV4 P433L mutations site was introduced into lung cancer cell lines, resulting in altered migration and stem-like properties of the cancer cells. Further investigation revealed that the activation of the Wnt/β-catenin signaling pathway, which is associated with stemness, could be attributed to the presence of the ETV4 P433L mutation, suggesting its involvement in tumor promotion. A novel pathogenic germline mutation, ETV4 P433L, was identified in a dominant MPLC family, with a mutation rate of 3.7% among MPLC family patients. The ETV4 P433L mutation was found to impact the stem-like properties and migration of tumors through Wnt/β-catenin signaling pathway.
Effective protective mechanisms of HO-1 in diabetic complications: a narrative review
Authors: Zhang Jing-jing , Ni Ping , Song Yi , Gao Man-jun , Guo Xi-ying , Zhao Bao-qing 
Published: October 2024

AbstractDiabetes mellitus is a metabolic disorder with persistent hyperglycemia caused by a variety of underlying factors. Chronic hyperglycemia can lead to diverse serious consequences and diversified complications, which pose a serious threat to patients. Among the major complications are cardiovascular disease, kidney disease, diabetic foot ulcers, diabetic retinopathy, and neurological disorders. Heme oxygenase 1 (HO-1) is a protective enzyme with antioxidant, anti-inflammatory and anti-apoptotic effects, which has been intensively studied and plays an important role in diabetic complications. By inducing the expression and activity of HO-1, it can enhance the antioxidant, anti-inflammatory, and anti-apoptotic capacity of tissues, and thus reduce the degree of damage in diabetic complications. The present study aims to review the relationship between HO-1 and the pathogenesis of diabetes and its complications. HO-1 is involved in the regulation of macrophage polarization and promotes the M1 state (pro-inflammatory) towards to the M2 state (anti-inflammatory). Induction of HO-1 expression in dendritic cells inhibits them maturation and secretion of pro-inflammatory cytokines and promotes regulatory T cell (Treg cell) responses. The induction of HO-1 can reduce the production of reactive oxygen species, thereby reducing oxidative stress and inflammation. Besides, HO-1 also has an important effect in novel programmed cell death such as pyroptosis and ferroptosis, thereby playing a protective role against diabetes. In conclusion, HO-1 plays a significant role in the occurrence and development of diabetic complications and is closely associated with a variety of complications. HO-1 is anticipated to serve as a novel target for addressing diabetic complications, and it holds promise as a potential therapeutic agent for diabetes and its associated complications. We hope to provide inspiration and ideas for future studies in the mechanism and targets of HO-1 through this review.
Peptide-mediated gene and protein delivery systems to plant mitochondria for modifying mitochondrial functions
Authors: Abe Naoya , Numata Keiji 
Published: October 2024

AbstractPlant mitochondria are essential for energy production and male sterility. The genetic transformation of plant mitochondria has attracted attention due to its potential to improve the mitochondrial function and agricultural productivity of energy crops. However, mitochondrial genome editing has been challenging because the delivery of the macromolecules needed for genome engineering to mitochondria has not been established until now. In addition, the genome editing efficiency in mitochondria needs to be improved as much as possible due to the lack of a selection marker for mitochondria. To achieve mitochondrial modification, the proteins and/or DNA/RNA needed for genome editing should be delivered to mitochondria precisely and efficiently. Peptides have been utilized to improve delivery efficiency to plant mitochondria. Thus, we herein review advances in delivery technologies related to plant mitochondrial genome engineering using various functional peptides.
A population of Vasa2 and Piwi1 expressing cells generates germ cells and neurons in a sea anemone
Authors: Miramón-Puértolas Paula , Pascual-Carreras Eudald , Steinmetz Patrick R. H. 
Published: October 2024

AbstractGermline segregation, essential for protecting germ cells against mutations, occurs during early embryogenesis in vertebrates, insects and nematodes. Highly regenerative animals (e.g., cnidarians), however, retain stem cells with both germinal and somatic potentials throughout adulthood, but their biology and evolution remain poorly understood. Among cnidarians (e.g., sea anemones, jellyfish), stem cells are only known in few hydrozoans (e.g., Hydra). Here, we identify and characterize a rare, multipotent population of stem and/or progenitor cells expressing the conserved germline and multipotency proteins Vasa2 and Piwi1 in the sea anemone Nematostella vectensis. Using piwi1 and vasa2 transgenic reporter lines, we reveal that the Vasa2+/Piwi1+ cell population generates not only gametes, but also a diversity of proliferative somatic cells, including neural progenitors, in juveniles and adults. Our work has uncovered a multipotent population of Vasa2+/Piwi1+ stem/progenitor cells that forms the cellular basis to understand body plasticity and regenerative capacities in sea anemones and corals.
Impact-based forecasting of tropical cyclone-related human displacement to support anticipatory action
Authors: Kam Pui Man , Ciccone Fabio , Kropf Chahan M. , Riedel Lukas , Fairless Christopher , Bresch David N. 
Published: October 2024

AbstractTropical cyclones (TCs) displace millions every year. While TCs pose hardships and threaten lives, their negative impacts can be reduced by anticipatory actions like evacuation and humanitarian aid coordination. In addition to weather forecasts, impact forecast enables more effective response by providing richer information on the numbers and locations of people at risk of displacement. We introduce a fully open-source implementation of a globally consistent and regionally calibrated TC-related displacement forecast at low computational costs, combining meteorological forecast with population exposure and respective vulnerability. We present a case study of TC Yasa which hit Fiji in December 2020. We emphasise the importance of considering the uncertainties associated with hazard, exposure, and vulnerability in a global uncertainty analysis, which reveals a considerable spread of possible outcomes. Additionally, we perform a sensitivity analysis on all recorded TC displacement events from 2017 to 2020 to understand how the forecast outcomes depend on these uncertain inputs. Our findings suggest that for longer forecast lead times, decision-making should focus more on meteorological uncertainty, while greater emphasis should be placed on the vulnerability of the local community shortly before TC landfall. Our open-source codes and implementations are readily transferable to other users, hazards, and impact types.
Modelling scenarios for water supply and sanitation technologies in Jordan
Authors: Garfias Royo Margarita , Parikh Himanshu , Campos Luiza , Talozi Samer , Parikh Priti 
Published: October 2024

AbstractThe influx of refugees, population growth and current agricultural practices have led to an increase in water demand in Jordan, placing pressure on existing water provision. Climate change further exacerbates declining water availability. Against this backdrop, the techno-economic feasibility of four water supply and sanitation alternatives for small and medium scale cities in Jordan were explored, using local unit costs and Al-Mafraq as a case study. City level piped network combined with household rooftop rainwater harvesting and surface runoff collection into local ponds and piped networks with treatment using the nature-based solution of root-zone for sanitation were demonstrated to provide the highest benefits in terms of cost, convenience and water conservation. Our work highlights the need to invest in long-term urban infrastructure networks to promote sustainable future growth of cities. This is vital to address severe water scarcity challenges that ultimately impact those at the urban fringes most.
Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides
Authors: Tomkova Marketa , McClellan Michael John , Crevel Gilles , Shahid Akbar Muhammed , Mozumdar Nandini , Tomek Jakub , Shepherd Emelie , Cotterill Sue , Schuster-Böckler Benjamin , Kriaucionis Skirmantas 
Published: October 2024

AbstractC-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism.
Zinc, copper, and selenium levels in vitiligo: a systematic review and meta-analysis
Authors: Anam Khan , Ananyan Sampath , Rishabh Mittal , Dinesh Asati , Ashwin Kotnis 
Published: October 2024

AbstractVitiligo is a dermatological disease characterized by loss of melanocytes, causing non-scaly white macules on the skin. Zinc, copper, and selenium are important micronutrients that play a role in the normal functioning of the body and have been found to potentially aid in vitiligo treatment, although the relationship between their serum levels and vitiligo is not yet fully understood. This is a systematic review aimed at assessing the levels of serum zinc, copper, and selenium and their association with vitiligo. This review was performed following the Preferred Reporting Items of the systematic Review and Meta-Analysis (PRISMA) checklist and Cochrane guidelines. A comprehensive literature search was conducted on PubMed, Google Scholar and 41 studies published between 1970 and 2022 including 3353 vitiligo cases and 10,638 controls were included in the meta-analysis conducted from August 2022 till September 2023. The quality of the studies was assessed using the National Heart Lung and Blood Institute Study Quality Assessment tool, and the risk of bias was represented using the RobVis tool. The statistical analysis was performed using Review Manager (RevMan) Version 5.4. This meta-analysis indicate a significant decline in serum zinc levels (Z = 4.97; P < 0.0001; SMD = − 0.86; 95% CI − 1.19 to − 0.52) in vitiligo group with high statistical heterogeneity (Tau2 = 0.74; Chi2 = 513.95, d.f. = 26 [P < 0.00001]; I2 = 95%). Similarly for serum copper levels there was decline (Z = 2.43; P < 0.0001; SMD = − 0.50; 95% confidence interval [CI] − 0.91 to − 0.10) in vitiligo group and high statistical heterogeneity (Tau2 = 0.92; Chi2 = 475.10, d.f. = 22 [P < 0.00001]; I2 = 95%). On the other hand, there was a increase of serum selenium levels in the vitiligo group (Z = 0.56; P < 0.0001; SMD = 0.23; 95% confidence interval [CI], 0.58 to 1.04) and the results reveals high statistical heterogeneity among studies (Tau2 = 1.93; Chi2 = 406.44, d.f. = 11 [P < 0.00001]; I2 = 97%) in vitiligo patients compared to healthy controls. Publication bias was not found for the studies analysed. This study analyses the association of serum micronutrient levels and vitiligo among patients and controls from published research along with sub-group analysis specific to Asian populations using a meta-analysis. Low serum levels of Zinc and copper and high selenium levels are associated with Vitiligo.