bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of cancer incidence among Marines and Navy personnel and civilian workers exposed to contaminated drinking water at USMC Base Camp Lejeune: a cohort study
Authors: Bove Frank J. 
Published: January 2024

AbstractBackgroundDrinking water at U.S. Marine Corps Base Camp Lejeune, North Carolina was contaminated with trichloroethylene and other industrial solvents from 1953 to 1985.MethodsA cohort cancer incidence study was conducted of Marines/Navy personnel who, between 1975 and 1985, began service and were stationed at Camp Lejeune, North Carolina (N=154,821) or Camp Pendleton, California (N=163,484), and civilian workers employed at Camp Lejeune (N=6,494) or Camp Pendleton (N=5,797) between October 1972 and December 1985. Camp Pendleton’s drinking water was not known to be contaminated between 1972 and 1985. Individual-level information on all primary invasive cancers and in-situ bladder cancer diagnosed from 1996 to 2017 was obtained from data linkages with 54 cancer registries in the U.S. Survival methods were used to calculate hazard ratios (HRs) comparing cancer incidence between the Camp Lejeune and Camp Pendleton cohorts. Precision of effect estimates were evaluated using the 95% confidence interval (CI) ratio.ResultsCancers among Camp Lejeune Marines/Navy personnel and civilian workers totaled 12,083 (354/100,000) and 1,563 (1,301/100,000), respectively. Cancers among Camp Pendleton Marines/Navy personnel and civilian workers totaled 12,144 (335/100,000) and 1,416 (1,372/100,000), respectively.Compared to Camp Pendleton, Camp Lejeune Marines/Navy personnel had adjusted HRs ≥1.20 with 95% CI ratios (CIRs) ≤3 for acute myeloid leukemia (HR=1.38, 95% CI: 1.03, 1.85), all myeloid cancers including polycythemia vera (HR=1.24, 95% CI:1.03, 1.49), myelodysplastic and myeloproliferative syndromes (HR=1.68, 95% CI: 1.07, 2.62), polycythemia vera alone (HR=1.41, 95% CI: 0.94, 2.11), cancers of the esophagus (HR=1.27, 95% CI: 1.03, 1.56), larynx (HR=1.21, 95% CI: 0.98, 1.50), soft tissue (HR=1.21, 95% CI: 0.92, 1.59) and thyroid (HR=1.22, 95% CI: 1.03, 1.45). Compared to Camp Pendleton, Camp Lejeune civilian workers had adjusted HRs ≥1.20 with 95% CIRs ≤3 for all myeloid cancers including polycythemia vera (HR=1.40, 95% CI: 0.83, 2.36), squamous cell lung cancer (HR=1.63, 95% CI: 1.10, 2.41) and female ductal breast cancer (HR=1.32, 95% CI:1.02, 1.71). Sensitivity analyses indicated that confounding bias due to unmeasured risk factors (e.g., smoking and alcohol consumption) is unlikely to significantly impact the findings.ConclusionIncreased risks of several cancers were observed among Marines/Navy personnel and civilian workers likely exposed to contaminated drinking water at Camp Lejeune compared to personnel at Camp Pendleton.
Evaluation of Autophagy in conjunctival fibroblasts
Authors: Mehrbod Parvaneh , Brun Paola , Rosani Umberto , Leonardi Andrea , Ghavami Saeid 
Published: January 2024

AbstractVernal keratoconjunctivitis (VKC) is a serious eye allergy characterized by poorly understood pathogenic mechanisms and a lack of effective treatments. Autophagy, a process involved in both triggering and suppressing immune and inflammatory responses, plays a role in VKC’s pathophysiology. Understanding autophagy’s involvement in VKC could lead to new treatment possibilities, such as utilizing specific topical substances to induce or inhibit autophagy and prevent severe complications of this eye condition. In our current protocol, we present a robust methodology established in our laboratory for studying autophagy in primary conjunctival fibroblasts. We assess autophagy through techniques like immunocytochemistry, immunoblotting, and qPCR.
Host-associated genetic differentiation in the face of ongoing gene flow: ecological speciation in a pathogenic parasite of freshwater fish
Authors: Nazarizadeh Masoud , Nováková Milena , Vlček Jakub , Štefka Jan 
Published: January 2024

AbstractAdaptation to varying environments, leading to population divergence, is one of the key processes of natural selection. However, its effectiveness amidst ongoing gene flow remains controversial. Our study explores this phenomenon by focusing on a tapeworm parasite (Ligula intestinalis), which is capable of parasitising a wide spectrum of fish species, overcoming their immunological defence and having a highly pathogenic impact. We analysed the population genetic structure, the degree of gene flow, and the level of genomic divergence between sympatrically occurring parasites from different cyprinid fish hosts. Utilising genome-wide Single Nucleotide Polymorphisms (SNPs) and transcriptome data, we investigated whether individual host species impose selection pressures on the parasite populations. Genetic clustering analyses indicated a divergence between the parasites infecting breams and those in roaches, bleaks and rudds. Historical demography modelling suggested that the most plausible scenario for this divergence is isolation with continuous gene flow. Selection analysis identified 896 SNPs under selection, exhibiting higher nucleotide diversity and genetic divergence compared to neutral loci. Transcriptome profiling corroborated these results, revealing distinct gene expression profiles for the two parasite populations. An in-depth examination of the selected SNPs and differentially expressed genes revealed specific genes and their physiological functions, as candidates for the molecular mechanisms of immune evasion and, thus, for driving ecological speciation in the parasite. This study showcases the interplay between host specificity, population demography and disruptive selection in ecological speciation. By dissecting the genomic factors at play, we gain a better understanding of the mechanisms facilitating population divergence in the presence of gene flow.
Oncogenic RAS signaling suppresses ferroptosis via transcriptional upregulation of GCH1
Authors: Lim Jonathan K. M. , Stölting Frauke , Levy Tal , Thewes Leonie , Picard Daniel , Tishina Sofya , Zhang Hai-Feng , Lewandowska Oksana , Reiff Tobias , Remke Marc , Brägelmann Johannes , Beleggia Filippo , Berndt Carsten , von Karstedt Silvia , Reifenberger Guido , Rotblat Barak , Leprivier Gabriel 
Published: January 2024

AbstractFerroptosis is an iron-dependent form of regulated cell death arising from excessive lipid peroxidation. While seminal work described that oncogenic RAS transformation drives synthetic lethal vulnerability to archetypal ferroptosis inducers including erastin (eradicator of RAS and ST-expressing cells) and RSL3 (Ras selective lethal 3), more recent work suggest that oncogenic RAS signaling may confer ferroptosis resistance. Thus, the impact of oncogenic RAS on the cellular response to ferroptosis is still unclear. Here, we provide unifying evidence across multiple cellular models that oncogenic RAS signaling suppresses ferroptosis. Using integrated proteo- and transcriptomic analyses, we uncovered that oncogenic RAS signaling upregulates the ferroptosis suppressor GTP cyclohydrolase I (GCH1) via transcriptional induction by the transcription factor ETS1 downstream of the RAS-MAPK signaling cascade. Targeted repression of Gch1 or of the tetrahydrobiopterin (BH4) synthesis pathway, which is mediated by GCH1, was sufficient to sensitize oncogenic RAS transformed cells to ferroptosis in 2D and 3D cell models, highlighting a mechanism through which RAS promotes resistance to ferroptosis induction. Furthermore, we found that GCH1 expression is clinically relevant and correlates with RAS signaling activation in human cancers. Overall, this study redefines oncogenic RAS signaling to be a ferroptosis suppressor, and identifies GCH1 as a mediator of this effect and a potential vulnerability for targeting RAS driven cancers.
Telencephalic eversion in embryos and early larvae of four teleost species
Authors: Folgueira Mónica , Clarke Jonathan D. W. 
Published: January 2024

1.AbstractThe telencephalon of ray-finned fishes undergoes eversion, which is very different to the evagination that occurs in most other vertebrates. Ventricle morphogenesis is key in order to build an everted telencephalon. Thus, here we use the apical markerzona occludens 1(ZO1) to understand ventricle morphology, extension of thetela choroideaand the eversion process during early telencephalon development of four teleost species: giant danio (Devario aequipinnatus),blind cavefish(Astyanax mexicanus),medaka(Oryzias latipes)and paradise fish (Macroposus opercularis).In addition, by using immunohistochemistry against tubulin and calcium binding proteins, we analyse the general morphology of the telencephalon, showing changes in the location and extension of the olfactory bulb and other telencephalic regions from 2 to 5 days of development. We also analyse the impact of abnormal eye and telencephalon morphogenesis on eversion, showing thatcyclopsmutants do undergo eversion despite very dramatic abnormal eye morphology. We discuss how the formation of the telencephalic ventricle in teleost fish, with its characteristic shape, is crucial event during eversion.
ACKR3 Proximity Labeling Identifies Novel G protein- and β-arrestin-independent GPCR Interacting Proteins
Authors: Hicks Chloe , Gardner Julia , Eiger Dylan Scott , Camarda Nicholas D. , Pham Uyen , Dhar Saisha , Rodriguez Hailey , Chundi Anand , Rajagopal Sudarshan 
Published: January 2024

ABSTRACTThe canonical paradigm of GPCR signaling recognizes G proteins and β-arrestins as the two primary transducers that promote GPCR signaling. Recent evidence suggests the atypical chemokine receptor 3 (ACKR3) does not couple to G proteins, and β-arrestins are dispensable for some of its functions. Here, we employed proximity labeling to identify proteins that interact with ACKR3 in cells devoid of β-arrestin. We identified proteins involved in the endocytic machinery and evaluated a subset of proteins conserved across several GPCR-based proximity labeling experiments. We discovered that the bone morphogenic protein 2-inducible kinase (BMP2K) interacts with many different GPCRs with varying dependency on β-arrestin. Together, our work highlights the existence of modulators that can act independently of G proteins and β-arrestins to regulate GPCR signaling and provides important evidence for other targets that may regulate GPCR signaling.Graphical Abstract
Inhibition of ADAM17 increases cytotoxic effect of cisplatin in cervical spheroids and organoids
Authors: Holthaus David , Rogmans Christoph , Gursinski Ina , Quevedo-Olmos Alvaro , Ehsani Marzieh , Mangler Mandy , Flörkemeier Inken , Weimer Jörg P. , Meyer Thomas F. , Maass Nicolai , Bauerschlag Dirk O. , Hedemann Nina 
Published: January 2024

AbstractBackgroundCervical cancer represents one of the main causes of female, cancer-related mortality worldwide. The majority of cancers are caused by human papillomaviruses such as HPV16 and HPV18. As chemotherapeutic resistance to first-line platinum treatment is still a predominant clinical challenge in advanced cervical cancer, novel treatment options including combinatorial therapies are urgently required to overcome chemotherapeutic resistance. Inhibition ofA Disintegrin And Metalloproteinase (ADAM)-family members, heavily involved in tumour progression of a vast range of solid tumours, strongly improved response to chemotherapeutic treatment in other tumour entities including ovarian cancer.MethodsWe established two- and three-dimensional models derived from three traditional cervical cancer cell lines and ectocervical cancer-derived organoids. Following characterisation, these models were used to investigate their response to cisplatin treatment in the absence and presence of ADAM inhibitors using viability assays and automated live cell imaging.ResultsThe pivotal role of the metalloprotease ADAM17 driving chemotherapy resistance was detectable in all ectocervical cultures irrespective of the model system used, whereas ADAM10 inhibition was predominantly effective only in loosely aggregated spheroids. We showed prominent differences regarding treatment responses between 2D monolayers compared to 3D spheroid and 3D organoid model systems. Particularly, the organoid system, regarded as the closest representation of primary tumours, exhibited reliably the combinatorial effect of ADAM17 inhibition and cisplatin in all three individual donors.ConclusionsAs two- and three-dimensional models of the same cell lines differ in their responses to chemotherapy it is essential to validate treatment strategies in more advanced model systems representing the patient situation more realistically. Ectocervical organoids showed reliable results regarding treatment responses closely mimicking the primary tumours and could therefore serve as an important tool for personalized medicine in cervical cancer. These findings strengthen the role of ADAM17 as a potential novel target for combinatorial treatments to overcome chemoresistance in cervical cancer.
Neural stem cells isolated from activated brain neurogenic niches after traumatic injury demonstrate distinct behaviorsin vitro
Authors: Schiro Lars Erik , Bauer Ulrich Stefan , Bjorkli Christiana , Sandvig Axel , Sandvig Ioanna 
Published: January 2024

AbstractThe subventricular zone (SVZ) of the lateral ventricle and subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus represents neurogenic niches within the brain housing distinct populations of neural stem cells (NSCs), known for their exclusive capacity to sustain neurogenesis in the adult mammalian CNS. These niches respond to traumatic brain injury (TBI) by becoming activated, leading to NSC proliferation, a small number of which subsequently migrate towards the injury site, and differentiate predominantly into astrocytes. Although the capacity of activated NSCs to differentiate into neurons appears to be limited, it is intrinsically interesting to determine whether these cells may represent a potential source of new neurons that may replenish and replace damaged and lost neuronal tissue.To address this question, it is necessary to understand the intrinsic behavior of NSCs derived from the activated SVZ and SGZ neurogenic niches after TBI, in terms of cell maturation, and differentiation capacity.In this study, we induced a focal TBI lesion specifically targeting the SVZ or SGZ neurogenic niche in adult rats, harvested NSCs three days post-lesioning, and subsequently expanded them in culture. We found that the isolated NSCs displayed distinct proliferation, differentiation, and spontaneous organizationin vitro, dependent on the activated niche of origin. Furthermore, these behaviors differed from NSCs derived from the SVZ or SGZ niche of uninjured control animals.
KSHV promotes oncogenic FOS to inhibit nuclease AEN and transactivate RGS2 for AKT phosphorylation
Authors: Majerciak Vladimir , Alvarado-Hernandez Beatriz , Ma Yanping , Duduskar Shivalee , Lobanov Alexei , Cam Maggie , Zheng Zhi-Ming 
Published: January 2024

AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) ORF57 is a lytic RNA-binding protein. We applied BCBL-1 cells in lytic KSHV infection and performed UV cross-linking immunoprecipitation (CLIP) followed by RNA-seq of the CLIPed RNA fragments (CLIP-seq). We identified ORF57-bound transcripts from 544 host protein-coding genes. By comparing with the RNA-seq profiles from BCBL-1 cells with latent and lytic KSHV infection and from HEK293T cells with and without ORF57 expression, we identified FOS and CITED2 RNAs being two common ORF57-specific RNA targets. FOS dimerizes with JUN as a transcription factor AP-1 involved in cell proliferation, differentiation, and transformation. Knockout of the ORF57 gene from the KSHV genome led BAC16-iSLK cells incapable of FOS expression in KSHV lytic infection. The dysfunctional KSHV genome in FOS expression could be rescued by Lenti-ORF57 virus infection. ORF57 protein does not regulate FOS translation but binds to the 13-nt RNA motif near the FOS RNA 5ʹ end and prolongs FOS mRNA half-life 7.7 times longer than it is in the absence of ORF57. This binding of ORF57 to FOS RNA is competitive to the binding of a host nuclease AEN (also referred to as ISG20L1). KSHV infection inhibits the expression of AEN, but not exosomal RNA helicase MTR4. FOS expression mediated by ORF57 inhibitsAENtranscription, but transactivatesRGS2,a regulator of G-protein coupled receptors. FOS binds a conserved AP-1 site in theRGS2promoter and enhances RGS2 expression to phosphorylate AKT. Altogether, we have discovered that KSHV ORF57 specifically binds and stabilizes FOS RNA to increase FOS expression, thereby disturbing host gene expression and inducing pathogenesis during KSHV lytic infection.SignificanceWe discovered that FOS, a heterodimer component of oncogenic transcription factor AP- 1, is highly elevated in KSHV infected cells by expression of a viral lytic RNA-binding protein, ORF57, which binds a 13-nt RNA motif near the FOS RNA 5ʹ end to prolong FOS RNA half-life. This binding of ORF57 to FOS RNA is competitive to the binding of host RNA destabilizer(s). KSHV infection inhibits expression of host nuclease AEN (or ISG20L1), but not MTR4. FOS inhibitsAENtranscription, but transactivatesRGS2by binding to a conserved AP-1 site in theRGS2promoter, thereby enhancing RGS2 expression and phosphorylation of AKT. Our data conclude that viral RNA-binding protein ORF57 controls the expression of a subset of genes for signaling, cell cycle progression, and proliferation to contribute viral pathogenesis.
Tooth Loss, Patient Characteristics, and Coronary Artery Calcification
Authors: Pham Tuan D. , Zou Lifong , Patel Mangala , Holmes Simon B. , Coulthard Barts Paul ,   The London Faculty of Medicine and Dentistry
Published: January 2024

AbstractThis study, for the first time, explores the integration of data science and machine learning for the classification and prediction of coronary artery calcium (CAC) scores, investigating both tooth loss and patient characteristics as key input features. By employing these advanced analytical techniques, we aim to enhance the accuracy of classifying CAC scores into tertiles and predicting their values. Our findings reveal that patient characteristics are particularly effective for tertile classification, while tooth loss provides more accurate predicted CAC scores. Moreover, the combination of patient characteristics and tooth loss demonstrates improved accuracy in identifying individuals at higher risk of cardiovascular issues related to CAC. This research contributes valuable insights into the relationship between oral health indicators, such as tooth loss, patient characteristics, and cardiovascular health, shedding light on their potential roles in predictive modeling and classification tasks for CAC scores.
High impact AMPAkines induce a Gq-protein coupled endoplasmic calcium release in cortical neurons: a possible mechanism for explaining the toxicity of high impact AMPAkines
Authors: Radin DP , Zhong S , Cerne Rok , Witkin Jeffrey , Lippa A 
Published: January 2024

AbstractPositive allosteric modulators of the AMPA receptor (AMPAkines) have a multitude of promising therapeutic properties. The pharmaceutical development of high impact AMPAkines has however been limited by the appearance of calcium-dependent neuronal toxicity and convulsions in vivo. Such toxicity is not observed at exceptionally high concentrations of low impact ampakines. Since most AMPAR are somewhat impermeable to calcium, the current study sought to examine the extent to which different mechanisms contribute to the rise in intracellular calcium in the presence of high impact ampakines. In the presence of AMPA alone, cytosolic calcium elevation is shown to be sodium-dependent. In the presence of high impact AMPAkines such as cyclothiazide (CTZ) or CX614, however, AMPAR potentiation also activates an additional mechanism that induces calcium release from endoplasmic reticular (ER) stores. The pathway that connects AMPAR to the ER system involves a Gq-protein, phospholipase Cβ–mediated inositol triphosphate (InsP3) formation and ultimately stimulation of InsP3-receptors located on the ER. The same linkage was not observed using high concentrations of the low impact AMPAkines, CX516 (Ampalex) and CX717. We also demonstrate that CX614 produces neuronal hyper-excitability at therapeutic doses while the newer generation low impact AMPAkine CX1739 is safe at exceedingly high doses. While earlier studies have demonstrated a functional linkage between AMPAR and G-proteins, this report demonstrates that in the presence of high impact AMPAkines, AMPAR also couple to a Gq-protein, which triggers a secondary calcium release from the ER and provides insight into the disparate actions of high and low impact AMPAkines.
Cerebrovascular pathology mediates associations between hypoxemia during rapid eye movement sleep and medial temporal lobe structure and function in older adults
Authors: Berisha Destiny E. , Rizvi Batool , Chappel-Farley Miranda G. , Tustison Nicholas , Taylor Lisa , Dave Abhishek , Sattari Negin S. , Chen Ivy Y. , Lui Kitty K. , Janecek John C. , Keator David , Neikrug Ariel B. , Benca Ruth M. , Yassa Michael A. , Mander Bryce A. 
Published: January 2024

AbstractObstructive sleep apnea (OSA) is common in older adults and is associated with medial temporal lobe (MTL) degeneration and memory decline in aging and Alzheimer’s disease (AD). However, the underlying mechanisms linking OSA to MTL degeneration and impaired memory remains unclear. By combining magnetic resonance imaging (MRI) assessments of cerebrovascular pathology and MTL structure with clinical polysomnography and assessment of overnight emotional memory retention in older adults at risk for AD, cerebrovascular pathology in fronto-parietal brain regions was shown to statistically mediate the relationship between OSA-related hypoxemia, particularly during rapid eye movement (REM) sleep, and entorhinal cortical thickness. Reduced entorhinal cortical thickness was, in turn, associated with impaired overnight retention in mnemonic discrimination ability across emotional valences for high similarity lures. These findings identify cerebrovascular pathology as a contributing mechanism linking hypoxemia to MTL degeneration and impaired sleep-dependent memory in older adults.