bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer cell – fibroblast crosstalk via HB-EGF/EGFR/MEK signaling promotes macrophage recruitment in squamous cell carcinoma
Authors: Giangreco Giovanni , Rullan Antonio , Naito Yutaka , Biswas Dhruva , Liu Yun-Hsin , Hooper Steven , Nenclares Pablo , Bhide Shreerang , Cheang Maggie Chon U , Chakravarty Probir , Hirata Eishu , Swanton Charles , Melcher Alan , Harrington Kevin , Sahai Erik 
Published: July 2023

SummaryInteractions between cells in the tumor microenvironment (TME) shape cancer progression and patient outcomes. To gain new insights into how the TME influences cancer outcomes, we derive gene expression signatures indicative of signaling between stromal fibroblasts and cancer cells, and demonstrate their prognostic significance in multiple and independent squamous cell carcinoma cohorts. By leveraging information within the signatures, we discover that the HB-EGF/EGFR/MEK axis represents a hub of tumor – stroma crosstalk, promoting the expression of CSF2 and LIF and favoring the recruitment of macrophages. Together these analyses demonstrate the utility of our approach for interrogating the extent and consequences of TME crosstalk.
TBP facilitates RNA Polymerase I transcription following mitosis
Authors: Kwan James Z.J. , Nguyen Thomas F. , Teves Sheila S. 
Published: July 2023

AbstractThe TATA-box binding protein (TBP) is the sole transcription factor common in the initiation complexes of the three major eukaryotic RNA Polymerases (Pol I, II, and III). Decades of research have shown that TBP is essential for proper transcription by the three RNA Pols, though the emergence of TBP paralogs throughout evolution have expanded the complexity in RNA Pol initiation. We have previously shown that acute TBP depletion in mouse embryonic stem cells led to a global decrease in Pol III activity, consistent with the requirement of TBP in Pol III inititation. In contrast, Pol II transcription remained unaffected in the absence of TBP and its paralogs. In this report, we show that, in contrast to Pol II-transcribed genes, the TBP paralog TRF2 does not bind to Pol I promoters, and therefore cannot functionally replace TBP upon depletion. Importantly, acute TBP depletion has no major effect on Pol I occupancy or activity on ribosomal RNA genes, but TBP binding in mitosis leads to efficient Pol I reactivation following cell division. These findings provide a more nuanced role for TBP in Pol I transcription in murine embryonic stem cells.SignificanceThe TATA-box binding protein (TBP) is a highly conserved and essential protein in eukaryotes. Decades ofin vitroand yeast research have established its role in the initiation of the three main eukaryotic RNA polymerases. However, the ability to rapidly deplete proteinsin vivois revealing more nuance in the function of TBP in mammalian cells. Using this technology, we reassess the role of TBP in RNA Polymerase I (Pol I) transcription in mouse embryonic stem cells. We find that neither TBP nor its paralog TRF2 are required for Pol I recruitment or activity, but TBP binding during mitosis promotes efficient reactivation after cell division. Overall, these findings provide new evidence into the complex function of TBP in eukaryotic transcription.
Molecular epidemiological study of Scrub Typhus in residence, farm and forest habitats from Yunnan Province, China
Authors: Tian Jia-Wei , Kong Yi-Chen , Han Pei-Yu , Xu Fen-Hui , Yang Wei-Hong , Zhang Yun-Zhi 
Published: July 2023

AbstractThe number of people suffering from scrub typhus, which is not of concern, is increasing year by year, especially in Yunnan Province, China. From June 1, 2021 to August 15, 2022, a total of 505 mammalian samples were collected from farm, forest, and residential habitats with high incidence of scrub typhus in Yunnan, China, for nPCR (nested PCR) and qPCR (quantitative real-time PCR) detection ofOrientia tsutsugamushi. A total of 4 orders of murine-like animals, Rodentia (87.52%, n=442), Insectivora (10.29%, n=52), Lagomorpha (1.79%, n=9) and Scandentia (0.40%, n=2) were trapped. Comparing the qPCR infection rates in the three habitats, it was no significant difference that the infection rate of residential habitat (44.44%) and that of the farm habitat (45.05%, P>0.05), which is much larger than that of the forest habitat (3.08%) (P<0.001). Three genotypes (Karp, Kato and TA763) ofO. tsutsugamushiwere found from Yunnan, China in this study. We found a tendency for scrub typhus to migrate from forests to residential habitats.Author SummaryScrub typhus is acute febrile infectious disease caused byOrientia tsutsugamushithat threatens nearly 1 billion people. According to the data we have obtained, the incidence rate of infected people has reached 23.84/100,000 population until December 2022 in Yunnan, China. The incidence rate has increased non-negligibly Compared with 0.65/100,000 population in 2006. Among them, the incidence rate has increased by 71.14% from 2019 to 2022. Scrub typhus is transmitted by the bite of chigger larvae with murine-like animals as the main source of infection Rodentia are the most important reservoir hosts, followed by Insectivora. Therefore, in view of the influencing factor of human habitat, we used qPCR (quantitative real-time PCR) and nPCR (nested PCR) techniques to analyze the prevalence ofO. tsutsugamushiin hosts of different human habitats from June 2021 to August 2022. Our research shows that the diversity ofO. tsutsugamushigenotypes in Yunnan Province provides guidance for the prevention and Control of scrub typhus. And it was found that the infection rate ofO. tsutsugamushiin murine-like animals is quite different in different human habitats, especially the high infection rate in residential habitat and farm habitat, suggesting thatO. tsutsugamushican be infected without wilderness history.
The substrate-binding domains of the osmoregulatory ABC importer OpuA transiently interact
Authors: van den Noort Marco , Drougkas Panagiotis , Paulino Cristina , Poolman Bert 
Published: July 2023

ABSTRACTBacteria utilize various strategies to prevent internal dehydration during hypertonic stress. A common approach to countering the effects of the stress is to import compatible solutes such as glycine betaine, leading to simultaneous passive water fluxes following the osmotic gradient. OpuA fromLactococcus lactisis a type I ABC-importer that uses two substrate-binding domains (SBDs) to capture extracellular glycine betaine and deliver the substrate to the transmembrane domains for subsequent transport. OpuA senses osmotic stress via changes in the internal ionic strength and is furthermore regulated by the 2ndmessenger cyclic-di-AMP. We now show, by means of solution-based single-molecule FRET and analysis with multi-parameter photon-by-photon hidden Markov modeling, that the SBDs transiently interact in an ionic strength-dependent manner. The smFRET data are in accordance with the apparent cooperativity in transport and supported by new cryo-EM data of OpuA. We propose that the physical interactions between SBDs and cooperativity in substrate delivery are part of the transport mechanism.
Challenging age-related decline in brain function: Evidence from fast neuroimaging of musical sequence recognition
Authors: Bonetti L. , Fernández Rubio G. , Lumaca M. , Carlomagno F. , Risgaard Olsen E. , Criscuolo A. , Kotz S.A. , Vuust P. , Brattico E. , Kringelbach M.L. 
Published: July 2023

AbstractAging is often associated with decline in brain processing power and neural predictive capabilities. To challenge this notion, we used the excellent temporal resolution of magnetoencephalography (MEG) to record the whole-brain activity of 39 older adults (over 60 years old) and 37 young adults (aged 18-25 years) during recognition of previously memorised and novel musical sequences. Our results demonstrate that independent of behavioural measures, older compared to young adults showed increased rapid auditory cortex responses (around 100 and 250 ms after each tone of the sequence) and decreased later responses (around 250 and 350 ms) in hippocampus, ventromedial prefrontal cortex and inferior frontal gyrus. Working memory abilities were associated with stronger brain activity for both young and older adults. Our findings unpick the complexity of the healthy aging brain, showing age-related neural transformations in predictive and memory processes and challenging simplistic notions that non-pathological aging merely diminishes neural predictive capabilities.
Characterising neutrophil subtypes in cancer using human and murine single-cell RNA sequencing datasets
Authors: Fetit Rana , White Mark , Mills Megan L. , Cortes-Lavaud Xabier , McLaren Alistair , Falconer John , Gilroy Kathryn , Nixon Colin , Kirschner Kristina , Jackstadt Rene , Campbell Andrew D. , Sansom Owen J. , Steele Colin W. 
Published: July 2023

ABSTRACTNeutrophils are a highly heterogenous cellular population. However, a thorough examination of the different transcriptional neutrophil states, between health and malignancy, has not been performed. We utilised single-cell RNA-sequencing of human and murine datasets, both publicly available and independently generated, to identify neutrophil transcriptomic subtypes and their developmental lineages in health and malignancy. Datasets of lung, breast and colorectal cancer (CRC) were integrated to establish and validate the reproducibility of neutrophil gene-signatures. Pseudo-time analysis was used to identify genes driving neutrophil development from health to cancer. Finally, ligand-receptor interactions and signalling pathways between neutrophils and other immune cell populations in primary CRC and metastatic CRC were investigated. We define two main neutrophil subtypes in primary tumours: an activated subtype sharing the transcriptomic signatures of healthy neutrophils; and a tumour-specific subtype. This signature is conserved in murine and human cancer, across different tumour types. In CRC metastases, neutrophils are more heterogenous, exhibiting additional transcriptomic subtypes. Pseudo-time analysis implicates an IL1B/CXCL8/CXCR2 axis in the progression of neutrophils from health to cancer and metastasis, with effects on T-cell effector function. Assessment of global communication signalling identified CD4+ T-cells and macrophages as dominant regulators of the immunosuppressive, metastatic niche, whereas CD8+ T-cells are receivers of signals from other immune cells. We propose that the emergence of metastatic-specific neutrophil subtypes is driven by an IL1/CXCL8/CXCR2 axis, with the evolution of different transcriptomic signals that impair T-cell function at the metastatic site. Thus, a better understanding of the neutrophil transcriptomic programming could optimise immunotherapeutic interventions into early and late interventions, targeting different neutrophil subtypes.
Effects of the G-quadruplex-binding drugs Quarfloxin and CX-5461 on the malaria parasitePlasmodium falciparum
Authors: Craven Holly M. , Nettesheim Guilherme , Cicuta Pietro , Blagborough Andrew M. , Merrick Catherine J. 
Published: July 2023

AbstractPlasmodium falciparumis the deadliest causative agent of human malaria. This parasite has historically developed resistance to many drugs, including the current frontline treatments, so new therapeutic targets are needed. Our previous work on guanine quadruplexes (G4s) in the parasite’s DNA and RNA has highlighted their influence on parasite biology, and revealed G4 stabilising compounds as promising candidates for drug repositioning. In particular, quarfloxin, a former anticancer agent, kills blood-stage parasites at all developmental stages, with fast rates of kill and nanomolar potency. Here we explored the molecular mechanism of quarfloxin and its related derivative CX-5461.In vitro,both compounds bound toP. falciparum-encoded G4 sequences.In cellulo, quarfloxin was more potent than CX-5461, and could prevent establishment of blood-stage malariain vivoin a murine model. CX-5461 showed clear DNA damaging activity, as reported in human cells, while quarfloxin caused weaker signatures of DNA damage. Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in bothPlasmodiumparasites and mammalian cells, whereas the complete antimalarial mode of action of quarfloxin may be parasite-specific and remains somewhat elusive.
Efficacy of aPseudomonas aeruginosaSerogroup O9 Vaccine
Authors: Moustafa Dina A. , DiGiandomenico Antonio , Raghuram Vishnu , Schulman Marc , Scarff Jennifer M. , Davis Michael R. , Varga John J. , Dean Charles R. , Goldberg Joanna B. 
Published: July 2023

ABSTRACTThere are currently no approved vaccines against the opportunistic pathogenPseudomonas aeruginosa. Among vaccine targets, the lipopolysaccharide (LPS) O antigen ofP. aeruginosais the most immunodominant protective candidate. There are twenty different O antigens composed of different repeat sugars structures conferring serogroup specificity, and ten are found most frequently in infection. Thus, one approach to combat infection byP. aeruginosacould be to generate immunity with a vaccine cocktail that includes all these serogroups. Serogroup O9 is one of the ten serogroups commonly found in infection, but it has never been developed into a vaccine, likely due, in part, to the acid labile nature of the O9 polysaccharide. Our laboratory has previously shown that intranasal administration of an attenuatedSalmonellastrain expressing theP. aeruginosaserogroup O11 LPS O antigen was effective in clearing and preventing mortality in mice following intranasal challenge with serogroup O11P. aeruginosa. Consequently, we set out to develop aP.aeruginosaserogroup O9 vaccine using a similar approach. Here we show thatSalmonellaexpressing serogroup O9 triggered an antibody-mediated immune response following intranasal administration to mice and that it conferred protection fromP. aeruginosaserogroup O9 in a murine model of acute pneumonia.
TW68, Cryptochromes stabilizer, regulates fasting blood glucose level inob/oband fat-induced diabetic mice
Authors: Surme Saliha , Ergun Cagla , Gul Seref , Akyel Yasemin Kubra , Gul Zeynep Melis , Ozcan Onur , Ipek Ozgecan Savlug , Akarlar Busra Aytul , Ozlu Nurhan , Taskin Ali Cihan , Turkay Metin , Gören Ahmet Ceyhan , Baris Ibrahim , Ozturk Nuri , Guzel Mustafa , Aydin Cihan , Okyar Alper , Kavakli Ibrahim Halil 
Published: July 2023

AbstractCryptochromes (CRYs), transcriptional repressors of the circadian clock in mammals, inhibit cAMP production when glucagon activates G-protein coupled receptors. Therefore, molecules that modulate CRYs have the potential to regulate gluconeogenesis. In this study, we discovered a new molecule called TW68 that interacts with the primary pockets of mammalian CRY1/2, leading to reduced ubiquitination levels and increased stability. In cell-based circadian rhythm assays using U2OS:Bmal1-dLuccells, TW68 extended the period length of the circadian rhythm. Additionally, TW68 decreased the transcriptional levels of two genes,Phosphoenolpyruvate carboxykinase 1(PCK1) andGlucose-6-phosphatase(G6PC), which play crucial roles in glucose biosynthesis during glucagon-induced gluconeogenesis in HepG2 cells. Oral administration of TW68 in mice showed good tolerance, a good pharmacokinetic profile, and remarkable bioavailability. Finally, when administered to fastingob/oband fat-induced diabetic animals, TW68 reduced blood glucose levels by enhancing CRY stabilization and subsequently decreasing the transcriptional levels ofPck1andG6pc. These findings collectively demonstrate the antidiabetic efficacy of TW68in vivo, suggesting its therapeutic potential for controlling fasting glucose levels in the treatment of type 2diabetes mellitus.
Paranannizziopsisspp. associated with skin lesions in wild snakes in North America and development of a real-time PCR assay for rapid detection of the fungus in clinical samples
Authors: Lorch Jeffrey M. , Winzeler Megan E. , Lankton Julia S. , Raverty Stephen , Snyman Heindrich N. , Schwantje Helen , Thacker Caeley , Knowles Susan , Cai Hugh Y. , Grear Daniel A. 
Published: July 2023

ABSTRACTThe emergence of ophidiomycosis (or snake fungal disease) in snakes has prompted increased awareness of the potential effects of fungal infections on wild reptile populations. Yet, aside fromOphidiomyces ophidiicola, little is known about other mycoses affecting wild reptiles. The closely related genusParanannizziopsishas been associated with dermatomycosis in snakes and tuataras in captive collections, andP. australasiensiswas recently identified as the cause of skin infections in non-native wild panther chameleons (Furcifer pardalis) in Florida, USA. Here we describe five cases ofParanannizziopsisspp. associated with skin lesions in wild snakes in North America and one additional case from a captive snake from Connecticut, USA. In addition to demonstrating that wild Nearctic snakes can serve as a host for these fungi, we also provide evidence that the genusParanannizziopsisis widespread in wild snakes, with cases being identified in Louisiana (USA), Minnesota (USA), Virginia (USA), and British Columbia (Canada). Phylogenetic analyses conducted on multiple loci of the fungal strains we isolated identifiedP. australasiensisin Louisiana and Virginia; the remaining strains from Minnesota and British Columbia did not cluster with any of the described species ofParanannizziopsis, although the strains from British Columbia appear to represent a single lineage. Finally, we designed a pan-Paranannizziopsisreal-time PCR assay targeting the internal transcribed spacer region 2. This assay successfully detected DNA of all described species ofParanannizziopsisand the two potentially novel taxa isolated in this study and did not cross-react with closely related fungi or other fungi commonly found on the skin of snakes. The assay was 100% sensitive and specific when screening clinical (skin tissue or skin swab) samples, although full determination of the assay’s performance will require additional follow up due to the small number of clinical samples (n=14 from 11 snakes) available for testing in our study. Nonetheless, the PCR assay can provide an important tool in further investigating the prevalence, distribution, and host range ofParanannizziopsisspp. and facilitate more rapid diagnosis ofParanannizziopsisspp. infections that are otherwise difficult to differentiate from other dermatomycoses.
Serpine1 negatively regulates Th1 cell responses in experimental autoimmune encephalomyelitis
Authors: Akbar Irshad , Tang Ruihan , Baillargeon Joanie , Roy Andrée-Pascale , Doss Prenitha Mercy Ignatius Arokia , Zhu Chen , Kuchroo Vijay K. , Rangachari Manu 
Published: July 2023

AbstractTh1 cells are critical in experimental autoimmune encephalomyelitis (EAE). Serpine1 has been posited as an inhibitor of IFNγfrom T cells though its role in autoimmunity remains unclear. Here, we show that Serpine1 knockout (KO) mice develop EAE of enhanced severity relative to wild-type (WT) controls. Serpine1 overexpression represses Th1 cell cytokine production and pathogenicity, while Serpine1-KO:2D2 Th1 cells transfer EAE of increased severity in comparison to WT 2D2 Th1 cells. Notably, polarized Serpine1-KO Th1 cells display delayed expression of the Th1-specific inhibitory receptor, Tim-3. Serpine1-KO:Tim-3-Tg Th1 cells, which transgenically over-express Tim-3, showed increased expression of IFNγand reduced expression of the checkpoint molecules Lag-3 and PD-1 relative to WT Tim-3-Tg counterparts. Further, Serpine1 deficiency restored the EAE phenotype of Tim-3-Tg mice that normally develop mild disease. Together, we identify Serpine1 as a negative regulator of Th1 cells.Key pointsSerpine1 inhibits EAE in a T cell-dependent manner.Serpine1 is upregulated in Th1 cells and inhibits their pathogenicity.Serpine1 promotes expression and function of Th1-specific inhibitory receptor Tim-3.
An Engineered 3D Co-culture Model of Primary Macrophages and Patient-Derived Tumour Cells to Explore Cellular Responses in the Graded Hypoxic Microenvironment of Pancreatic Cancer
Authors: Co Ileana L. , Yu Chengxin , Lamorte Sara , Ciudad M. Teresa , Landon-Brace Natalie , Cadavid Jose L. , Xia Ziting , Fomina Aleksandra , Nurse Michelle , McGaha Tracy L. , Campbell Kieran R. , McGuigan Alison P. 
Published: July 2023

AbstractIn pancreatic ductal adenocarcinoma (PDAC), tumour associated macrophages (TAMs) are a heterogeneous immune cell population that interact with cancer cells to promote malignancy, chemo-resistance, and immunosuppression. Aside from TAMs, hypoxia is a prominent feature of PDAC that can rewire cells to survive and enhance malignancy in the tumour microenvironment (TME). Deciphering the interactions between macrophages, cancer cells and hypoxia could lead to the development of effective immune-targeted therapies for PDAC. However, there are only a few models that physiologically recapitulate the PDAC TME and allow for meaningful interrogation of cancer-immune cell interactions in hypoxia. Here, we develop a model of primary macrophages and PDAC patient organoid-derived cells by adapting TRACER, a paper-based, engineered 3D model that allows snapshot analysis of cellular response in hypoxia. In this study, we establish a direct co-culture method of primary macrophages and PDAC organoid cells in TRACER and demonstrate that TRACER co-cultures generate hypoxic gradients and show expected phenotypic responses to this hypoxic gradient. Moreover, we report for the first time in a humanin vitromodel that hypoxic macrophages exert a graded chemoprotective effect on gemcitabine-treated PDAC organoid cells, and that interactions between cancer cells and macrophages from the inner layers of TRACER indirectly attenuate the inflammatory response of donor-derived T-cells. Overall, the TRACER co-culture system is a novel, fully human 3Din vitrocancer-immune model for evaluating the response of macrophages and cancer cells in a hypoxic gradient.
Multiple genetic variants at theSLC30A8locus affect local super-enhancer activity and influence pancreatic β-cell survival and function
Authors: Hu Ming , Kim Innah , Morán Ignasi , Peng Weicong , Sun Orien , Bonnefond Amélie , Khamis Amna , Bonas-Guarch Silvia , Froguel Philippe , Rutter Guy A. 
Published: July 2023

AbstractVariants at theSLC30A8locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression ofSLC30A8mRNA in protective allele carriers. In the present study, combined allele-specific expression (cASE) analysis in human islets revealed multiple variants that influenceSLC30A8expression. Epigenomic mapping identified an islet-selective enhancer cluster at theSLC30A8locus, hosting multiple T2D risk and cASE associations, which is spatially associated with theSLC30A8promoter and additional neighbouring genes. Deletions of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowered the expression ofSLC30A8and several neighbouring genes, and improved insulin secretion. Whilst down-regulation ofSLC30A8had no effect on beta cell survival, loss ofUTP23,RAD21 or MED30markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at theSLC30A8locus and enhanced stimulated insulin secretion.