bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fis family members synergistically control the virulence ofLegionella pneumophila
Authors: Andréa Claire , Bresson Julie , Ginévra Christophe , Vianney Anne , Bailo Nathalie , Chapalain Annelise , Attaiech Laetitia , Picq Kevin , Ranquet Caroline , Nasser William , Doublet Patricia , Kay Elisabeth 
Published: September 2024

ABSTRACTLegionella pneumophilavirulence is controlled in a growth phase-dependent manner by a complex regulatory network involving several two-component systems, small regulatory RNAs and the translational CsrA regulator. Here, we address the additional role of Nucleoid-associated proteins (NAP) regulators in this network, by investigating the regulatory functions of the three Fis paralogs (Fis1, Fis2, Fis3), a unique feature among bacteria, in the infection cycle ofL. pneumophila. Specifically, we show that deletion offis1has a major impact onL. pneumophilavirulence, and that deletion offis2enhances the intensity of this phenotype. Consistently, RNA-seq analysis and reporter gene fusions demonstrate the predominant role of Fis1 in the regulation of many virulence-related genes, including those involved in the flagellum, pili biosynthesis, and Dot/Icm type 4 secretion machinery, as well as several genes encoding Dot/Icm effectors. Both Fis1 and Fis2 bind to AT-rich motifs upstream their target genes, but Fis1 with higher affinity than Fis2. Importantly, Fis1 and Fis2 would be capable of forming heterodimers that could bind with variable affinity to this AT-rich motif. It is also important to note that the three Fis proteins are not produced at the same time and in the same amounts. We therefore hypothesize that the duplication offisgenes inL. pneumophilais not simply a back-up system to compensate for potentially deleterious mutations in afisgene, but rather a means to fine-tune the expression of targeted genes, particularly virulence genes.IMPORTANCEAppropriate control of virulence gene expression is crucial to the success of bacterial infection. Nucleoid-associated protein regulators, including Fis proteins, have been shown to participate in the virulence of several human pathogens. The importance of our discovery lies in the fact thatL. pneumophilapossesses three non-homologous Fis proteins instead of just one. We demonstrate that Fis1 and Fis2 are not functional duplicates of each other. On the contrary, Fis1 and Fis2 are synthesized neither simultaneously nor in equal amounts during the bacterial growth phase, and they cooperate to regulate virulence gene expression by targeting similar AT-rich motifs, albeit with distinct affinity, and by being capable of forming heterodimers. Taken together, our data suggest that the high conservation offisgene duplication results from the need for fine-tuned control ofLegionellavirulence in response to its different environmental and human hosts, rather than from functional redundancy to circumvent deleteriousfismutations.
Testing for heavy metals in drinking water collected from Dog Aging Project participants
Authors: Sexton Courtney L. , O’Brien Janice , Lytle Justin , Rodgers Sam , Keyser Amber , Kauffman Mandy , Dunbar Matthew D. ,   Dog Aging Project Consortium, Edwards Marc , Krometis Leigh Anne , Ruple Audrey 
Published: September 2024

AbstractHeavy metals are commonly found in groundwater and can affect the quality of drinking water. In this pilot study, we analyzed the quality of drinking water for dogs participating in the Dog Aging Project (DAP) who lived in homes not served by a municipal water supply. In order to capture both diverse and localized environmental factors that may affect drinking water, 200 owners of DAP dogs located in one of 10 selected states were invited to participate. We tested for the presence of 28 metals in dogs’ drinking water, including eight (8) heavy metals that have maximum contaminant levels (MCLs) designated by the Environmental Protection Agency (EPA) and five (5) heavy metals that have EPA health guidance levels. The eight metals with MCLs are known to cause chronic health issues in humans after long-term ingestion. Our aim in this pilot was to determine whether such elements could be detected by at-home sampling of dogs’ drinking water. We found detectable levels of all metals tested. There were 126 instances when an analyte (arsenic, lead, copper, sodium, strontium, nickel, or vanadium) was above the EPA MCL or health guidance level. We further identified potential association between the presence of titanium and chromium, and occurrence of a known health condition in dogs. This prompts further investigation with a larger, stratified sample analyzing dogs’ drinking water composition and long-term health and wellness outcomes in dogs living in diverse geographies. These results may impact veterinary care decisions and husbandry, and underscore the validity and importance of utilizing dogs as sentinels of human health outcomes in the context of drinking water contamination.
Rapid Emergence of Resistance to Broad-Spectrum Direct Antimicrobial Activity of Avibactam
Authors: Nägeli Michelle , Rodriguez Shade , Manson Abigail L. , Earl Ashlee M. , Brennan-Krohn Thea 
Published: September 2024

ABSTRACTAvibactam (AVI) is a diazabicyclooctane (DBO) β-lactamase inhibitor used clinically in combination with ceftazidime. At concentrations higher than those typically achievedin vivo, it also has broad-spectrum direct antibacterial activity againstEnterobacteralesstrains, including metallo-β-lactamase-producing isolates, mediated by inhibition of penicillin-binding protein 2 (PBP2). This activity is mechanistically similar to that of more potent novel DBOs (zidebactam, nacubactam) in late clinical development. We found that resistance to AVI emerged readily, with a mutation frequency of 2×10−6to 8×10−5. Whole genome sequencing of resistant isolates revealed a heterogeneous mutational target that permitted bacterial survival and replication despite PBP2 inhibition, in line with prior studies of PBP2-targeting drugs. While such mutations are believed to act by upregulating the bacterial stringent response, we found a similarly high mutation frequency in bacteria deficient in components of the stringent response, although we observed a different set of mutations in these strains. Although avibactam-resistant strains had increased lag time, suggesting a fitness cost that might render them less problematic in clinical infections, there was no statistically significant difference in growth rates between susceptible and resistant strains. The finding of rapid emergence of resistance to avibactam as the result of a large mutational target has important implications for novel DBOs with potent direct antibacterial activity, which are being developed with the goal of expanding cell wall-active treatment options for multidrug-resistant gram-negative infections but may be vulnerable to treatment-emergent resistance.
JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac Events
Authors: Gurevic Ilya , Meudec Loic , Mariette Xavier , Nocturne Gaetane , McCoy Sara S. 
Published: September 2024

ABSTRACTObjectiveOur objective was to define the effect of JAK1/2 inhibitor (JAKinib) withdrawal on JAK/STAT biochemical response in the context of systemic rheumatic diseases.MethodsWe tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells and endothelial cells. We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate.ResultsType I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFNγ-stimulated MSCs and HUVECs in a time- and dose-dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapidincreaseof pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate.ConclusionsType I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might be associated with adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy.
Skeletons in the Forest: Using Entropy-Based Rogue Detection on Bayesian Phylogenetic Tree Distributions
Authors: Klawitter Jonathan , Bouckaert Remco R. , Drummond Alexei J. 
Published: September 2024

AbstractIn a phylogenetic analysis, rogue taxa and clades are those that, due to their uncertain placement, contribute disproportionally to the variance in a set of phylogenetics trees. They can obscure clear evolutionary relationships and complicate the interpretation of results. While existing rogue detection algorithms focus on improving the consensus tree for a set of trees, we introduce algorithms based on phylogenetic entropy to improve the analysis in a Bayesian framework. In particular, we introduce a tool that extracts a skeleton distribution of the posterior tree distribution that contains the core relationships by removing a minimal subset of rogues. Additionally, we enable detailed analyses of rogues at both the taxon and clade levels, including the visualisation of different rogue placements.
Environmental Enrichment Reducesadgrl3.1-Related Anxiety and Attention Deficits but Not Impulsivity
Authors: Fontana Barbara D. , Norton William H.J. , Parker Matthew O. 
Published: September 2024

AbstractEnvironmental factors play a role in the development and severity of neuropsychiatric disorders. Externalizing disorders (EDs) are linked to genetic and environmental factors and frequently co-occur with internalizing disorders (ID), such as anxiety. Individuals experiencing both ED/ID are often among the most likely to seek healthcare services, as this co-occurrence is associated with more severe symptomatology and greater functional impairment. Here, we investigate the role of environmental enrichment (EE) on a gene associated with impulsivity and attention deficits in zebrafish,adgrl3.1. Zebrafish were reared in either standard or enriched environments (from 15 days-post fertilization), and attention, impulsivity, and anxiety-related phenotypes were assessed at adult stages (4 months-post fertilization) using the open field test and 5-choice serial reaction time task. EE mitigated anxiety-related behaviors inadgrl3.1knockouts, normalizing locomotor patterns and decreasing thigmotaxis. Although attention deficits were reduced inadgrl3.1-/-fish reared in EE, impulsive behaviors were not. Together, these findings suggest that while EE can alleviate some externalizing and internalizing phenotypes in zebrafish, impulsivity remains resistant to environmental modification. This study suggests that impulsivity is a stable trait inadgrl3.1-/-fish, but highlights the importance of EE in mitigating some externalizing and internalizing symptoms.Summary statementEnvironmental enrichment reduces attention deficits and anxiety-like behavior, but not impulsivity inadgr3.1knockout zebrafish, highlighting the interaction between genetic and environmental factors in shaping externalizing and internalizing phenotypes.
Metal Ion Sensing by Tetraloop-Like RNA Fragment: Role of Compact Intermediates with Non-Native Metal Ion-RNA Inner Shell Contacts
Authors: Habibullah Sk , Baidya Lipika , Kumar Sunil , Reddy Govardhan 
Published: September 2024

AbstractDivalent metal ions influence the folding and function of RNA in the cells. The mechanism of how RNA structural elements in riboswitches sense specific metal ions is unclear. RNA interacts with ions through two distinct binding modes: direct interaction between the ion and RNA (inner-shell (IS) coordination) and indirect interaction between the ion and RNA mediated through water molecules (outer-shell (OS) coordination). To understand how RNA senses metal ions such as Mg2+and Ca2+, we studied the folding of a small RNA segment from the Mg2+sensing M-Box riboswitch using computer simulations. This RNA segment has the characteristics of a GNRA tetraloop motif and interestingly requires binding of a single Mg2+ion. The folding free energy surface of this simple tetraloop system is multidimensional, with a population of multiple intermediates where the tetraloop and cation interact through IS and OS coordination. The partially folded compact tetraloop intermediates form multiple non-native IS contacts with the metal ion. Thermal fluctuations should break these strong non-native IS contacts so that the tetraloop can fold to the native state, resulting in higher folding free energy barriers. Ca2+undergoes rapid OS to IS transitions and vice-versa due to its lower charge density than Mg2+. However, the ability of Ca2+to stabilize the native tetraloop state is weaker as it could not hold the loop-closing nucleotides together due to its weaker interactions with the nucleotides. These insights are critical to understanding the specific ion sensing mechanisms in riboswitches, and the predictions are amenable for verification by NMR experiments.
Single Versus Repeated Intravenous Oncolytic Virus Infusions – Implications for Rationalised Scheduling of Therapy in Hepatocellular Carcinoma
Authors: Scott Karen J. , West Emma , Brownlie Rebecca , Ismail Fay , Ralph Christy , Coffey Matt , Melcher Alan A. , Taylor Alison , Papa Salvatore , Samson Adel 
Published: September 2024

ABSTRACTBackgroundOncolytic virus (OV) immunotherapy stands to widely improve patient outcomes in multiple solid malignancies. However, to date, the scheduling of OV therapy, with single versus multiple infusions on consecutive days, has not been correlated with immunological or clinical response. In hepatocellular carcinoma (HCC) patients, where the background liver is frequently chronically injured, repeated dosing may have deleterious implications, resulting in off-target immune-mediated damage, thereby tipping the balance between favourable clinical response and hepatotoxicity. As such, elucidation of the optimum dosing regime is necessary to ensure therapy, whilst limiting damage to the background liver.MethodsHerein, we expand upon our previous experience in neoadjuvant OV therapy to compare the immunological response from single versus repeated doses of reovirus in cancer patients. The impact of OV immunotherapy on HCC outcomes was examinedin vivofollowing a high fat diet or induced liver fibrosis in the context of an abnormal background liver. Furthermore, we assess, in a syngeneic model of HCC, the potential immune-mediated toxicity of single versus multiple virus infusions in combination with PD-1 and PD-L1 blockade.ResultsClinical trial data indicate that a single dose of reovirus is equivalent or superior to repeat doses in achieving: (a) induction of an inflammatory cytokine/chemokine response; (b) peripheral blood immune cell activation; and (c) migration of activated CD8+ CTLs. Repeated doses on consecutive days do not improve the amplitude or duration of the immune response following virus infusion. Furthermore, repeated viral dosing leads to an unwanted influx of activated T cells into background liver. An increase in PD-L1 expression on T cells resulting from a single virus dose was observed. Combination therapy of reovirus plus anti-PD-L1, but not anti-PD-1, limited tumour growth and extended survivalin vivo.ConclusionsA single dose of oncolytic virus is equivalent or superior to multiple consecutive doses in inducing an anti-tumour immune response. Combination immune checkpoint blockade with anti-PD-L1 holds potential to maximise the beneficial effects of a single dose, whilst simultaneously avoiding undesirable toxicities in the background liver in the context of HCC.
Exploring the potential benefits and challenges of artificial intelligence for research funding organisations: a scoping review
Authors: Blatch-Jones Amanda Jane , Church Hazel , Crane Ksenia 
Published: September 2024

AbstractBackgroundArtificial Intelligence (AI) is at the forefront of today’s technological revolution, enhancing efficiency in many organisations and sectors. However, in some research environments, its adoption is tempered by the risks AI poses to data protection, ethics, and research integrity. For research funding organisations (RFOs), although there is interest in the application of AI to boost productivity, there is also uncertainty around AI’s utility and its safe integration into organisational systems and processes. The scoping review explored:‘What does the evidence say about the current and emerging use of AI?’; ‘What are the potential benefits of AI for RFOs?’and‘What are the considerations and risks of AI for RFOs?’MethodsA scoping review was undertaken with no study, language, or field limits. Due to the rapidly evolving AI field, searches were limited to the last three years (2022-2024). Four databases were searched for academic and grey literature in February 2024 (including 13 funding and professional research organisation websites). A classification framework captured the utility and potential, and considerations and risks of AI for RFOs.Results122 eligible articles revealed that current and emerging AI solutions could potentially benefit RFOs by enhancing data processes, administration, research insights, operational management, and strategic decision-making. These solutions ranged from AI algorithms to data management platforms, frameworks, guidelines, and business models. However, several considerations and risks need to be addressed before RFOs can successfully integrate AI (e.g., improving data quality, regulating ethical use, data science training).ConclusionWhile RFOs could potentially benefit from a breadth of AI-driven solutions to improve operations, decision-making and data management, there is a need to assess organisational ‘AI readiness’. Although technological advances could be the solution there is a need to address AI accountability, governance and ethics, address societal impact, and the risks to the research funding landscape.
Associations of Smoking Status and Leisure-time Physical Activity with Waist Circumference Change – Ten-year Follow-up among Twin Adults
Authors: Piirtola Maarit , Filippone Eeva-Liisa , Ranjit Anu , Kinnunen Taru , Kaprio Jaakko , Korhonen Tellervo 
Published: September 2024

ABSTRACTBACKGROUNDThis follow-up study investigated the associations of smoking status and leisure-time physical activity (LTPA) with weight circumference (WC) change.METHODSIn the FinnTwin16 cohort, 3,431 twins (47% men) reported smoking status, LTPA, and WC in early adulthood and 10 years later. Regression models were conducted to investigate associations of smoking status and of LTPA change (metabolic equivalent tasks [MET]-h/week) with WC change (cm) during the follow-up. Within-pair associations were analyzed using linear mixed fixed-effect regression among 800 same-sexed (409 identical) pairs.RESULTSDuring the 10-year follow-up, 40% (n=454) quit smoking. Among those who quit smoking, the mean WC increase was 7.4 cm (SD 8.2) and the mean LTPA decrease was -0.02 MET-h/week (SD 35.8). Compared to individuals continuing daily smoking, only quitters who smoked daily at baseline (β 1.87; 95% CI 0.68, 3.06) increased their WC. This association was not robust after shared familial influences were controlled for. Each additional MET-h/week lowered the risk for WC increase among individuals who smoked occasionally (β -0.054; -0,08, -0.003), quitters who smoked daily (β -0.05; -0.06, -0.02) and those who had never smoked (β -0.04; -0.05, -0.03). In the analyses among identical twin pairs, LTPA was associated with less WC increase among those who quit occasional smoking or had never smoked. For quitters from daily smoking, this association approached significance, but no association remained for those continuing smoking.CONCLUSIONSSmoking cessation seems to be associated with WC increase, but familial confounding is involved in this process. LTPA may inhibit post-cessation WC increase.KEY MESSAGESThis will be published as a summary box after the abstract in the final published article.What is already known on this topic1. Individuals quitting smoking tend to gain weight, but less is known of post-cessation abdominal obesity and the role of leisure-time physical activity in this process.What this study adds2. Smoking cessation associates with moderate increase in waist circumference among those who quit daily smoking, but shared familial influences are involved in this process.3. Increase in leisure-time physical activity may prevent post-cessation waist circumference increase.How this study might affect research, practice, or policy4. More research is needed to unravel genetic and epigenetic mechanisms underlying post-cessation waist circumference increase.5. In practice, individuals who quit smoking should be encouraged to be physically active.
The post-pandemic hospital and mortality burden of COVID-19 compared with influenza: A national cohort study in Denmark, May 2022 to June 2024
Authors: Bager Peter , Bech Svalgaard Ingrid , Kristensen Lomholt Frederikke , Emborg Hanne-Dorthe , Engbo Christiansen Lasse , Soborg Bolette , Hviid Anders , Skafte Vestergaard Lasse 
Published: September 2024

ABSTRACTBackgroundIn the post-pandemic period, COVID-19 continues to cause significant numbers of hospitalisations and deaths. We describe this burden and compare it to the burden of influenza in the first two post-pandemic years in Denmark.MethodsA cohort study including residents in Denmark from May 16, 2022, to June 7, 2024. Data were obtained from national registries, including information on Polymerase chain reaction (PCR) test-positive COVID-19 and influenza admissions, mortality within 30 days of admission, sex, age, COVID-19 and influenza vaccination, comorbidity, and living in long-term care facility for elderly. Negative binomial regression was used to estimate adjusted incidence rate ratios (aIRRs) to compare rates of admissions between COVID-19 and influenza. To assess severity of COVID-19 among hospitalized patients, we used Cox proportional hazard models to estimate adjusted hazard ratios (aHR) of 30-day mortality between COVID-19 and influenza.ResultsAmong 5,899,170 individuals, admissions with COVID-19 (n=24,687) were more frequent than admissions with influenza (n=8,682; aIRR 2.01, 95%CI 1.37-2.95), in particular during the first year (p=0.01), in the summer (p<0.001) and among people above 65 years of age (p<0.001). The number of deaths were also higher (COVID-19, n=2,393; influenza, n=522). Among patients, the risk of mortality of COVID-19 was higher than influenza in the 12-30 days following admission (0-11 days, aHR 1.08, 95%CI 0.94-1.25; 12-30 days, aHR 1.50, 95%CI 1.21-1.84), in particular among non-vaccinated for both COVID-19 and influenza (aHR 1.81, 95%CI 1.25-2.62), while it was similar to influenza among patients without comorbidities (aHR 1.07, 95%CI 0.63-1.80).ConclusionCOVID-19 represented a greater disease burden than influenza, with more hospitalisations and deaths, and more severe disease primarily among non-vaccinated and comorbid patients. These results highlight the continued need for attention and public health efforts to mitigate the impact of SARS-CoV-2.