Pollution gradients shape microbial communities associated with ae. albopictus larval habitats in urban community gardens.

The Asian tiger mosquito Aedes albopictus is well adapted to urban environments and takes advantage of the artificial containers that proliferate in anthropized landscapes. Little is known about the physicochemical, pollutant and microbiota compositions of Ae. albopictus-colonized aquatic habitats and whether these properties differ with noncolonized habitats. We specifically addressed this question in French community gardens by investigating whether pollution gradients (characterized either by water physicochemical properties combined with pollution variables or by the presence of organic molecules in water) influence water microbial composition and then the presence/absence of Ae. albopictus mosquitoes. Interestingly, we showed that the physicochemical and microbial compositions of noncolonized and colonized waters did not significantly differ, with the exception of N2O and CH4 concentrations, which were higher in noncolonized water samples. Moreover, the microbial composition of larval habitats covaried differentially along the pollution gradients according to colonization status. This study opens new avenues on the impact of pollution on mosquito habitats in urban areas and raises questions on the influence of biotic and abiotic interactions on adult life history traits and their ability to transmit pathogens to humans.

The neural signature of an erroneous thought.

The human brain detects errors in overt behavior fast and efficiently. However, little is known about how errors are monitored that emerge on a mental level. We investigate whether neural correlates of error monitoring can be found during inner speech and whether the involved neural processes differ between these non-motor responses and behavioral motor responses. Therefore, electroencephalographic data were collected while participants performed two versions of a decision task that only differed between these response modalities. Erroneous responses were identified based on participants' metacognitive judgments. Correlates of error monitoring in event-related potentials were analyzed by applying residue iteration decomposition on stimulus-locked activity. Non-motor responses elicited the same cascade of early error-related negativity and late error positivity as motor responses. An analysis of oscillatory brain activity showed a similar theta response for both error types. A multivariate pattern classifier trained on theta from the motor condition could decode theta from the non-motor condition, demonstrating the similarity of both neural responses. These results show that errors in inner speech are monitored and detected utilizing the same neural processes as behavioral errors, suggesting that goal-directed cognition and behavior are supported by a generic error-monitoring system.

Orthopoxvirus-specific antibodies wane to undetectable levels 1 year after MVA-BN vaccination of at-risk individuals, the Netherlands, 2022 to 2023.

In response to the mpox outbreak in 2022 and 2023, widespread vaccination with modified vaccinia Ankara-Bavarian Nordic (MVA-BN, also known as JYNNEOS or Imvanex) was initiated. Here, we demonstrate that orthopoxvirus-specific binding and MVA-neutralising antibodies waned to undetectable levels 1 year post vaccination in at-risk individuals who received two doses of MVA-BN administered subcutaneously with an interval of 4 weeks, without prior smallpox or mpox vaccination. Continuous surveillance is essential to understand the impact of declining antibody levels.

Incidental Pulmonary Nodules: Differential Diagnosis and Clinical Management.

BACKGROUND: According to data from the USA, the incidence of incidentally discovered pulmonary nodules is 5.8 per 100 000 person-years for women and 5.2 per 100 000 person-years for men. Their management as recommended in the pertinent guidelines can substantially improve clinical outcomes. More than 95% of all pulmonary nodules revealed by computed tomography (CT) are benign, but many cases are not managed in conformity with the guidelines. In this article, we summarize the appropriate clinical approach and provide an overview of the pertinent diagnostic studies and when they should be performed. METHODS: This review is based on relevant publications retrieved by a selective search in PubMed. The authors examined English-language recommendations issued since 2010 for the management of pulmonary nodules, supplemented by comments from the German lung cancer guideline. RESULTS: In general, the risk that an incidentally discovered pulmonary nodule is malignant is low but rises markedly with increasing size and the presence of risk factors. When such a nodule is detected, the further recommendation, depending on size, is either for follow-up examinations with chest CT or else for an extended evaluation with positron emission tomography-CT and biopsy for histology. The diagnostic evaluation should include consideration of any earlier imaging studies that may be available as an indication of possible growth over time. Single nodules measuring less than 6 mm, in patients with few or no risk factors, do not require any follow-up. Lung cancer is diagnosed in just under 10% of patients with a nodule measuring more than 8 mm. CONCLUSION: The recommendations of the guidelines for the management of incidentally discovered pulmonary nodules are intended to prevent both over- and undertreatment. If a tumor is suspected, further care should be provided by an interdisciplinary team.

Assessing the Quality of Solvent-Assisted Lipid Bilayers Formed at Different Phases and Aqueous Buffer Media: A QCM-D Study.

Supported lipid bilayers (SLBs) are low-complexity biomimetic membranes, serving as popular experimental platforms to study membrane organization and lipid transfer, membrane uptake of nanoparticles and biomolecules, and many other processes. Quartz crystal microbalance with dissipation monitoring has been utilized to probe the influence of several parameters on the quality of SLBs formed on Au- and SiO2-coated sensors. The influence of the aqueous medium (i.e., buffer type) and the adsorption temperature, above and below the lipid melting point, is neatly explored for SLBs of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine formed by a solvent exchange. Below the lipid melting temperature, quality variations are observed upon the formation on Au and SiO2 surfaces, with the SLBs being more homogeneous for the latter. We further investigate how the buffer affects the detection of lipid melting in SLBs, a transition that necessitates high-sensitivity and time-consuming surface-sensitive techniques to be detected.

Altering glycopeptide antibiotic biosynthesis through mutasynthesis allows incorporation of fluorinated phenylglycine residues.

Glycopeptide antibiotics (GPAs) are peptide natural products used as last resort treatments for antibiotic resistant bacterial infections. They are produced by the sequential activities of a linear nonribosomal peptide synthetase (NRPS), which assembles the heptapeptide core of GPAs, and cytochrome P450 (Oxy) enzymes, which perform a cascade of cyclisation reactions. The GPAs contain proteinogenic and nonproteinogenic amino acids, including phenylglycine residues such as 4-hydroxyphenylglycine (Hpg). The ability to incorporate non-proteinogenic amino acids in such peptides is a distinctive feature of the modular architecture of NRPSs, with each module selecting and incorporating a desired amino acid. Here, we have exploited this ability to produce and characterise GPA derivatives containing fluorinated phenylglycine (F-Phg) residues through a combination of mutasynthesis, biochemical, structural and bioactivity assays. Our data indicate that the incorporation of F-Phg residues is limited by poor acceptance by the NRPS machinery, and that the phenol moiety normally present on Hpg residues is essential to ensure both acceptance by the NRPS and the sequential cyclisation activity of Oxy enzymes. The principles learnt here may prove useful for the future production of GPA derivatives with more favourable properties through mixed feeding mutasynthesis approaches.

The third symposium on treatment-induced neuroendocrine prostate cancer: insights and future directions.

Neuroendocrine prostate cancer (NEPC) is a rare and aggressive subtype of prostate cancer (PCa), emerging from advanced treatments and characterized by loss of androgen receptor (AR) signaling and neuroendocrine features, leading to rapid progression and treatment resistance. The third symposium on treatment-induced NEPC, held from 21 to 23 June 2024, at Harrison Hot Springs Resort, BC, Canada, united leading global researchers and clinicians. Sponsored by the Vancouver Prostate Centre (VPC), Canadian Institute of Health Research, Prostate Cancer Foundation Canada and Pharma Planter Inc, the event focused on the latest NEPC research and innovative treatment strategies. Co-chaired by Drs. Yuzhuo Wang and Martin Gleave, the symposium featured sessions on NEPC's historical context, molecular pathways, epigenetic regulation and the role of the tumor microenvironment and metabolism in its progression. Keynotes from experts like Dr. Himisha Beltran and Dr. Martin Gleave highlighted the complexity of NEPC. The Emerging Talent session showcased new research, pointing to the future of NEPC treatment. The symposium concluded with a consensus on the need for early detection, targeted therapies and personalized medicine to effectively combat NEPC, emphasizing the importance of global collaboration in advancing NEPC understanding and treatment.

Prescription and switching patterns of direct oral anticoagulants in patients with atrial fibrillation.

Background: The patterns of direct oral anticoagulant (DOAC) selection and switching to a different oral anticoagulant (OAC) in patients with atrial fibrillation (AF) are unknown. Objectives: To describe temporal patterns in first DOAC prescriptions, estimate the incidence, and identify predictors of switching to a different OAC within 1 year in OAC-naive AF patients. Methods: In this retrospective cohort study, using a near-nationwide prescription registry (IQVIA, the Netherlands), we determined the number of patients per month initiated on each DOAC and identified predictors of switching within 1 year with robust Poisson regression. Results: We included 94,874 patients. From November 2015 to November 2019, the monthly use of apixaban (n = 366 to n = 1066, +191%), rivaroxaban (n = 379 to n = 868, +129%), and edoxaban (n = 2 to n = 305, +15,150%) increased, whereas that of dabigatran decreased (n = 317 to n = 179, -44%). In the 66,090 patients with ≥1 year of available calendar time, 7% switched to a different OAC within 1 year. Strong predictors of switching to a different DOAC were using dabigatran (adjusted risk ratio [aRR], 3.33; 95% CI, 3.02-3.66) or edoxaban (aRR, 1.56; 95% CI, 1.34-1.82) rather than apixaban and using a standard DOAC dose (aRR, 2.54; 95% CI, 2.23-2.88). Strong predictors of switching to a vitamin K antagonist were using rivaroxaban (aRR, 1.36; 95% CI, 1.19-1.54 vs apixaban) and using a standard DOAC dose (aRR, 1.49; 95% CI, 1.26-1.77). Conclusion: In the Netherlands, factor Xa inhibitors are increasingly being selected for OAC-naive AF patients. Seven percent of patients switch to a different OAC within 1 year, and the initial DOAC type and dose are strong predictors of switching.

Isolation of a NHC-stabilized heavier nitrile and its conversion into an isonitrile analogue.

Nitriles (R-C≡N) have been investigated since the late eighteenth century and are ubiquitous encounters in organic and inorganic syntheses. In contrast, heavier nitriles, which contain the heavier analogues of carbon and nitrogen, are sparsely investigated species. Here we report the synthesis and isolation of a phosphino-silylene featuring an N-heterocyclic carbene-phosphinidene and a highly sterically demanding silyl group as substituents. Due to its unique structural motif, it can be regarded as a Lewis base-stabilized heavier nitrile. The Si-P bond displays multiple bond character and a bent R-Si-P geometry, the latter indicating fundamental differences between heavier and classical nitriles. In solution, a quantitative unusual rearrangement to a phosphasilenylidene occurs. This rearrangement is consistent with theoretical predictions of rearrangements from heavier nitriles to heavier isonitriles. Our preliminary reactivity studies revealed that both isomers exhibit highly nucleophilic silicon centres capable of oxidative addition and coordination to iron tetracarbonyl.

Phosphorylation of CRYAB Induces a Condensatopathy to Worsen Post-Myocardial Infarction Left Ventricular Remodeling.

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.

Recent trends and disparities in 24-hour movement behaviors among US youth with mental, behavioral and neurodevelopmental conditions.

BACKGROUND: Meeting 24-h movement behaviors (24-HMB: physical activity [PA], screen time [ST], and sleep [SL]) recommendations may be associated with positive health outcomes among youth with specific mental, behavioral, and neurodevelopmental (MBD) conditions. However, temporal trends and disparities in meeting 24-HMB guidelines in these higher-risk groups have not been investigated, hampering the development of evidence-based clinical and public health interventions. METHODS: Serial, cross-sectional analyses of nationally National Survey of Children's Health (NSCH) data (including U.S. youth aged 6-17 years with MBD conditions) were conducted. The time-trends survey data was conducted between 2016 and 2021. The prevalence of 24-HMB adherence estimates were reported for the overall sample and for various sociodemographic subgroups. The subgroups analyzed included: age group (children[aged 6 to 13 years], adolescents[aged 14 to 17 years]), sex, socioeconomic status, and ethnicity. RESULTS: Data on 52,634 individuals (mean age, 12.0 years [SD,3.5]; 28,829 [58.0 %] boys) were analyzed. From 2016 to 2021 the estimated trend in meeting PA + ST + SL guidelines declined (-0.8 % [95%CI, -1.0 % to -0.5 %], P for trend <0.001), whereas meeting none of 24-HMB guidelines increased (2.2 % [1.8 % to 2.6 %], P for trend <0.001). White participants, children, and boys reported higher estimated prevalence of meeting full integrated (PA + ST + SL) guidelines. DISCUSSION: The temporal trends observed in this study highlight the importance of consistently monitoring movement behavior among MBD youth and identifying variations by sociodemographic groups in meeting 24-HMB guidelines for health promotion within these vulnerable groups.

The chicken or the egg? Mycoplasma pneumoniae complicated by left ventricle thrombus and anterior myocardial infarction: a case report.

Background: Mycoplasma pneumoniae can be associated with extrapulmonary manifestations, including vasculitis, myocarditis, and thrombosis. In rare cases, it has also been implicated in intracardiac thrombus formation. Case Summary: A previously healthy 25-year-old male presented with worsening abdominal pain, an episode of acute chest pain, new lightheadedness, and gait instability in the setting of M. pneumoniae. Initial blood tests were notable for mild coagulopathy, thrombocytosis, transaminitis, and elevated high-sensitivity troponin. Further, workup revealed systematic emboli to the cerebellum, kidneys, spleen, anterior myocardial infarction, and a left ventricular multilobular mural mass. Due to the unknown composition of the mass with concern for further embolic events, the patient underwent successful surgical excision with the mass ultimately defined as a thrombus. Hypercoagulable workup was notably inconclusive and intraoperative myocardial biopsies revealed organizing infarction without inflammation or healed myocarditis. Post-operative course was complicated by left ventricular dysfunction and acute kidney injury, both with eventual improvement. Patient has remained on guideline-directed medical therapy and prophylactic anticoagulation. Discussion: We presume that the formation of the ventricular thrombus in this case was a result of transient thrombophilia in the setting of M. pneumonia resulting in coronary obstruction and subsequent myocardial injury. This case underscores the challenge of determining the pathophysiological sequence of events in patients with mycoplasma who develop systemic embolism and the management of a large residual thrombus, particularly in regard to surgical consideration.

[Metabolic, clinical and body composition changes in Mexican adults undergoing bariatric surgery]. / Cambios metabólicos, clínicos y de composición corporal en adultos mexicanos sometidos a cirugía bariátrica.

BACKGROUND: morbid obesity is a major public health problem that is increasing. Currently, there are a limited number of studies carried out in the Mexican population that describe the effects of bariatric surgery. OBJECTIVE: to establish in people undergoing a bariatric procedure the metabolic and body composition difference before and after bariatric surgery. MATERIAL AND METHODS: an observational, analytical, and longitudinal study was carried out in 50 patients with morbid obesity who underwent laparoscopic Sleeve Gastrectomy (LSG) and Laparoscopic Roux-en-Y gastric bypass (LRYGB). Body composition and metabolic markers in blood were measured. Differences in the metabolic profile before and after surgery were analyzed in the entire study group and a subanalysis was performed by bariatric surgical technique, determining the percentage of remission of comorbidities. RESULTS: after the intervention, there is a significant decrease in all metabolic and body composition markers, except HDL cholesterol, which showed a tendency to increase without being significant. Women with LRYGB have a greater decrease in fat-free mass. LRYGB decreased the prevalence of fatty liver, gastroesophageal reflux, insulin resistance, and hypercholesterolemia more, while LSG decreased the prevalence of hypertension, osteoarthritis, hypothyroidism, and hypertriglyceridemia more. CONCLUSION: bariatric surgery induces metabolic changes that could contribute to improving comorbidities associated with obesity. In general, metabolic improvement is greater in LRYGB compared to LSG.

Cine-MRI and T1TSE Sequence for Mediastinal Mass.

Background/Objectives: Contrast-enhanced computed tomography (CT) is the standard radiologic examination for evaluating the extent of mediastinal tumors. If tumor infiltration into the large central thoracic vessels, the pericardium, or the myocardium is suspected, cine magnetic resonance imaging (cine-MRI) can provide additional valuable information. Methods: We conducted a retrospective study of patients with mediastinal tumors who were staged with CT, cine-MRI, and a T1-weighted turbo spin echo (T1TSE) prior to surgical resection. Imaging was re-evaluated regarding tumor infiltration into the pericardium, myocardium, superior vena cava, aorta, pulmonary arteries, and atria and compared with intraoperative findings and postoperative histopathological reports (gold standard). Unclear CT findings were further investigated. Results: Forty-seven patients (29 female and 18 male patients; median age: 58 years) met the inclusion criteria. Cine-MRI was able to predict infiltration of the aorta in 86%, pulmonary arteries in 85%, and atria in 80% of unclear CT cases. Aortic tumor infiltration in unclear CT cases was significantly more often correctly diagnosed with cine-MRI than with T1TSE sequence. Conclusions: Additional cine-MRI is of crucial benefit in unclear CT cases. We recommend performing cine-MRI if infiltration into the large central vessels and atria is suspected. T1TSE sequence is of very limited additional value.

Direct Oral Anticoagulants in Older and Frail Patients with Atrial Fibrillation: A Decade of Experience.

INTRODUCTION: Both the prevalence of atrial fibrillation (AF) and its subsequent use of direct oral anticoagulants (DOACs) are rapidly increasing in patients of older age. In the absence of contra-indications, guidelines advocate anticoagulation based on the CHA2DS2-VASc score for all AF patients aged 75 and above. However, some practitioners are hesitant to prescribe anticoagulants to older and frail patients due to perceived elevated bleeding risks. This review delves into the comparative treatment outcomes of DOACs versus vitamin K antagonists (VKAs) in older patients with AF, particularly focusing on those of advanced age, frailty, increased risk of falling, chronic kidney disease (CKD), or with a history of major bleeding. Additionally, considerations on the use of off-label DOAC doses, the role of left atrial appendage (LAA) closure and future developments in factor XIa-inhibitors will be discussed. RESULTS: While strong evidence supports the use of DOACs in the vital older patients with nonvalvular AF, it remains scant in frail patient groups. There is some evidence from non-randomized studies suggesting that the effect of DOACs compared with VKAs is consistent between frail and nonfrail patients. However, recent findings from a single randomized trial showed increased bleeding risks but comparable thromboembolic outcomes in frail individuals switching from VKAs to DOACs. In patients with an increased risk of falling, data suggest no relevant interaction of increased risk of falling on the effectiveness and safety of DOACs compared with warfarin. Resuming oral anticoagulants in patients with Af after major bleeding seems to be beneficial. Off-label low-dose DOAC is often prescribed to patients who were underrepresented in larger randomized trails because of an elevated risk of bleeding or overexposure to DOACs, but its effect on clinical outcomes remains uncertain. CONCLUSIONS: DOACs are the recommended oral anticoagulant for vital older patients with AF. The scarcity of data backing DOAC use in frail individuals, those with renal impairments, or significant bleeding history underscores the necessity for further investigation. However, existing evidence suggests at least similar effectiveness and safety and potential benefits for DOACs in these patient subsets. Therefore, there is no reason to suggest these patients should be treated differently than the established guidelines regarding anticoagulation.

Bayesian spatial analysis of incomplete vaccination among children aged 12-23 months in Nigeria.

High childhood disease prevalence and under-five mortality rates have been consistently reported in Nigeria. Vaccination is a cost-effective preventive strategy against childhood diseases. Therefore, this study aimed to identify the determinants of Incomplete Vaccination (IV) among children aged 12-23 months in Nigeria. This cross-sectional design study utilized the 2018 Nigeria Demographic and Health Survey (NDHS) dataset. A two-stage cluster sampling technique was used to select women of reproductive age who have children (n = 5475) aged 12-23 months. The outcome variable was IV of children against childhood diseases. Data were analyzed using Integrated Nested Laplace Approximation and Bayesian binary regression models (α0.05). Visualization of incomplete vaccination was produced using the ArcGIS software. Children's mean age was 15.1 ± 3.2 months and the median number of vaccines received was four. Northern regions contributed largely to the IV. The likelihood of IV was lower among women aged 25-34 years (aOR = 0.67, 95% CI = 0.54-0.82, p < 0.05) and 35-49 years (aOR = 0.59, 95%CI = 0.46-0.77, p < 0.05) compared to younger women in the age group 15-24 years. An increasing level of education reduces the risk of odds of IV. Other predictors of IV were delivery at the health facility (aOR = 0.64, 95% CI = 053-0.76, p < 0.05), and media exposure (aOR = 0.63, 95%CI = 0.54-0.79, p < 0.05). Mothers' characteristics explained most of the variability in the IV, relatively to smaller overall contributions from the community and state-level factors (p < 0.05). The level of IV against childhood diseases was high in Nigeria. However, disparities exist across the regions and other socioeconomic segments of the population. More efforts are required to improve vaccination sensitization programs and campaigns in Nigeria.

A worldwide study of white matter microstructural alterations in people living with Parkinson's disease.

The progression of Parkinson's disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20-89 years; 33% female) and 885 controls (age: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen's d effect sizes reached d = -1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Tumor-derived GLI1 promotes remodeling of the immune tumor microenvironment in melanoma.

BACKGROUND: Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored. METHODS: The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays. RESULTS: Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8. CONCLUSION: Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.

Knowledge and Perceptions about Diagnosis, Clinical Management, and Prevention of Dengue Fever among Physicians during the 2023 Outbreak: A Cross-Sectional Study in Peru.

The objective of this study was to evaluate the knowledge level and perception of dengue fever management among Peruvian physicians and to determine the factors associated with higher knowledge. We conducted an analytical cross-sectional study based on an online survey. To evaluate the factors associated with a high level of knowledge (≥70% of correct answers), we used crude (cPR) and adjusted (aPR) prevalence ratios by the Poisson regression model. Of 359 respondents (median age: 33 years; male: 56.5%), 78.8% achieved a high level of knowledge. Multivariable analysis showed an independent association with having read the Peruvian clinical practice guidelines for dengue management (aPR: 1.29; 95% CI: 1.12-1.49), having experience in treating patients (aPR: 1.32; 95% CI: 1.03-1.68), and having treated cases frequently (aPR: 1.22; 95% CI: 1.02-1.46). Residing in the eastern macroregion (aPR: 0.83; 95% CI: 0.71-0.97) was associated with a low level of knowledge. In conclusion, Peruvian physicians had a high level of knowledge about dengue fever. This was associated with having clinical experience in dengue management. However, given the low level of knowledge in the eastern macroregion, educational campaigns are necessary in this area.