ABSTRACT
BACKGROUND: Frequent premature ventricular contractions (PVCs) in children are usually considered benign. Symptoms and/or left ventricular dysfunction are indications for treatment with anti-arrhythmic drugs (AAD). OBJECTIVE: To evaluate the efficacy of flecainide versus metoprolol in reducing PVCs in children. METHODS: A randomized open label cross-over trial children with a PVC-burden of >15% on Holter; successively treated with metoprolol and flecainide or vice versa, with a drug free interval of at least two weeks. Holter measurements were repeated before and after the start of the AAD. RESULTS: Sixty patients were screened, 19 patients could be included. Median age was 13.9 years (IQR 5.5 years). Mean baseline PVC-burden was 21.7% (N=18, SD±14.0) before the start of flecainide and 21.2% (N=17, SD±11.5) before the start of metoprolol. In a mixed model analysis the estimated mean reduction in PVC-burden was 10.6 percentage-points (95%-CI 5.8-15.3) for flecainide and 2.4 percentage-points (95%-CI -2.7-7.5) for metoprolol, with a significant difference of 8.2 percentage-points (95%-CI of 0.86-15.46, P=0.031). Exploratory analysis revealed that 9/18 patients treated with flecainide and 1/17 patients treated with metoprolol, had a reduction to a PVC-burden below 5%. No discriminating factors between flecainide-responders and non-responders were found; the mean plasma level was not significantly different (0.34 mg/L versus 0.52 mg/L, P=0.277). CONCLUSIONS: In children with frequent PVCs flecainide led to a significant greater reduction of PVC-burden, compared to metoprolol. Flecainide was effective in only a subgroup of patients, which appears to be unrelated to the plasma level. (Dutch Trial Register number 26689).
ABSTRACT
Huntington's disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington's disease and other polyglutamine diseases.
Subject(s)
Huntington Disease , Nuclear Envelope , Peptides , Nuclear Envelope/metabolism , Nuclear Envelope/ultrastructure , Humans , Peptides/metabolism , Peptides/genetics , Huntington Disease/metabolism , Huntington Disease/pathology , Huntington Disease/genetics , Animals , Huntingtin Protein/metabolism , Huntingtin Protein/genetics , Protein Aggregates , Nuclear Lamina/metabolism , Nuclear Lamina/ultrastructure , Cell Nucleus/metabolismSubject(s)
Cold Temperature , Humans , Cold Temperature/adverse effects , Neurosciences , Water , ImmersionABSTRACT
BACKGROUND: Long-term disability after stroke is standardly assessed 3 months post-onset, using the modified Rankin Scale (mRS). The value of an early, day 4 mRS assessment for projecting the 3-month disability outcome has not been formally investigated. METHODS: In this cohort of patients with acute cerebral ischemia and intracranial hemorrhage, we analyzed day 4 and day 90 mRS assessments in the NIH Field Administration of Stroke Therapy- Magnesium (FAST-MAG) Phase 3 trial. The performance of day 4 mRS, alone and as part of multivariate models, in predicting day 90 mRS was assessed using correlation coefficients, percent agreement, and the kappa statistics. RESULTS: Among the 1573 acute cerebrovascular disease (ACVD) patients, 1206 (76.7%) had acute cerebral ischemia (ACI), while 367 (23.3%) had intracranial hemorrhage. Among all 1573 ACVD patients, day 4 mRS and day 90 mRS correlated strongly, Spearman's rho=0.79, in unadjusted analysis with weighted kappa of 0.59. For dichotomized outcomes, simple carry-forward of the day 4 mRS performed fairly well in agreeing with day 90 mRS: mRS 0-1 (kappa=0.67), 85.4%; mRS 0-2 (k=0.59), 79.5%; fatal outcome, 88% (k=0.33). Correlations of 4d and 90d mRS were stronger for ACI than ICH patients, 0.76 vs 0.71. CONCLUSIONS: In this acute cerebrovascular disease patient cohort, assessment of global disability performed on day 4 is highly informative regarding long-term, 3-month mRS disability outcome, alone, and even more strongly in combination with baseline prognostic variables. The day 4 mRS is a useful measure for imputing the final patient disability outcome in clinical trials and quality improvement programs.
ABSTRACT
Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.
Subject(s)
Drug Resistance, Neoplasm , Ovarian Neoplasms , Phthalazines , Piperazines , Poly(ADP-ribose) Polymerase Inhibitors , Female , Phthalazines/pharmacology , Phthalazines/therapeutic use , Piperazines/pharmacology , Humans , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Ovarian Neoplasms/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Animals , Cell Line, Tumor , Mice , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Xenograft Model Antitumor Assays , Polo-Like Kinase 1 , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Apoptosis/drug effects , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , DNA Damage/drug effects , G2 Phase Cell Cycle Checkpoints/drug effectsABSTRACT
The kidney and brain play critical roles in the regulation of blood pressure. Neuropeptide FF (NPFF), originally isolated from the bovine brain, has been suggested to contribute to the pathogenesis of hypertension. However, the roles of NPFF and its receptors, NPFF-R1 and NPFF-R2, in the regulation of blood pressure, via the kidney, are not known. In this study, we found that the transcripts and proteins of NPFF and its receptors, NPFF-R1 and NPFF-R2, were expressed in mouse and human renal proximal tubules (RPTs). In mouse RPT cells (RPTCs), NPFF, but not RF-amide-related peptide-2 (RFRP-2), decreased the forskolin-stimulated cAMP production in a concentration- and time-dependent manner. Furthermore, dopamine D1-like receptors colocalized and co-immunoprecipitated with NPFF-R1 and NPFF-R2 in human RPTCs. The increase in cAMP production in human RPTCs caused by fenoldopam, a D1-like receptor agonist, was attenuated by NPFF, indicating an antagonistic interaction between NPFF and D1-like receptors. The renal subcapsular infusion of NPFF in C57BL/6 mice decreased renal sodium excretion and increased blood pressure. The NPFF-mediated increase in blood pressure was prevented by RF-9, an antagonist of NPFF receptors. Taken together, our findings suggest that autocrine NPFF and its receptors in the kidney regulate blood pressure, but the mechanisms remain to be determined.
Subject(s)
Autocrine Communication , Blood Pressure , Cyclic AMP , Oligopeptides , Signal Transduction , Animals , Humans , Mice , Cyclic AMP/metabolism , Oligopeptides/pharmacology , Oligopeptides/metabolism , Receptors, Neuropeptide/metabolism , Kidney Tubules, Proximal/metabolism , Male , Kidney/metabolism , Mice, Inbred C57BL , Receptors, Dopamine D1/metabolismABSTRACT
Racial biases, which harm marginalized and excluded communities, may be combatted by clarifying misconceptions about race during biology lessons. We developed a human genetics laboratory activity that challenges the misconception that race is biological (biological essentialism). We assessed the relationship between this activity and student outcomes using a survey of students' attitudes about biological essentialism and color-evasive ideology and a concept inventory about phylogeny and human diversity. Students in the human genetics laboratory activity showed a significant decrease in their acceptance of biological essentialism compared with a control group, but did not show changes in color-evasive ideology. Students in both groups exhibited increased knowledge in both areas of the concept inventory, but the gains were larger in the human genetics laboratory. In the second iteration of this activity, we found that only white students' decreases in biological essentialist beliefs were significant and the activity failed to decrease color-evasive ideologies for all students. Concept inventory gains were similar and significant for both white and non-white students in this iteration. Our findings underscore the effectiveness of addressing misconceptions about the biological origins of race and encourage more research on ways to effectively change damaging student attitudes about race in undergraduate genetics education.
Subject(s)
Racial Groups , Students , Humans , Racial Groups/genetics , Male , Female , Attitude , Genetics/education , Human Genetics , Universities , RacismABSTRACT
To interpret our surroundings, the brain uses a visual categorization process. Current theories and models suggest that this process comprises a hierarchy of different computations that transforms complex, high-dimensional inputs into lower-dimensional representations (i.e., manifolds) in support of multiple categorization behaviors. Here, we tested this hypothesis by analyzing these transformations reflected in dynamic MEG source activity while individual participants actively categorized the same stimuli according to different tasks: face expression, face gender, pedestrian gender, and vehicle type. Results reveal three transformation stages guided by the pre-frontal cortex. At stage 1 (high-dimensional, 50-120 ms), occipital sources represent both task-relevant and task-irrelevant stimulus features; task-relevant features advance into higher ventral/dorsal regions, whereas task-irrelevant features halt at the occipital-temporal junction. At stage 2 (121-150 ms), stimulus feature representations reduce to lower-dimensional manifolds, which then transform into the task-relevant features underlying categorization behavior over stage 3 (161-350 ms). Our findings shed light on how the brain's network mechanisms transform high-dimensional inputs into specific feature manifolds that support multiple categorization behaviors.
Subject(s)
Occipital Lobe , Humans , Male , Female , Adult , Occipital Lobe/physiology , Young Adult , Prefrontal Cortex/physiology , MagnetoencephalographyABSTRACT
Three-dimensional (3D) cell culture creates a more physiologically relevant environment for enhanced drug screening capabilities using microcarriers. An automated 3D system that integrates robotic manipulators, liquid handling systems, sensors, and environment control systems has the capacity to handle multiple samples in parallel, perform repetitive tasks, and provide real-time monitoring and analysis. This chapter describes a potential 3D cell culture drug screening model by combining renal proximal tubule cells as a representative normal cell line with cancer cell lines. This combination is subjected to drug screening to evaluate the drug's efficacy in suppressing cancer cells while minimizing impact on normal cells with the added benefit of having the ability to separate the two cell types by magnetic isolation for high content screens including mass spectrometry-based proteomics. This study presents advancements in 3D cell culture techniques, emphasizing the importance of automation and the potential of microcarriers in drug screening and disease modeling.
Subject(s)
Cell Culture Techniques, Three Dimensional , Humans , Cell Culture Techniques, Three Dimensional/methods , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , Drug Screening Assays, Antitumor/methods , Kidney Tubules, Proximal/cytology , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Cell Culture Techniques/methods , Antineoplastic Agents/pharmacology , Automation , Automation, Laboratory/methods , Neoplasms/pathology , Neoplasms/drug therapyABSTRACT
Schizophyllum commune is a mushroom-forming fungus notable for its distinctive fruiting bodies with split gills. It is used as a model organism to study mushroom development, lignocellulose degradation and mating type loci. It is a hypervariable species with considerable genetic and phenotypic diversity between the strains. In this study, we systematically phenotyped 16 dikaryotic strains for aspects of mushroom development and 18 monokaryotic strains for lignocellulose degradation. There was considerable heterogeneity among the strains regarding these phenotypes. The majority of the strains developed mushrooms with varying morphologies, although some strains only grew vegetatively under the tested conditions. Growth on various carbon sources showed strain-specific profiles. The genomes of seven monokaryotic strains were sequenced and analyzed together with six previously published genome sequences. Moreover, the related species Schizophyllum fasciatum was sequenced. Although there was considerable genetic variation between the genome assemblies, the genes related to mushroom formation and lignocellulose degradation were well conserved. These sequenced genomes, in combination with the high phenotypic diversity, will provide a solid basis for functional genomics analyses of the strains of S. commune.
Subject(s)
Genetic Variation , Genome, Fungal , Genotype , Lignin , Phenotype , Schizophyllum , Schizophyllum/genetics , Schizophyllum/growth & development , Schizophyllum/classification , Lignin/metabolism , Genome, Fungal/genetics , Phylogeny , Agaricales/genetics , Agaricales/growth & development , Agaricales/classification , Sequence Analysis, DNAABSTRACT
OBJECTIVE: To compare total immunoglobulin (Ig) E assay performance characteristics between Abbott Architect and Siemens Immulite test systems. Reference intervals were also determined for both platforms in an American population of healthy adults. METHODS: Agreement of the two total IgE assays was evaluated in a cohort of 331 subjects with normal complete blood count (CBC) and comprehensive metabolic panel (CMP) results. Reference intervals were established in 302 subjects after exclusion of atopic individuals on the Abbott Architect and Siemens Immulite test systems. RESULTS: We demonstrated a 32% positive bias for total IgE quantitation on the Siemens Immulite platform compared to the Abbott Architect, despite both methods calibrated against the same WHO international reference material (75/502), Furthermore, the upper limit of the reference interval (95th percentile) was determined to be higher for the Siemens Immulite assay compared to the Abbott Architect (132 and 102 IU/mL, respectively). CONCLUSION: Despite the use of a common WHO reference material for total IgE assay calibration, significant differences in quantitation was observed between two FDA-cleared test systems. Given that, it is warranted for clinical laboratories to verify vendor established reference intervals and adjust accordingly based on internal assessment of the normal range.
Subject(s)
Immunoglobulin E , Humans , Immunoglobulin E/blood , Adult , Reference Values , Female , Male , Middle Aged , Young Adult , Aged , Healthy Volunteers , Adolescent , Immunoassay/standards , Immunoassay/methods , Reproducibility of Results , CalibrationABSTRACT
The neuronal tricarboxylic acid and glutamate/glutamine (Glu/Gln) cycles play important roles in brain function. These processes can be measured in vivo using dynamic 1H-[13C] MRS during administration of 13C-labeled glucose. Proton-observed carbon-edited (POCE) MRS enhances the signal-to-noise ratio (SNR) compared with direct 13C-MRS. Ultra-high field further boosts the SNR and increases spectral dispersion; however, even at 7 T, Glu and Gln 1H-resonances may overlap. Further gain can be obtained with selective POCE (selPOCE). Our aim was to create a setup for indirect dynamic 1H-[13C] MRS in the human brain at 7 T. A home-built non-shielded transmit-receive 13C-birdcage head coil with eight transmit-receive 1H-dipole antennas was used together with a 32-channel 1H-receive array. Electromagnetic simulations were carried out to ensure that acquisitions remained within local and global head SAR limits. POCE-MRS was performed using slice-selective excitation with semi-localization by adiabatic selective refocusing (sLASER) and stimulated echo acquisition mode (STEAM) localization, and selPOCE-MRS using STEAM. Sequences were tested in a phantom containing non-enriched Glu and Gln, and in three healthy volunteers during uniformly labeled 13C-glucose infusions. In one subject the voxel position was alternated between bi-frontal and bi-occipital placement within one session. [4-13C]Glu-H4 and [4-13C]Gln-H4 signals could be separately detected using both STEAM-POCE and STEAM-selPOCE in the phantom. In vivo, [4,5-13C]Glx could be detected using both sLASER-POCE and STEAM-POCE, with similar sensitivities, but [4,5-13C]Glu and [4,5-13C]Gln signals could not be completely resolved. STEAM-POCE was alternately performed bi-frontal and bi-occipital within a single session without repositioning of the subject, yielding similar results. With STEAM-selPOCE, [4,5-13C]Glu and [4,5-13C]Gln could be clearly separated. We have shown that with our setup indirect dynamic 1H-[13C] MRS at 7 T is feasible in different locations in the brain within one session, and by using STEAM-selPOCE it is possible to separate Glu from Gln in vivo while obtaining high quality spectra.
ABSTRACT
BACKGROUND AND PURPOSE: Thromboxane A2 (TXA2) is a prostanoid produced during platelet activaton, important in enhancing platelet reactivity by activation of TP receptors. However, due to the short half-life, studying TXA2 signalling is challenging. To enhance our understanding of TP receptor-mediated platelet biology, we therefore synthesised mono and difluorinated TXA2 analogues and explored their pharmacology on heterologous and endogenously expressed TP receptor function. EXPERIMENTAL APPROACH: Platelet functional and signalling responses were studied using aggregometry, Ca2+ mobilisation experiments and immunoblotting and compared with an analogue of the TXA2 precursor prostaglandin H2, U46619. Gαq/Gαs receptor signalling was determined using a bioluminescence resonance energy transfer (BRET) assay in a cell line overexpression system. KEY RESULTS: BRET studies revealed that F-TXA2 and F2-TXA2 promoted receptor-stimulated TP receptor G-protein activation similarly to U46619. Unexpectedly, F2-TXA2 caused reversible aggregation in platelets, whereas F-TXA2 and U46619 induced sustained aggregation. Blocking the IP receptor switched F2-TXA2-mediated reversible aggregation into sustained aggregation. Further BRET studies confirmed F2-TXA2-mediated IP receptor activation. F2-TXA2 rapidly and potently stimulated platelet TP receptor-mediated protein kinase C/P-pleckstrin, whereas IP-mediated protein kinase A/P-vasodilator-stimulated phosphoprotein was more delayed. CONCLUSION AND IMPLICATIONS: F-TXA2 is a close analogue to TXA2 used as a selective tool for TP receptor platelet activation. In contrast, F2-TXA2 acts on both TP and IP receptors differently over time, resulting in an initial wave of TP receptor-mediated platelet aggregation followed by IP receptor-induced reversibility of aggregation. This study reveals the potential difference in the temporal aspects of stimulatory and inhibitory pathways involved in platelet activation.
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BACKGROUND: Pain and dysfunction persist for most patients following hip-related pain treatment. Additionally, individuals with hip-related pain are typically less physically active than individuals without hip pain, despite evidence that regular physical activity reduces chronic musculoskeletal pain. Poor psychological health is common in patients with hip-related pain and further reinforces low physical activity. Mind-body interventions can improve psychological health and activity levels but have yet to be integrated to provide comprehensive, psychologically informed care for patients with hip-related pain. Thus, we are using the NCCIH intervention development framework to develop Helping Improve PSychological Health (HIPS), a novel, multimodal mind-body intervention to improve physical activity for individuals with hip-related pain and poor psychological health. METHODS: We will recruit physical therapists (N = 20) and patients with hip-related pain (N = 20) to participate in 60 min qualitative interviews (focus groups with therapists; one-on-one interviews with patients). Using these data, we will develop the initial HIPS intervention and provider training materials. One physical therapist will be trained to deliver the HIPS intervention to five participants in an open pilot trial. Participants will attend six 30 min HIPS intervention sessions. We will collect quantitative data on satisfaction, improvement, and physical activity, alongside qualitative exit interviews with participants and the physical therapist in order to refine the HIPS intervention and provider training materials. RESULTS: This study has been approved by the MGB IRB. We aim to develop and test the initial feasibility of the HIPS intervention in an open pilot trial. The findings from this project will inform a subsequent feasibility RCT.
ABSTRACT
Historically, back pain has been an inciting complaint for the initiation of opioids. Aggressive marketing of opioids to treat back pain coupled with the initiation of pain being treated as "the fifth vital sign" contributed to the emerging opioid crisis in the USA. West Virginia (WV) has long been considered the epicenter of the crisis. In 2018, the WV legislature passed a bill that placed prescribing limits on opioids. Our group set out to investigate the impacts of opioid prescribing restrictions through a sequential, mixed methods study evaluating prescription trends and stakeholder experiences. These stakeholder experiences generated emergent themes regarding the evolution of the opioid crisis up to and beyond the implementation of the bill, which is of relevance to neurosurgeons and back pain treatment. This study explores those findings for a neurosurgical audience. This study consisted of open-ended, semi-structured interviews with a purposive sample of 50 physicians, pharmacists, and patients in WV. Interviews were recorded and transcribed verbatim. Content analysis was utilized as the methodological orientation. Five theoretical domains relevant to the treatment of back pain emerged, describing the prevalence of opioid use, barriers to access care, the importance of opioids for function in resource-poor rural areas, disconnected and siloed care, and patient views on the impacts of pain care gaps and solutions. Spinal pain care in rural WV is complex due to identified challenges. Care siloing factors in suboptimal spinal pain care. Future work should define, implement, and assess the real-world effectiveness of treatment paradigms for the full spectrum of surgical and non-surgical back pain complaints. Neurosurgeons should be present in this arena.
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A 40-year-old woman admitted for hyponatremia and anasarca due to decompensated cirrhosis after a recent steroid taper developed extremely painful cutaneous breast lesions clinically mimicking cellulitis and inflammatory breast cancer and was biopsy-diagnosed instead with diffuse dermal angiomatosis (DDA) of the breasts, a rare and painful disease that can be a diagnostic chameleon. This case highlights the importance of early surgical consultation and tissue biopsy to correctly diagnose the etiology of severely painful mastitis and prevent prolonged symptomology and repeated administrations of ineffective treatments. Diffuse dermal angiomatosis should be considered when suspected breast cellulitis is refractory to treatment or there is concern for inflammatory breast cancer, especially in pendulous-breasted women with comorbidities that increase susceptibility to local tissue hypoxia.
ABSTRACT
Oral health is associated with overall health, especially in older adults (age 65 and older). Chronic conditions in older adults may affect oral health, and poor oral health may increase the risk of certain chronic conditions (1-3). Poor oral health has also been associated with increased cardiovascular disease risk (4). Several factors, including chronic conditions, health status, race, and income have been associated with reduced dental care use among older adults (5-9). This report describes the percentage of older adults who had a dental visit in the past 12 months by selected sociodemographic characteristics and chronic conditions using the 2022 National Health Interview Survey (NHIS). .
Subject(s)
Dental Care , Humans , United States/epidemiology , Aged , Male , Female , Dental Care/statistics & numerical data , Chronic Disease/epidemiology , Oral Health , Aged, 80 and over , Socioeconomic Factors , Sex DistributionABSTRACT
Mycoplasma hyopneumoniae (Mhyo) is the causative agent of porcine enzootic pneumonia (EP), as well as one of the main pathogens involved in the porcine respiratory disease complex. The host-pathogen interaction between Mhyo and infected pigs is complex and not completely understood; however, improving the understanding of these intricacies is essential for the development of effective control strategies of EP. In order to improve our knowledge about this interaction, laser-capture microdissection was used to collect bronchi, bronchi-associated lymphoid tissue, and lung parenchyma from animals infected with different strains of Mhyo, and mRNA expression levels of different molecules involved in Mhyo infection (ICAM1, IL-8, IL-10, IL-23, IFN-α, IFN-γ, TGF-ß, and TNF-α) were analyzed by qPCR. In addition, the quantification of Mhyo load in the different lung compartments and the scoring of macroscopic and microscopic lung lesions were also performed. Strain-associated differences in virulence were observed, as well as the presence of significant differences in expression levels of cytokines among lung compartments. IL-8 and IL-10 presented the highest upregulation, with limited differences between strains and lung compartments. IFN-α was strongly downregulated in BALT, implying a relevant role for this cytokine in the immunomodulation associated with Mhyo infections. IL-23 was also upregulated in all lung compartments, suggesting the potential involvement of a Th17-mediated immune response in Mhyo infections. Our findings highlight the relevance of Th1 and Th2 immune response in cases of EP, shedding light on the gene expression levels of key cytokines in the lung of pigs at a microscopic level.
ABSTRACT
A relevant question concerning inter-areal communication in the cortex is whether these interactions are synergistic. Synergy refers to the complementary effect of multiple brain signals conveying more information than the sum of each isolated signal. Redundancy, on the other hand, refers to the common information shared between brain signals. Here, we dissociated cortical interactions encoding complementary information (synergy) from those sharing common information (redundancy) during prediction error (PE) processing. We analyzed auditory and frontal electrocorticography (ECoG) signals in five common awake marmosets performing two distinct auditory oddball tasks and investigated to what extent event-related potentials (ERP) and broadband (BB) dynamics encoded synergistic and redundant information about PE processing. The information conveyed by ERPs and BB signals was synergistic even at lower stages of the hierarchy in the auditory cortex and between auditory and frontal regions. Using a brain-constrained neural network, we simulated the synergy and redundancy observed in the experimental results and demonstrated that the emergence of synergy between auditory and frontal regions requires the presence of strong, long-distance, feedback, and feedforward connections. These results indicate that distributed representations of PE signals across the cortical hierarchy can be highly synergistic.