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BACKGROUND: Lipids produced using oleaginous yeast cells are an emerging feedstock to manufacture commercially valuable oleochemicals ranging from pharmaceuticals to lipid-derived biofuels. Production of biofuels using oleaginous yeast is a multistep procedure that requires yeast cultivation and harvesting, lipid recovery, and conversion of the lipids to biofuels. The quantitative recovery of the total intracellular lipid from the yeast cells is a critical step during the development of a bioprocess. Their rigid cell walls often make them resistant to lysis. The existing methods include mechanical, chemical, biological and thermochemical lysis of yeast cell walls followed by solvent extraction. In this study, an aqueous thermal pretreatment was explored as a method for lysing the cell wall of the oleaginous yeast Rhodotorula toruloides for lipid recovery. RESULTS: Hydrothermal pretreatment for 60 min at 121 °C with a dry cell weight of 7% (w/v) in the yeast slurry led to a recovery of 84.6 ± 3.2% (w/w) of the total lipids when extracted with organic solvents. The conventional sonication and acid-assisted thermal cell lysis led to a lipid recovery yield of 99.8 ± 0.03% (w/w) and 109.5 ± 1.9% (w/w), respectively. The fatty acid profiles of the hydrothermally pretreated cells and freeze-dried control were similar, suggesting that the thermal lysis of the cells did not degrade the lipids. CONCLUSION: This work demonstrates that hydrothermal pretreatment of yeast cell slurry at 121 °C for 60 min is a robust and sustainable method for cell conditioning to extract intracellular microbial lipids for biofuel production and provides a baseline for further scale-up and process integration.
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Candida spp. are the fourth leading cause of bloodstream infections in hospitalized patients and the most common cause of invasive fungal infection. No vaccine against Candida spp. or other fungal pathogens of humans is available. We recently discovered the Blastomyces Dectin-2 ligand endoglucanase 2 that harbors antigenic and adjuvant functions and can function as a protective vaccine against that fungus. We also reported that the adjuvant activity, which is mediated by O-mannans decorating the C terminus of Blastomyces Dectin-2 ligand endoglucanase 2, can augment peptide Ag-induced vaccine immunity against heterologous agents, including Cryptococcus, Candida, and influenza. In this article, we report that the O-linked mannans alone, in the absence of any antigenic peptide, can also protect against systemic candidiasis, reducing kidney fungal load and increasing survival in a Dectin-2-dependent manner. We found that this long-term glycan-induced protection is mediated by innate lymphocyte populations including TCR-γδ+ T cells, innate lymphoid cells, and NK cells that subsequently activate and release reactive oxygen species from neutrophils and monocytes. Our findings suggest that Blastomyces O-mannan displayed by Eng2 induces a form of protective trained immunity mediated by innate lymphocyte populations.
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BACKGROUND: Dorsal thoracic arachnoid web is a rare diagnosis and is not commonly seen in neurosurgical practice. Patients can present with symptoms and signs of thoracic myelopathy in the setting of an arachnoid cyst and a presyrinx state. OBSERVATIONS: A 57-year-old male with a 10-year history of worsening bilateral leg weakness and chronic back pain re-presented to the neurosurgery clinic after being seen by neurology and orthopedic spine surgery. Initial imaging was concerning for myelomalacia and syringomyelia, and repeat delayed computed tomography myelography findings were consistent with an evolving thoracic arachnoid web, now demonstrating spinal cord compression secondary to arachnoid cyst formation and consistent with the signs of thoracic myelopathy. Intraoperative ultrasound displayed the arachnoid web as the cause of the evolving arachnoid cyst, edematous spinal cord, and a presyrinx-like state. The patient underwent surgical decompression, which restored cerebrospinal fluid (CSF) dynamics, resulting in clinical improvement. LESSONS: Dorsal thoracic arachnoid web is a dynamic condition that can occur in the setting of an arachnoid cyst. There appears to be a relationship between dorsal thoracic arachnoid web formation and the presence of an arachnoid cyst resulting from a ball-valve mechanism leading to the creation of a pressure gradient effect that alters CSF fluid dynamics. https://thejns.org/doi/10.3171/CASE24313.
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Reactions of bis(benzene)chromium (Bz2Cr) and ozone (O3) were studied using low-temperature argon matrix-isolation infrared spectroscopy with supporting DFT calculations. When Bz2Cr and O3 were co-deposited, they reacted upon matrix deposition to produce two new prominent peaks in the infrared spectrum at 431 cm-1 and 792 cm-1. These peaks increased upon annealing the matrix to 35 K and decreased upon UV irradiation at λ = 254 nm. The oxygen-18 and mixed oxygen-16,18 isotopic shift pattern of the peak at 792 cm-1 is consistent with the antisymmetric stretch of a symmetric ozonide species. DFT calculations of many possible ozonide products of this reaction were made. The formation of a hydrogen ozonide (H2O3) best fits the original peaks and the oxygen-18 isotope shift pattern. Energy considerations lead to the conclusion that the chromium-containing product of this reaction is the coupled product benzene-chromium-biphenyl-chromium-benzene (BzCrBPCrBz). 2Bz2Cr+O3âH2O3+BzCrBPCrBz, ∆Ecalc=-52.13kcal/mol.
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BACKGROUND: We previously developed a prediction score for MRI-quantified abdominal visceral adipose tissue (VAT) based on concurrent measurements of height, body mass index (BMI), and nine blood biomarkers, for optimal performance in five racial/ethnic groups. Here we evaluated the VAT score for prediction of future VAT and examined if enhancement with additional biomarkers, lifestyle behavior information, and medical history improves the prediction. METHODS: We examined 500 participants from the Multiethnic Cohort (MEC) with detailed data (age 50-66) collected 10 years prior to their MRI assessment of VAT. We generated three forecasted VAT prediction models: first by applying the original VAT equation to the past data on the predictors ("original"), second by refitting the past data on anthropometry and biomarkers ("refit"), and third by building a new prediction model based on the past data enhanced with lifestyle and medical history ("enhanced"). We compared the forecasted prediction scores to future VAT using the coefficient of determination (R2). In independent nested case-control data in MEC, we applied the concurrent and forecasted VAT models to assess association of the scores with subsequent incident breast cancer (950 pairs) and colorectal cancer (831 pairs). RESULTS: Compared to the VAT prediction by the concurrent VAT score (R2 = 0.70 in men, 0.68 in women), the forecasted original VAT score (R2 = 0.54, 0.48) performed better than past anthropometry alone (R2 = 0.47, 0.40) or two published scores (VAI, METS-VF). The forecasted refit (R2 = 0.61, 0.51) and enhanced (R2 = 0.62, 0.55) VAT scores each showed slight improvements. Similar to the concurrent VAT score, the forecasted VAT scores were associated with breast cancer, but not colorectal cancer. Both the refit score (adjusted OR for tertile 3 vs. 1 = 1.27; 95% CI: 1.00-1.62) and enhanced score (1.27; 0.99-1.62) were associated with breast cancer independently of BMI. CONCLUSIONS: Predicted VAT from midlife data can be used as a surrogate to assess the effect of VAT on incident diseases associated with obesity, as illustrated for postmenopausal breast cancer.
Subject(s)
Adiposity , Intra-Abdominal Fat , Aged , Female , Humans , Male , Middle Aged , Body Mass Index , Case-Control Studies , Cohort Studies , Ethnicity , Intra-Abdominal Fat/diagnostic imaging , Magnetic Resonance Imaging , Neoplasms/diagnostic imaging , Racial GroupsABSTRACT
Millions of hibernating bats across North America have died from white-nose syndrome (WNS), an emerging disease caused by a psychrophilic (cold-loving) fungus, Pseudogymnoascus destructans, that invades their skin. Mechanisms of P. destructans invasion of bat epidermis remain obscure. Guided by our in vivo observations, we modeled hibernation with a newly generated little brown bat (Myotis lucifugus) keratinocyte cell line. We uncovered the stealth intracellular lifestyle of P. destructans, which inhibits apoptosis of keratinocytes and spreads through the cells by two epidermal growth factor receptor (EGFR)-dependent mechanisms: active penetration during torpor and induced endocytosis during arousal. Melanin of endocytosed P. destructans blocks endolysosomal maturation, facilitating P. destructans survival and germination after return to torpor. Blockade of EGFR aborts P. destructans entry into keratinocytes.
Subject(s)
Arousal , Ascomycota , Chiroptera , ErbB Receptors , Hibernation , Keratinocytes , Animals , Apoptosis , Ascomycota/physiology , Ascomycota/pathogenicity , Cell Line , Chiroptera/microbiology , Chiroptera/physiology , Endocytosis , ErbB Receptors/metabolism , Keratinocytes/microbiology , Melanins/metabolismABSTRACT
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation in the United States, but the actual roles that eosinophils play in CRSwNP remain largely unclear. OBJECTIVE: To reveal the roles and heterogeneity of eosinophils in nasal polyp (NP) tissue, we performed single cell RNA sequencing (scRNA-Seq) analysis of NP tissue. METHODS: Sinonasal tissues (NP and control sinus tissue) and patient matched peripheral blood (PB) samples were obtained from 5 control patients and 5 patients with CRSwNP. Eosinophils were enriched before processing for scRNA-Seq. The gene expression profiles in eosinophils were determined by microwell-based scRNA-Seq technology (BD Rhapsody platform). We predicted the overall function of NP eosinophils by Gene Ontology (geneontology.org) enrichment and pathway analyses and confirmed expression of selected genes by flow cytometry. RESULTS: After filtering out contaminating cells, we detected 5,542 eosinophils from control PB, 3,883 eosinophils from CRSwNP PB, 101 eosinophils from control sinus tissues (not included in further analyses), and 9,727 eosinophils from NPs by scRNA-Seq. We found that 204 genes were downregulated and 354 genes upregulated in NP eosinophils compared to all PB eosinophils (>1.5-fold, Padj < .05). Upregulated genes in NP eosinophils were associated with activation, cytokine-mediated signaling, growth factor activity, NF-κB signaling, and antiapoptotic molecules. NP eosinophils displayed 4 clusters revealing potential heterogeneity of eosinophils in NP tissue. CONCLUSIONS: Elevated eosinophils in NP tissue appear to exist in several subtypes that may play important pathogenic roles in CRSwNP, in part by controlling inflammation and hyperproliferation of other cells.
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Neutrophils and eosinophils share common hematopoietic precursors and usually diverge into distinct lineages with unique markers before being released from their hematopoietic site, which is the bone marrow (BM). However, previous studies identified an immature Ly6g(+) Il-5Rα(+) neutrophil population in mouse BM, expressing both neutrophil and eosinophil markers suggesting hematopoietic flexibility. Moreover, others have reported neutrophil populations expressing eosinophil-specific cell surface markers in tissues and altered disease states, confusing the field regarding eosinophil origins, function, and classification. Despite these reports, it is still unclear whether hematopoietic flexibility exists in human granulocytes. To answer this, we utilized single-cell RNA sequencing (scRNA-seq) and CITE-seq to profile human BM and circulating neutrophils and eosinophils at different stages of differentiation and determine whether neutrophil plasticity plays role in asthmatic inflammation. We show that immature metamyelocyte neutrophils in humans expand during severe asthmatic inflammation and express both neutrophil and eosinophil markers. We also show an increase in tri-lobed eosinophils with mixed neutrophil and eosinophil markers in allergic asthma and that IL-5 promotes differentiation of immature blood neutrophils into tri-lobed eosinophilic phenotypes suggesting a mechanism of emergency granulopoiesis to promote myeloid inflammatory or remodeling response in patients with chronic asthma. By providing insights into unexpectedly flexible granulocyte biology and demonstrating emergency hematopoiesis in asthma, our results highlight the importance of granulocyte plasticity in eosinophil development and allergic diseases.
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The Norrish type I (α-cleavage) reaction is an excellent photochemical method for radical-pair formation in solution. However, in cryogenic matrices, the starting material typically re-forms before the radical pair diffuses apart. This study focused on N2 extrusion from an azido alkyl radical to prevent radical-pair recombination. Irradiation of 2,2-diazido-2,3-dihydroinden-1-one (1) in methanol mainly yielded methyl 2-cyanomethylbenzoate (2) and 2-cyanomethylbenzoic acid (3) via α-cleavage. Laser flash photolysis of 1 in argon-saturated acetonitrile resulted in α-cleavage to form triplet biradical 31Br1 (λmax â¼ 410 nm, τ â¼ 400 ns). In contrast, upon irradiation in glassy 2-methyltetrahydrofuran matrices, triplet alkylnitrene 31N was directly detected using electron spin resonance (D/hc = 1.5646 cm-1, E/hc = 0.00161 cm-1) and absorption spectroscopy (λmax = 276 and 341 nm). Irradiation of 1 in argon matrices generated 31N, benzoyl azide 4, singlet benzoylnitrene 14N, and isocyanide 5, as revealed by IR spectroscopy. The experimental results supported by density functional theory calculations [B3PW91/6-311++G(d,p)] suggest that irradiation of 1 in matrices results in α-cleavage to form biradical 31Br1, which extrudes N2 to yield 31Br2. Rearrangement of 31Br2 into 31N competes with cleavage of a N3 radical to form radical 1Ra3. The N3/1Ra3 radical pair combines to form 4, which upon irradiation yields 14N and 5.
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Measuring inbreeding and its consequences on fitness is central for many areas in biology including human genetics and the conservation of endangered species. However, there is no consensus on the best method, neither for quantification of inbreeding itself nor for the model to estimate its effect on specific traits. We simulated traits based on simulated genomes from a large pedigree and empirical whole-genome sequences of human data from populations with various sizes and structures (from the 1,000 Genomes project). We compare the ability of various inbreeding coefficients ([Formula: see text]) to quantify the strength of inbreeding depression: allele-sharing, two versions of the correlation of uniting gametes which differ in the weight they attribute to each locus and two identical-by-descent segments-based estimators. We also compare two models: the standard linear model and a linear mixed model (LMM) including a genetic relatedness matrix (GRM) as random effect to account for the nonindependence of observations. We find LMMs give better results in scenarios with population or family structure. Within the LMM, we compare three different GRMs and show that in homogeneous populations, there is little difference among the different [Formula: see text] and GRM for inbreeding depression quantification. However, as soon as a strong population or family structure is present, the strength of inbreeding depression can be most efficiently estimated only if i) the phenotypes are regressed on [Formula: see text] based on a weighted version of the correlation of uniting gametes, giving more weight to common alleles and ii) with the GRM obtained from an allele-sharing relatedness estimator.
Subject(s)
Inbreeding Depression , Models, Genetic , Humans , Pedigree , Genetics, Population/methods , Inbreeding , AllelesABSTRACT
Metabolomics provides powerful tools that can inform about heterogeneity in disease and response to treatments. In this study, we employed an electrochemistry-based targeted metabolomics platform to assess the metabolic effects of three randomly-assigned treatments: escitalopram, duloxetine, and Cognitive Behavior Therapy (CBT) in 163 treatment-naïve outpatients with major depressive disorder. Serum samples from baseline and 12 weeks post-treatment were analyzed using targeted liquid chromatography-electrochemistry for metabolites related to tryptophan, tyrosine metabolism and related pathways. Changes in metabolite concentrations related to each treatment arm were identified and compared to define metabolic signatures of exposure. In addition, association between metabolites and depressive symptom severity (assessed with the 17-item Hamilton Rating Scale for Depression [HRSD17]) and anxiety symptom severity (assessed with the 14-item Hamilton Rating Scale for Anxiety [HRSA14]) were evaluated, both at baseline and after 12 weeks of treatment. Significant reductions in serum serotonin level and increases in tryptophan-derived indoles that are gut bacterially derived were observed with escitalopram and duloxetine arms but not in CBT arm. These include indole-3-propionic acid (I3PA), indole-3-lactic acid (I3LA) and Indoxyl sulfate (IS), a uremic toxin. Purine-related metabolites were decreased across all arms. Different metabolites correlated with improved symptoms in the different treatment arms revealing potentially different mechanisms between response to antidepressant medications and to CBT.
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BACKGROUND: Acute infusion reactions to oxaliplatin, a chemotherapeutic used to treat gastrointestinal cancers, are observed in about 20% of patients. Rapid drug desensitization (RDD) protocols often allow the continuation of oxaliplatin in patients with no alternative options. Breakthrough symptoms, including anaphylaxis, can still occur during RDD. OBJECTIVE: Our aim was to evaluate whether pretreatment with acalabrutinib, a Bruton tyrosine kinase inhibitor, can prevent anaphylaxis during RDD in a patient sensitized to oxaliplatin. METHODS: A 52-year-old male with locally advanced gastric carcinoma developed anaphylaxis during his fifth cycle of oxaliplatin. As he required 6 additional cycles to complete his curative-intent treatment regimen, he underwent RDD to oxaliplatin but still developed severe acute reactions. The risks and benefits of adding acalabrutinib before and during RDD were reviewed, and the patient elected to proceed. RESULTS: With acalabrutinib taken before and during the RDD, the patient was able to tolerate oxaliplatin RDD without complication. Consistent with its mechanism of action, acalabrutinib completely blocked the patient's positive skin prick response to oxaliplatin. Acalabrutinib did not alter the percentage of circulating basophils (1.24% vs 0.98%) before the RDD but did protect against basopenia (0.74% vs 0.09%) after the RDD. Acalabrutinib was associated with a drastic reduction in the ability of basophils to upregulate CD63 in vitro following incubation with oxaliplatin (0.11% vs 2.38%) or polyclonal anti-human IgE antibody (0.08% vs 44.2%). CONCLUSIONS: Five doses of acalabrutinib, 100 mg, orally twice daily starting during the evening 2 days before and continuing through RDD allowed a sensitized patient to receive oxaliplatin successfully and safely.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Antineoplastic Agents , Benzamides , Desensitization, Immunologic , Drug Hypersensitivity , Oxaliplatin , Pyrazines , Humans , Oxaliplatin/adverse effects , Middle Aged , Male , Drug Hypersensitivity/immunology , Drug Hypersensitivity/prevention & control , Desensitization, Immunologic/methods , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Pyrazines/adverse effects , Pyrazines/administration & dosage , Pyrazines/therapeutic use , Benzamides/therapeutic use , Benzamides/administration & dosage , Antineoplastic Agents/adverse effects , Anaphylaxis/prevention & control , Anaphylaxis/chemically induced , Anaphylaxis/immunology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/immunologyABSTRACT
Rare eosinophil-associated disorders (EADs), including hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic gastrointestinal disorders, are a heterogeneous group of conditions characterized by blood and/or tissue hypereosinophilia and eosinophil-related clinical manifestations. Although the recent availability of biologic therapies that directly and indirectly target eosinophils has the potential to dramatically improve treatment options for all EADs, clinical trials addressing their safety and efficacy in rare EADs have been relatively few. Consequently, patient access to therapy is limited for many biologics, and the establishment of evidence-based treatment guidelines has been extremely difficult. In this regard, multicenter retrospective collaborative studies focusing on disease manifestations and treatment responses in rare EADs have provided invaluable data for physicians managing patients with these conditions and helped identify important questions for future translational research. During the Clinical Pre-Meeting Workshop held in association with the July 2023 biennial meeting of the International Eosinophil Society in Hamilton, Ontario, Canada, the successes and limitations of pivotal multicenter retrospective studies in EADs were summarized and unmet needs regarding the establishment of guidelines for use of biologics in rare EADs were discussed. Key topics of interest included (1) clinical outcome measures, (2) minimally invasive biomarkers of disease activity, (3) predictors of response to biologic agents, and (4) long-term safety of eosinophil depletion. Herein, we report a summary of these discussions, presenting a state-of-the-art overview of data currently available for each of these topics, the limitations of the data, and avenues for future data generation through implementation of multidisciplinary and multicenter studies.
Subject(s)
Eosinophils , Translational Research, Biomedical , Humans , Eosinophils/immunology , Biological Therapy/methods , Rare Diseases/drug therapy , Rare Diseases/therapy , Eosinophilia/drug therapy , Hypereosinophilic Syndrome/drug therapy , Hypereosinophilic Syndrome/therapyABSTRACT
Combining classification systems potentially improves predictive accuracy, but outcomes have proven impossible to predict. Similar to improving binary classification with fusion, fusing ranking systems most commonly increases Pearson or Spearman correlations with a target when the input classifiers are "sufficiently good" (generalized as "accuracy") and "sufficiently different" (generalized as "diversity"), but the individual and joint quantitative influence of these factors on the final outcome remains unknown. We resolve these issues. Building on our previous empirical work establishing the DIRAC (DIversity of Ranks and ACcuracy) framework, which accurately predicts the outcome of fusing binary classifiers, we demonstrate that the DIRAC framework similarly explains the outcome of fusing ranking systems. Specifically, precise geometric representation of diversity and accuracy as angle-based distances within rank-based combinatorial structures (permutahedra) fully captures their synergistic roles in rank approximation, uncouples them from the specific metrics of a given problem, and represents them as generally as possible.
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Allergic asthma is a chronic inflammatory disease that affects millions of individuals worldwide. Exposure to allergens produced by a variety of otherwise harmless microbes, including fungi, predisposes individuals to immunopathologic disease upon subsequent encounters with allergen. We developed a mouse model that employs a purified protease produced by Aspergillus (Asp f 13) to investigate the contributions of CD4+ Th cells to recurrent lung inflammation. Notably, memory CD4+ T cells enhanced the eosinophil response of sensitized/rechallenged animals. In addition, memory CD4+ T cells maintained allergenic features, including expression of GATA-binding protein 3 and IL-5. Th2 memory T cells persisted in the peribronchiolar interstitium of the lung and expressed markers of tissue residence, such as CD69, CCR8, and IL-33R. Lastly, we identified a peptide epitope contained within Asp f 13 and generated a peptide-MHC class II tetramer. Using these tools, we further demonstrated the durability and exquisite sensitivity of memory T cells in promoting lung eosinophilia. Our data highlight important features of memory T cells that strengthen the notion that memory T cells are principal drivers of eosinophilic disease in murine models of allergic sensitization and episodic airway inflammation.
Subject(s)
Allergens , Asthma , Mice , Animals , Peptide Hydrolases , Lung , Asthma/pathology , Peptides , Endopeptidases , Th2 CellsABSTRACT
BACKGROUND: Cardiovascular disease is the most common cause of death worldwide, including infection and inflammation related conditions. Multiple studies have demonstrated potential advantages of hybrid positron emission tomography combined with computed tomography (PET/CT) as an adjunct to current clinical inflammatory and infectious biochemical markers. To quantitatively analyze vascular diseases at PET/CT, robust segmentation of the aorta is necessary. However, manual segmentation is extremely time-consuming and labor-intensive. PURPOSE: To investigate the feasibility and accuracy of an automated tool to segment and quantify multiple parts of the diseased aorta on unenhanced low-dose computed tomography (LDCT) as an anatomical reference for PET-assessed vascular disease. METHODS: A software pipeline was developed including automated segmentation using a 3D U-Net, calcium scoring, PET uptake quantification, background measurement, radiomics feature extraction, and 2D surface visualization of vessel wall calcium and tracer uptake distribution. To train the 3D U-Net, 352 non-contrast LDCTs from (2-[18F]FDG and Na[18F]F) PET/CTs performed in patients with various vascular pathologies with manual segmentation of the ascending aorta, aortic arch, descending aorta, and abdominal aorta were used. The last 22 consecutive scans were used as a hold-out internal test set. The remaining dataset was randomly split into training (n = 264; 80%) and validation (n = 66; 20%) sets. Further evaluation was performed on an external test set of 49 PET/CTs. The dice similarity coefficient (DSC) and Hausdorff distance (HD) were used to assess segmentation performance. Automatically obtained calcium scores and uptake values were compared with manual scoring obtained using clinical softwares (syngo.via and Affinity Viewer) in six patient images. intraclass correlation coefficients (ICC) were calculated to validate calcium and uptake values. RESULTS: Fully automated segmentation of the aorta using a 3D U-Net was feasible in LDCT obtained from PET/CT scans. The external test set yielded a DSC of 0.867 ± 0.030 and HD of 1.0 [0.6-1.4] mm, similar to an open-source model with a DSC of 0.864 ± 0.023 and HD of 1.4 [1.0-1.8] mm. Quantification of calcium and uptake values were in excellent agreement with clinical software (ICC: 1.00 [1.00-1.00] and 0.99 [0.93-1.00] for calcium and uptake values, respectively). CONCLUSIONS: We present an automated pipeline to segment the ascending aorta, aortic arch, descending aorta, and abdominal aorta on LDCT from PET/CT and to accurately provide uptake values, calcium scores, background measurement, radiomics features, and a 2D visualization. We call this algorithm SEQUOIA (SEgmentation, QUantification, and visualizatiOn of the dIseased Aorta) and is available at https://github.com/UMCG-CVI/SEQUOIA. This model could augment the utility of aortic evaluation at PET/CT studies tremendously, irrespective of the tracer, and potentially provide fast and reliable quantification of cardiovascular diseases in clinical practice, both for primary diagnosis and disease monitoring.
Subject(s)
Automation , Image Processing, Computer-Assisted , Positron Emission Tomography Computed Tomography , Humans , Image Processing, Computer-Assisted/methods , Aorta/diagnostic imaging , Aortic Diseases/diagnostic imaging , Female , Feasibility Studies , MaleABSTRACT
Matrix isolation infrared spectroscopy combined with density functional calculations has been used to form, isolate, and characterize the 1:1 hydrogen-bonded complexes of HCl with ferrocene and ruthenocene. Two unique structures were calculated for each complex, analogous to the two binding sites proposed for the attachment of proton to these metallocenes. The spectra, combined with calculated shifts of the H-Cl stretching mode, support the formation of a complex with the HCl hydrogen bonding to one of the cyclopentadienyl rings, exo to the plane of the ring. Evidence also was obtained for a second structure with the hydrogen of the HCl subunit directed toward the Fe or Ru center between the two cyclopentadienyl rings. This structure is similar to the proposed metal-bound proton structure based on earlier mass spectrometric and computational studies. Importantly, these results were supported by parallel experiments with DCl and the two metallocenes.
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WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a clinical research study called RAPID. The study looked at the potential for how safe and effective etripamil was at stopping an episode of rapid heartbeats in people with atrioventricularnodal-dependent supraventricular tachycardia (AV-node-dependent SVT). An episode is used to describe the period of time when a person experiences an abnormally very fast heartbeat. This was done by comparing an investigational drug called etripamil with a placebo, each administered via a rapidly acting nasal spray. AV-node-dependent SVT affects the rhythm of the heart, causing it to suddenly beat rapidly. The condition often requires medical treatment to help return the heart to its normal, healthy heartbeat pattern and speed, called 'sinus rhythm'. Researchers are looking at ways of improving the management of supraventricular tachycardias (SVT) by reducing the need for patients to attend an urgent care clinic, emergency ward or hospital for treatment. In the RAPID study, participants used a nasal spray containing either 70 mg etripamil or a placebo solution when they experienced an episode of SVT. The researchers wanted to know how long it took for each participant's rapid heartbeat to return to sinus rhythm after administering the etripamil or placebo nasal spray. Participants in the study were considered successfully treated if their heartbeats returned to sinus rhythm for at least 30 seconds within 30 minutes of using the nasal spray. Although 30 seconds may seem brief, it's medically important because it shows that a person's heartbeat has been temporarily stabilized and returned to normal functioning. WHAT WERE THE RESULTS?: Out of 99 people who used etripamil during an SVT episode, 63 participants (64%) experienced a return to sinus rhythm for at least 30 seconds within 30 minutes after using the nasal spray. In contrast, 26 out of 85 participants (31%) who used the placebo nasal spray experienced a return to sinus rhythm for at least 30 seconds within 30 minutes after use. Furthermore, the average time taken for the return to sinus rhythm was 17 minutes for the etripamil group which was 3-times faster than the placebo group at 53 minutes. Also, in the study no serious side effects occurred that were related to etripamil. WHAT DO THE RESULTS OF THE STUDY MEAN?: The RAPID study supports the potential that etripamil may be safe and well tolerated by participants as a treatment for episodes of rapid heartbeat in people with AV-node-dependent SVT. The results also showed a significant improvement in symptoms following treatment with etripamil.
Subject(s)
Tachycardia, Paroxysmal , Tachycardia, Supraventricular , Humans , Benzoates/therapeutic use , Electrocardiography , Nasal Sprays , Tachycardia, Paroxysmal/drug therapy , Tachycardia, Supraventricular/diagnosis , Tachycardia, Supraventricular/drug therapyABSTRACT
BACKGROUND: Stress-induced illnesses, like major depression, are among the leading causes of disability across the world. Consequently, there is a dire need for the validation of translationally-suited animal models incorporating social stress to uncover the etiology of depression. Prairie voles (Microtus ochrogaster) are more translationally relevant than many other rodent models as they display monogamous social and bi-parental behaviors. Therefore, we evaluated whether a novel social defeat stress (SDS) model in male prairie voles induces depression-relevant behavioral outcomes. METHODS: Adult sexually-naïve male prairie voles experienced SDS bouts from a conspecific pair-bonded male aggressor, 10 min per day for 10 consecutive days. Non-stressed controls (same-sex siblings) were housed in similar conditions but never experienced physical stress. Twenty-four h later, voles were evaluated in social interaction, sucrose preference, and Morris water maze tests - behavioral endpoints validated to assess social withdrawal, anhedonia-related behavior, and spatial memory performance, respectively. RESULTS: SDS-exposed voles displayed lower sociability and body weight, decreased preference for a sucrose solution, and impairment of spatial memory retrieval. Importantly, no differences in general locomotor activity were observed as a function of SDS exposure. LIMITATIONS: This study does not include female voles in the experimental design. CONCLUSIONS: We found that repeated SDS exposure, in male prairie voles, results in a depression-relevant phenotype resembling an anhedonia-like outcome (per reductions in sucrose preference) along with social withdrawal and spatial memory impairment - highlighting that the prairie vole is a valuable model with potential to study the neurobiology of social stress-induced depression-related outcomes.