Targeting IL-1 controls refractory pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1ß as a key mediator, orchestrating an NF-κB-mediated IL-1ß-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1ß. With the central role of IL-1ß underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1ß antagonists in PRP.

Modeling of collision-induced excitation and quenching of atomic nitrogen.

Excited atomic nitrogen atoms play an important role in plasma formation in hypersonic shock-waves, as happens during spacecraft reentry and other high velocity vehicle applications. In this study, we have thoroughly studied collision induced excitation associated with two colliding nitrogen atoms in the N(4S), N(2D), and N(2P) states at collision energies up to 6 eV, using time-independent scattering calculations to determine cross sections and temperature-dependent rate coefficients. The calculations are based on potential curves and couplings determined in earlier multireference configuration interaction calculations with large basis sets, and the results are in good agreement with experiments where comparisons are possible. To properly consider the spin-orbit coupling matrix, we have developed a scaling method for treating transitions between different fine-structure components that only require calculations with two coupled states, and with this, we define accurate degeneracy factors for determining cross sections and rate coefficients that include all states. The results indicate that both spin-orbit and derivative coupling effects can play important roles in collisional excitation and quenching, and that although derivative coupling is always much stronger than spin-orbit, there are many transitions where only spin-orbit can contribute. As part of this, we identify two distinct pathways associated with N(2P) relaxation and one Auger-like mechanism leading to two N(2D) that could be important at high temperatures.

Associations of Socio-Demographic Characteristics of Dairy Goat Farmers in Greece with Biosecurity-Related Practices in the Farms.

Given the significance of goat farming in Greece, our study aimed to explore biosecurity conditions on goat farms and refers to an investigation performed on 119 farms countrywide in Greece. The objective of the present work was to evaluate and report on potential associations between the socio-demographic characteristics of goat farmers and practices that play a role in biosecurity on farms. Data were obtained during a large cross-sectional study performed across Greece in 119 goat herds. The socio-demographic characteristics of farmers, as well as 16 variables related to biosecurity, were recorded; these were practices or events that could potentially enhance or compromise biosecurity on farms. A score based on all the biosecurity-related variables was devised by assigning a '1' or '-1' mark for each variable recorded on a farm that could enhance or compromise, respectively, biosecurity. Among variables potentially enhancing biosecurity on farms, the application of disinfections on the farm and the maintenance of isolation for sick animals were practiced more frequently; among variables potentially compromising biosecurity on farms, the presence of hunters in the area around the farm and grazing practices for animals were recorded more frequently. The median overall score for biosecurity-related practices for all farms in the study was 1 (interquartile range: 2.5; minimum: -4; maximum: 5). Among socio-demographic characteristics, the presence of working staff on a farm was associated with five individual biosecurity-related practices and the length of farming experience with three individual biosecurity-related practices. In the multivariable analysis, female farmers (p = 0.007) and the presence of working staff on the farm (p = 0.025) emerged as the two significant socio-demographic characteristics with an association with the overall biosecurity level on farms. This knowledge can be useful when developing biosecurity programs on goat farms. Recognition of locally applied farm-level practices enhancing biosecurity could form a basis for farmers to apply more rigorous and effective relevant plans.

Investigation of Machine and Deep Learning Techniques to Detect HPV Status.

BACKGROUND: This study investigated alternative, non-invasive methods for human papillomavirus (HPV) detection in head and neck cancers (HNCs). We compared two approaches: analyzing computed tomography (CT) scans with a Deep Learning (DL) model and using radiomic features extracted from CT images with machine learning (ML) models. METHODS: Fifty patients with histologically confirmed HNC were included. We first trained a modified ResNet-18 DL model on CT data to predict HPV status. Next, radiomic features were extracted from manually segmented regions of interest near the oropharynx and used to train four ML models (K-Nearest Neighbors, logistic regression, decision tree, random forest) for the same purpose. RESULTS: The CT-based model achieved the highest accuracy (90%) in classifying HPV status. Among the ML models, K-Nearest Neighbors performed best (80% accuracy). Weighted Ensemble methods combining the CT-based model with each ML model resulted in moderate accuracy improvements (70-90%). CONCLUSIONS: Our findings suggest that CT scans analyzed by DL models hold promise for non-invasive HPV detection in HNC. Radiomic features, while less accurate in this study, offer a complementary approach. Future research should explore larger datasets and investigate the potential of combining DL and radiomic techniques.

Molecular and cellular rhythms in excitatory and inhibitory neurons in the mouse prefrontal cortex.

Previous studies have shown that there are rhythms in gene expression in the mouse prefrontal cortex (PFC); however, the contribution of different cell types and potential variation by sex has not yet been determined. Of particular interest are excitatory pyramidal cells and inhibitory parvalbumin (PV) interneurons, as interactions between these cell types are essential for regulating the excitation/inhibition balance and controlling many of the cognitive functions regulated by the PFC. In this study, we identify cell-type specific rhythms in the translatome of PV and pyramidal cells in the mouse medial PFC (mPFC) and assess diurnal rhythms in PV cell electrophysiological properties. We find that while core molecular clock genes are conserved and synchronized between cell types, pyramidal cells have nearly twice as many rhythmic transcripts as PV cells (35% vs. 18%). Rhythmic transcripts in pyramidal cells also show a high degree of overlap between sexes, both in terms of which transcripts are rhythmic and in the biological processes associated with them. Conversely, in PV cells, rhythmic transcripts from males and females are largely distinct. Moreover, we find sex-specific effects of phase on action potential properties in PV cells that are eliminated by environmental circadian disruption. Together, this study demonstrates that rhythms in gene expression and electrophysiological properties in the mouse mPFC vary both by cell type and by sex. Moreover, the biological processes associated with these rhythmic transcripts may provide insight into the unique functions of rhythms in these cells, as well as their selective vulnerabilities to circadian disruption.

The Prodrug DHED Delivers 17ß-Estradiol into the Retina for Protection of Retinal Ganglion Cells and Preservation of Visual Function in an Animal Model of Glaucoma.

We report a three-pronged phenotypic evaluation of the bioprecursor prodrug 10ß,17ß-dihydroxyestra-1,4-dien-3-one (DHED) that selectively produces 17ß-estradiol (E2) in the retina after topical administration and halts glaucomatous neurodegeneration in a male rat model of the disease. Ocular hypertension (OHT) was induced by hyperosmotic saline injection into an episcleral vein of the eye. Animals received daily DHED eye drops for 12 weeks. Deterioration of visual acuity and contrast sensitivity by OHT in these animals were markedly prevented by the DHED-derived E2 with concomitant preservation of retinal ganglion cells and their axons. In addition, we utilized targeted retina proteomics and a previously established panel of proteins as preclinical biomarkers in the context of OHT-induced neurodegeneration as a characteristic process of the disease. The prodrug treatment provided retina-targeted remediation against the glaucomatous dysregulations of these surrogate endpoints without increasing circulating E2 levels. Collectively, the demonstrated significant neuroprotective effect by the DHED-derived E2 in the selected animal model of glaucoma supports the translational potential of our presented ocular neuroprotective approach owing to its inherent therapeutic safety and efficacy.

Model-based multifacet clustering with high-dimensional omics applications.

High-dimensional omics data often contain intricate and multifaceted information, resulting in the coexistence of multiple plausible sample partitions based on different subsets of selected features. Conventional clustering methods typically yield only one clustering solution, limiting their capacity to fully capture all facets of cluster structures in high-dimensional data. To address this challenge, we propose a model-based multifacet clustering (MFClust) method based on a mixture of Gaussian mixture models, where the former mixture achieves facet assignment for gene features and the latter mixture determines cluster assignment of samples. We demonstrate superior facet and cluster assignment accuracy of MFClust through simulation studies. The proposed method is applied to three transcriptomic applications from postmortem brain and lung disease studies. The result captures multifacet clustering structures associated with critical clinical variables and provides intriguing biological insights for further hypothesis generation and discovery.

Laser pulse induced second- and third-harmonic generation of gold nanorods with real-time time-dependent density functional tight binding (RT-TDDFTB) method.

In this study, we investigate second- and third-harmonic generation processes in Au nanorod systems using the real-time time-dependent density functional tight binding method. Our study focuses on the computation of nonlinear signals based on the time dependent dipole response induced by linearly polarized laser pulses interacting with nanoparticles. We systematically explore the influence of various laser parameters, including pump intensity, duration, frequency, and polarization directions, on harmonic generation. We demonstrate all the results using Au nanorod dimer systems arranged in end-to-end configurations, and disrupting the spatial symmetry of regular single nanorod systems is crucial for second-harmonic generation processes. Furthermore, we study the impact of nanorod lengths, which lead to variable plasmon energies, on harmonic generation, and estimates of polarizabilities and hyper-polarizabilities are provided.

Reverse aging to treat lupus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multifaceted pathogenetic processes, including abnormalities of T-cell subset distribution and function. Accumulation of senescent CD4+ T cells has been found to contribute to the development of the disease. In this issue, Jiang et al. provide compelling evidence that links an expanded pool of CD4+CD57+ senescent T cells in patients with SLE to disease activity favored by interleukin-15. Importantly, treatment of lupus-prone mice with a senolytic drug resulted in decreased autoimmune pathology. The findings of this study suggest possible novel therapeutics to treat patients with SLE.

The immunology of systemic lupus erythematosus.

Understanding the pathogenesis and clinical manifestations of systemic lupus erythematosus (SLE) has been a great challenge. Reductionist approaches to understand the nature of the disease have identified many pathogenetic contributors that parallel clinical heterogeneity. This Review outlines the immunological control of SLE and looks to experimental tools and approaches that are improving our understanding of the complex contribution of interacting genetics, environment, sex and immunoregulatory factors and their interface with processes inherent to tissue parenchymal cells. Efforts to advance precision medicine in the care of patients with SLE along with treatment strategies to correct the immune system hold hope and are also examined.

First do no harm: Predicting futility of intervention in geriatric emergency general surgery.

BACKGROUND: Emergent surgical conditions are common in geriatric patients, often necessitating major operative procedures on frail patients. Understanding risk profiles is crucial for decision-making and establishing goals of care. METHODS: We queried NSQIP 2015-2019 for patients ≥65 years undergoing open abdominal surgery for emergency general surgery conditions. Logistic regression was used to identify 30-day mortality predictors. RESULTS: Of 41,029 patients, 5589 (13.6 â€‹%) died within 30 days of admission. The highest predictors of mortality were ASA status 5 (aOR 9.7, 95 â€‹% CI,3.5-26.8, p â€‹< â€‹0.001), septic shock (aOR 4.9, 95 â€‹% CI,4.5-5.4, p â€‹< â€‹0.001), and dialysis (aOR 2.1, 95 â€‹% CI,1.8-2.4, p â€‹< â€‹0.001). Without risk factors, mortality rates were 11.9 â€‹% after colectomy and 10.2 â€‹% after small bowel resection. Patients with all three risk factors had a mortality rate of 79.4 â€‹% and 100 â€‹% following colectomy and small bowel resection, respectively. CONCLUSIONS: In older adults undergoing emergent open abdominal surgery, septic shock, ASA status, and dialysis were strongly associated with futility of surgical intervention. These findings can inform goals of care and informed decision-making.

High-dimensional causal mediation analysis by partial sum statistic and sample splitting strategy in imaging genetics application.

Causal mediation analysis provides a systematic approach to explore the causal role of one or more mediators in the association between exposure and outcome. In omics or imaging data analysis, mediators are often high-dimensional, which brings new statistical challenges. Existing methods either violate causal assumptions or fail in interpretable variable selection. Additionally, mediators are often highly correlated, presenting difficulties in selecting and prioritizing top mediators. To address these issues, we develop a framework using Partial Sum Statistic and Sample Splitting Strategy, namely PS5, for high-dimensional causal mediation analysis. The method provides a powerful global mediation test satisfying causal assumptions, followed by an algorithm to select and prioritize active mediators with quantification of individual mediation contributions. We demonstrate its accurate type I error control, superior statistical power, reduced bias in mediation effect estimation, and accurate mediator selection using extensive simulations of varying levels of effect size, signal sparsity, and mediator correlations. Finally, we apply PS5 to an imaging genetics dataset of chronic obstructive pulmonary disease (COPD) patients ( N =8,897) in the COPDGene study to examine the causal mediation role of lung images ( p =5,810) in the associations between polygenic risk score and lung function and between smoking exposure and lung function, respectively. Both causal mediation analyses successfully estimate the global indirect effect and detect mediating image regions. Collectively, we find a region in the lower lobe of the right lung with a strong and concordant mediation effect for both genetic and environmental exposures. This suggests that targeted treatment toward this region might mitigate the severity of COPD due to genetic and smoking effects.

Posttraumatic Arthritis Is More Common in Patients Undergoing Total Knee Arthroplasty Before Age 50.

Primary total knee arthroplasty (TKA) in patients under 50 is becoming more common. The goal of this study was to identify the diagnoses and predisposing factors for TKA prior to age 50. The Military Data Repository was queried for patients undergoing TKA prior to age 50. The cohort was matched to older patients. A total of 1,504 patients underwent manual record review for demographics, prior knee surgery, and indication for TKA. Primary osteoarthritis was the most common indication in both cohorts. Posttraumatic osteoarthritis was more common in patients who underwent TKA before age 50 (28%) compared with patients 50 and older (7%; p < 0.001). Patients who underwent TKA before age 50 were more likely to have previous anterior cruciate ligament injury, or any previous ipsilateral knee surgery (p < 0.001). These data suggest an association between prior knee injury and age at time of TKA. (Journal of Surgical Orthopaedic Advances 33(2):072-076, 2024).

Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer.

The paucity of targeted therapies for triple-negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular ß-catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis. To suppress Wnt signaling in TNBC cells, we developed therapeutic nanoparticles (NPs) functionalized with FZD7 antibodies and ß-catenin small interfering RNAs (siRNAs). The antibodies enable TNBC cell-specific binding and inhibit Wnt signaling by locking FZD7 receptors in a ligand unresponsive state, while the siRNAs suppress ß-catenin through RNA interference. Compared to NPs coated with antibodies or siRNAs individually, NPs coated with both agents more potently reduce the expression of several Wnt related genes in TNBC cells, leading to greater inhibition of cell proliferation, migration, and spheroid formation. In two murine models of metastatic TNBC, the dual antibody/siRNA nanocarriers outperformed controls in terms of inhibiting tumor growth, metastasis, and recurrence. These findings demonstrate suppressing Wnt signaling at both the receptor and mRNA levels via antibody/siRNA nanocarriers is a promising approach to combat TNBC.

Rapid and Precise Computation of Fractional Flow Reserve from Routine Two-Dimensional Coronary Angiograms Based on Fluid Mechanics: The Pilot FFR2D Study.

Objective: To present a novel pipeline for rapid and precise computation of fractional flow reserve from an analysis of routine two-dimensional coronary angiograms based on fluid mechanics equations (FFR2D). Material and methods: This was a pilot analytical study that was designed to assess the diagnostic performance of FFR2D versus the gold standard of FFR (threshold ≤ 0.80) measured with a pressure wire for the physiological assessment of intermediate coronary artery stenoses. In a single academic center, consecutive patients referred for diagnostic coronary angiography and potential revascularization between 1 September 2020 and 1 September 2022 were screened for eligibility. Routine two-dimensional angiograms at optimal viewing angles with minimal overlap and/or foreshortening were segmented semi-automatically to derive the vascular geometry of intermediate coronary lesions, and nonlinear pressure-flow mathematical relationships were applied to compute FFR2D. Results: Some 88 consecutive patients with a single intermediate coronary artery lesion were analyzed (LAD n = 74, RCA n = 9 and LCX n = 5; percent diameter stenosis of 45.7 ± 11.0%). The computed FFR2D was on average 0.821 ± 0.048 and correlated well with invasive FFR (r = 0.68, p < 0.001). There was very good agreement between FFR2D and invasive-wire FFR with minimal measurement bias (mean difference: 0.000 ± 0.048). The overall accuracy of FFR2D for diagnosing a critical epicardial artery stenosis was 90.9% (80 cases classified correctly out of 88 in total). FFR2D identified 24 true positives, 56 true negatives, 4 false positives, and 4 false negatives and predicted FFR ≤ 0.80 with a sensitivity of 85.7%, specificity of 93.3%, positive likelihood ratio of 13.0, and negative likelihood ratio of 0.15. FFR2D had a significantly better discriminatory capacity (area under the ROC curve: 0.95 [95% CI: 0.91-0.99]) compared to 50%DS on 2D-QCA (area under the ROC curve: 0.70 [95% CI: 0.59-0.82]; p = 0.0001) in predicting wire FFR ≤ 0.80. The median time of image analysis was 2 min and the median time of computation of the FFR2D results was 0.1 s. Conclusion: FFR2D may rapidly derive a precise image-based metric of fractional flow reserve with high diagnostic accuracy based on a single two-dimensional coronary angiogram.

Environmental complexity impacts anxiety in broiler chickens depending on genetic strain and body weight.

The objective was to assess the impact of environmental complexity on affective state (anxiety) in fast- and slow-growing broilers (Gallus gallus domesticus) as they gain weight. Six hundred fast-growing broilers (Ross 708; "fast-growers") and 600 slow-growing broilers (Hubbard Redbro Mini; "slow-growers") were raised in 24 pens with simple (standard; SE) or complex (permanent and temporary enrichments; CE) environments. Six birds/pen underwent the attention bias test on day 23 (fast-growers only), 28-29, 35-36, 42-43, and 56-57 (slow-growers only), with individuals only tested once (n = 576). Proportion of birds feeding, time spent vigilant and latencies to eat and step were recorded. Greater vigilance and longer latencies indicate more anxiety. Slow-growers fed more (p = 0.001), were less vigilant (p = 0.003), and stepped sooner than fast-growers (p = 0.007). For both strains, likelihood of feeding was unrelated to weight in SE, but decreased with increasing weight in CE (p = 0.048). Birds in CE stepped sooner than birds in SE (p = 0.030). Vigilance increased with body weight (p = 0.024). These results indicate that affective state (anxiety) can change as birds gain weight, depending on environmental complexity and genetic strain. Overall, slow-growers showed reduced anxiety compared to fast-growers, across housing treatments or weights.

Reclassification of type strains of Rhizobium indigoferae and Sinorhizobium kummerowiae into the species Rhizobium leguminosarum and Sinorhizobium meliloti, respectively.

The species Rhizobium indigoferae and Sinorhizobium kummerowiae were isolated from legume nodules and the 16S rRNA sequences of their respective type strains, CCBAU 71042T and CCBAU 71714T, were highly divergent from those of the other species of the genera Rhizobium and Sinorhizobium, respectively. However, the 16S rRNA gene sequences obtained for strains CCBAU 71042T and CCBAU 71714T several years after description, were different from the original ones, showing 100 % similarity to the type strains of Rhizobium leguminosarum and Sinorhizobium meliloti, respectively. Phylogenetic analyses of two housekeeping genes, recA and atpD, confirmed the high phylogenetic closeness of strains CCBAU 71042T and CCBAU 71714T to the respective type strains of R. leguminosarum and S. meliloti. In the present work, we compared the genomes of the type strains of R. indigoferae and S. kummerowiae available in several culture collections with those of the respective type strains of R. leguminosarum and S. meliloti, some of them obtained in this study. The calculated average nucleotide identity-blast and digital DNA-DNA hybridization values in both cases were higher than those recommended for species differentiation, supporting the proposal for the reclassification of the type strains of R. indigoferae and S. kummerowiae into the species R. leguminosarum and S. meliloti, respectively.

Mechanisms of controlled stabilizer-free synthesis of gold nanoparticles in liquid aerosol containing plasma.

The interaction between low-temperature plasma and liquid enables highly reactive solution phase chemistry and fast reaction kinetics. In this work, we demonstrate the rapid synthesis of stabilizer-free, spherical and crystalline gold nanoparticles (AuNP). More than 70% of gold ion complex (AuCl- 4) conversion is achieved within a droplet residence time in the plasma of ∼10 ms. The average size of the AuNPs increases with an increase in the droplet residence time and the particle synthesis showed a power threshold effect suggesting the applicability of the classical nucleation theory. Leveraging UV-vis absorption and emission spectroscopy, and nanoparticle size distributions obtained from TEM measurements, we showed that the AuCl- 4 conversion exceeded by 250 times the maximum faradaic efficiency. We identified important roles of both short-lived reducing species including solvated electrons and possibly vacuum ultraviolet (VUV) photons, and long-lived species, H2O2, in the reduction of AuCl- 4. A quantitative investigation was performed by a 1-D reaction-diffusion model which includes transport, plasma-enabled interfacial reduction of AuCl- 4, classical nucleation, monomer absorption and autocatalytic surface growth enabled by H2O2. The model shows good agreement with the experimental results. The timescale analysis of the simulation revealed that nucleation is enabled by fast reduction of gold ions, and autocatalytic growth mainly determines the particle size and is responsible for the majority of the ion precursor conversion while also explaining the excessively large faradaic efficiency found experimentally.