The blood proteomic signature of prurigo nodularis reveals distinct inflammatory and neuropathic endotypes: A cluster analysis.

BACKGROUND: Prurigo nodularis (PN) is an extremely pruritic, chronic inflammatory skin disease. Little is known about systemic inflammation in PN. OBJECTIVE: To characterize plasma inflammatory biomarkers in patients with PN and investigate the presence of disease endotypes. METHODS: In this cross-sectional study, Olink proteomic analysis was performed on plasma samples from patients with PN (n = 29) and healthy controls (n = 18). RESULTS: Patients with PN had increased levels of 8 circulating biomarkers compared to controls, including tumor necrosis factor, C-X-C Motif Chemokine Ligand 9, interleukin-12B, and tumor necrosis factor receptor superfamily member 9 (P < .05). Two PN clusters were identified in cluster 1 (n = 13) and cluster 2 (n = 16). Cluster 2 had higher levels of 25 inflammatory markers than cluster 1. Cluster 1 had a greater percentage of patients with a history of myelopathy and spinal disc disease compared with cluster 2 (69% vs 25%, P = .03). Patients in cluster 2 were more likely to have a history of atopy (38% in cluster 2 vs 8% in cluster 1, P = .09). LIMITATIONS: Small sample size precludes robust subgroup analyses. CONCLUSION: This study provides evidence of neuroimmune-biased endotypes in PN and can aid clinicians in managing patients with PN that are nonresponsive to traditional therapies.

Pyrazine as a More Efficient Luminophore than Benzene for Producing Red-Shifted and Enhanced Photoluminescence.

The development of organic photoluminescent (PL) materials with red-shifted and enhanced emissions is beneficial to promoting their applications. Luminescent materials based on aromatic heterocycles (e.g., pyrazine) usually have red-shifted and enhanced photoluminescence compared with phenyl-based luminescent materials. In this work, the photoluminescence behaviors of pyrazine and its derivatives (o-dichloro-, o-dicyano-, and dichlorodicyano-substituted) are compared with those of benzene and its derivatives. All compounds exhibit fluorescence emissions ranging from blue to yellow, and the fluorescence emissions of pyrazinyl compounds are more red-shifted than those of phenyl compounds. Except for the o-dicyano-substituted compound, pyrazinyl compounds exhibit stronger fluorescence emissions than corresponding phenyl compounds in both pure substances and ethanol solutions. In addition, both 5,6-dichloro-2,3-dicyanopyrazine (P4) and 4,5-dichloro-1,2-dicyanobenzene (B4) exhibit room temperature phosphorescence, and the maximum delayed emission wavelength is red-shifted from 575 nm of B4 to 637 nm of P4. The energy gaps between the highest occupied molecular orbital and the lowest unoccupied molecular orbital of the monomers of pyrazinyl compounds are reduced by 0.07-1.37 eV compared with the monomers of phenyl compounds, which is the fundamental reason for the red-shifted emissions of the pyrazinyl compounds. Moreover, compared to B4, the smaller molecular spacing in the P4 crystal structure facilitates interlayer electron transfer and hence the formation of more extended through-space conjugation, resulting in the red-shifted emission of P4. This work proves that pyrazine is a more efficient luminophore than benzene for constructing PL compounds with longer emission wavelengths and higher quantum yields, which are important in guiding the design and preparation of organic PL materials.

Downregulation of a mitochondrial micropeptide, MPM, promotes hepatoma metastasis by enhancing mitochondrial complex I activity.

We and others have shown that MPM (micropeptide in mitochondria) regulates myogenic differentiation and muscle development. However, the roles of MPM in cancer development remain unknown. Here we revealed that MPM was downregulated significantly in human hepatocellular carcinoma (HCC) tissues and its decrease was associated with increased metastasis potential and HCC recurrence. Gain- and loss-of-function investigations disclosed that in vitro migration/invasion and in vivo liver/lung metastasis of hepatoma cells were repressed by restoring MPM expression and increased by silencing MPM. Mechanism investigations revealed that MPM interacted with NDUFA7. Mitochondrial complex I activity was inhibited by overexpressing MPM and enhanced by siMPM, and this effect of siMPM was attenuated by knocking down NDUFA7. The NAD+/NADH ratio, which was regulated by complex I, was reduced by MPM but increased by siMPM. Treatment with the NAD+ precursor nicotinamide abrogated the inhibitory effect of MPM on hepatoma cell migration. Further investigations showed that miR-17-5p bound to MPM and inhibited MPM expression. miR-17-5p upregulation was associated with MPM downregulation in HCC tissues. These findings indicate that a decrease in MPM expression may promote hepatoma metastasis by increasing mitochondrial complex I activity and the NAD+/NADH ratio.

The research progress on the anxiolytic effect of plant-derived flavonoids by regulating neurotransmitters.

Phytopharmaceuticals have attracted a lot of attention due to their multicomponent and multiple targets. The natural phenolic chemicals known as flavonoids are found in a wide variety of plants, fruits, vegetables, and herbs. Recently, they have been found to have modulatory effects on anxiety disorders, with current research focusing on the modulation of neurotransmitters. There has not yet been a review of the various natural flavonoid monomer compounds and total plant flavonoids that have been found to have anxiolytic effects. The study on the anti-anxiety effects of plant-derived flavonoids on neurotransmitters was reviewed in this paper. We, therefore, anticipate that further study on the conformational interaction underlying flavonoids' anti-anxiety effects will offer a theoretical framework for the creation of pertinent treatments.

Hydrogen-Bonding-Driven Nontraditional Photoluminescence of a ß-Enamino Ester.

Nontraditional luminogens (NTLs) do not contain any conventional chromophores (large π-conjugated structures), but they do show intrinsic photoluminescence. To achieve photoluminescence from NTLs, it is necessary to increase the extent of through-space conjugation (TSC) and suppress nonradiative decay. Incorporating strong physical interactions such as hydrogen bonding is an effective strategy to achieve this. In this work, we carried out comparative studies on the photoluminescence behaviors of two ß-enamino esters with similar chemical structures, namely methyl 3-aminocrotonate (MAC) and methyl (E)-3-(1-pyrrolidinyl)-2-butenoate (MPB). MAC crystal emits blue fluorescence under UV irradiation. The critical cluster concentration of MAC in ethanol solutions was determined by studying the relationship between the photoluminescence intensity (UV-visible absorbance) and concentration. Furthermore, MAC exhibits solvatochromism, and its emission wavelength redshifts as the solvent polarity increases. On the contrary, MPB is non-emissive in both solid state and solutions. Crystal structures and theoretical calculation prove that strong inter- and intramolecular hydrogen bonds lead to the formation of large amounts of TSC of MAC molecules in aggregated states. No hydrogen bonds and thus no effective TSC can be formed between or within MPB molecules, and this is the reason for its non-emissive nature. This work provides a deeper understanding of how hydrogen bonding contributes to the luminescence of NTLs.

Real-world comorbidities of atopic dermatitis in the US adult ambulatory population.

BACKGROUND: Atopic dermatitis (AD) is a pruritic, inflammatory skin disease associated with various comorbidities. However, comprehensive analyses of real-world comorbidities in adult patients with AD are limited. OBJECTIVE: To characterize the real-world comorbidities associated with adult AD in an ambulatory population. METHODS: We queried the MarketScan Commercial Claims and Encounters database from January 1, 2017 to December 31, 2017. Multivariable logistic regressions were performed to compare comorbidities in adult patients with AD versus age- and sex-matched controls. RESULTS: A total of 39,779 patients with AD and 353,743 controls were identified. Increased odds of psychiatric conditions, including anxiety (odds ratio [OR] 1.44) and mood disorders (OR 1.31), were observed in patients with AD. Patients with AD had higher likelihoods of autoimmune diseases, including vitiligo (OR 4.44) and alopecia areata (OR 6.01). Adult AD was also associated with infections, including impetigo (OR 9.72), methicillin-resistant Staphylococcus aureus (OR 3.92), and cellulitis (OR 2.52). Patients with AD were more likely to have systemic conditions, including lymphoid/hematopoietic malignancy (OR 1.91), atherosclerosis (OR 1.69), and metabolic syndrome (OR 1.47). For all the above, P < .001. LIMITATIONS: Retrospective analysis of health care claims data. CONCLUSION: Adult AD is associated with various psychiatric and systemic comorbidities, emphasizing the systemic nature of AD and the need for the collaborative management of these patients.

Deep-Learning-Based Wireless Visual Sensor System for Shiitake Mushroom Sorting.

The shiitake mushroom is the second-largest edible mushroom in the world, with a high nutritional and medicinal value. The surface texture of shiitake mushrooms can be quite different due to different growing environments, consequently leading to fluctuating market prices. To maximize the economic profit of the mushroom industry, it is necessary to sort the harvested mushrooms according to their qualities. This paper aimed to develop a deep-learning-based wireless visual sensor system for shiitake mushroom sorting, in which the visual detection was realized by the collection of images and cooperative transmission with the help of visual sensors and Wi-Fi modules, respectively. The model training process was achieved using Vision Transformer, then three data-augmentation methods, which were Random Erasing, RandAugment, and Label Smoothing, were applied under the premise of a small sample dataset. The training result of the final model turned out nearly perfect, with an accuracy rate reaching 99.2%. Meanwhile, the actual mushroom-sorting work using the developed system obtained an accuracy of 98.53%, with an 8.7 ms processing time for every single image. The results showed that the system could efficiently complete the sorting of shiitake mushrooms with a stable and high accuracy. In addition, the system could be extended for other sorting tasks based on visual features. It is also possible to combine binocular vision and multisensor technology with the current system to deal with sorting work that requires a higher accuracy and minor feature identification.

Student engagement in voluntary service in response to COVID-19 in Guangzhou, China: Implications for disease control and public health education from a cross-sectional study.

Public health students have been seen as a potential force to meet the demand for health workers during the coronavirus disease 2019 (COVID-19) pandemic. However, few studies have provided empirical data. This study was conducted to summarize the experiences of public health students who engaged in voluntary service in response to the COVID-19 outbreak in Guangzhou, China. A cross-sectional study was conducted among postgraduate and undergraduate students at the School of Public Health, Guangdong Pharmaceutical University, in August 2021. A self-designed online questionnaire was used to collect data on the experience of voluntary service during the early stage of the outbreak (in February 2020) and during the normalization stage of the prevention and control of COVID-19 (in June 2021) in China. Among the 96 students, 40 (41.7%) participated in voluntary service in February 2020, and 56 (58.3%) participated in voluntary service in June 2021. Most of the students participated in the voluntary service due to the motivations to help others (55.2%), to apply theoretical knowledge to practice (74.0%), to improve their fieldwork skills (72.9%), and to gain the experience for future careers (80.2%). Most volunteers were driven by professional responsibility (81.3%). More than half (53.1%) of the students felt anxious during their voluntary service. A lower proportion of students felt anxious in June 2021 than in February 2020 (44.6% vs 65.0%, P = .049), while a higher proportion of students found voluntary service harder than expected in June 2021 than in February 2020 (33.9% vs 7.5%, P = .002). Most students improved their knowledge and skills about COVID-19 after the training, but some knowledge and skills still needed improvement after their voluntary service. Public health students could help support the health system during the COVID-19 pandemic by providing adequate training and protection. More efforts should be made to provide psychological support for student volunteers and to optimize the curriculum to bridge the gap in public health education between theoretical knowledge and practical skills in responding to public health emergencies.

Dysregulation of the Skin-Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis.

Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin-liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.

Integrated plasma metabolomic and cytokine analysis reveals a distinct immunometabolic signature in atopic dermatitis.

Importance: Disease models for atopic dermatitis (AD) have primarily focused on understanding underlying environmental, immunologic, and genetic etiologies. However, the role of metabolic mechanisms in AD remains understudied. Objective: To investigate the circulating blood metabolomic and cytokine profile of AD as compared to healthy control patients. Design: This study collected plasma from 20 atopic dermatitis with moderate-to-severe itch (score of ≥5 on the itch Numeric Rating Scale and IGA score ≥3) and 24 healthy control patients. Mass-spectrometry based metabolite data were compared between AD and healthy controls. Unsupervised and supervised machine learning algorithms and univariate analysis analyzed metabolic concentrations. Metabolite enrichment and pathway analyses were performed on metabolites with significant fold change between AD and healthy control patients. To investigate the correlation between metabolites levels and cytokines, Spearman's rank correlation coefficients were calculated between metabolites and cytokines. Setting: Patients were recruited from the Johns Hopkins Itch Center and dermatology outpatient clinics in the Johns Hopkins Outpatient Center. Participants: The study included 20 atopic dermatitis patients and 24 healthy control patients. Main outcomes and measures: Fold changes of metabolites in AD vs healthy control plasma. Results: In patients with AD, amino acids isoleucine, tyrosine, threonine, tryptophan, valine, methionine, and phenylalanine, the amino acid derivatives creatinine, indole-3-acrylic acid, acetyl-L-carnitine, L-carnitine, 2-hydroxycinnamic acid, N-acetylaspartic acid, and the fatty amide oleamide had greater than 2-fold decrease (all P-values<0.0001) compared to healthy controls. Enriched metabolites were involved in branched-chain amino acid (valine, leucine, and isoleucine) degradation, catecholamine biosynthesis, thyroid hormone synthesis, threonine metabolism, and branched and long-chain fatty acid metabolism. Dysregulated metabolites in AD were positively correlated cytokines TARC and MCP-4 and negatively correlated with IL-1a and CCL20. Conclusions and relevance: Our study characterized novel dysregulated circulating plasma metabolites and metabolic pathways that may be involved in the pathogenesis of AD. These metabolic pathways serve as potential future biomarkers and therapeutic targets in the treatment of AD.

Spatial Mass Cytometry-Based Single-Cell Imaging Reveals a Disrupted Epithelial-Immune Axis in Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic, inflammatory skin condition that disproportionately affects African Americans and features intensely pruritic, hyperkeratotic nodules on the extremities and trunk. PN is understudied compared with other inflammatory skin diseases, with the spatial organization of the cutaneous infiltrate in PN yet to be characterized. In this work, we employ spatial imaging mass cytometry to visualize PN lesional skin inflammation and architecture with single-cell resolution through an unbiased machine learning approach. PN lesional skin has increased expression of caspase 3, NF-kB, and phosphorylated signal transducer and activator of transcription 3 compared with healthy skin. Keratinocytes in lesional skin are subdivided into CD14+CD33+, CD11c+, CD63+, and caspase 3-positive innate subpopulations. CD14+ macrophage populations expressing phosphorylated extracellular signal-regulated kinase 1/2 correlate positively with patient-reported itch (P = .006). Hierarchical clustering reveals a cluster of patients with PN with greater atopy, increased NF-kB+ signal transducer and activator of transcription 3-positive phosphorylated extracellular signal-regulated kinase 1/2-positive monocyte-derived myeloid dendritic cells, and increased vimentin expression (P < .05). Neighborhood analysis finds interactions between CD14+ macrophages, CD3+ T cells, monocyte-derived myeloid dendritic cells, and keratinocytes expressing innate immune markers. These findings highlight phosphorylated extracellular signal-regulated kinase-positive CD14+ macrophages as contributors to itch and suggest an epithelial-immune axis in PN pathogenesis.

Developments of PROTACs technology in immune-related diseases.

Traditional chemotherapy and immunotherapy are primary disease-treatment strategies. However, they face numerous challenges, including limited therapeutic benefits, off-target effects, serious adverse effects, drug resistance, long half-life time, poor oral bioavailability, and drugging undruggable proteins. Proteolytic targeted chimeras (PROTACs) were suggested to solve these problems. PROTACs are heterogeneous functional molecules linked by a chemical linker and contain a binding ligand for the protein of interest and a recruiting ligand for the E3 ligand. The binding of a PROTAC to a target protein brings the E3 ligand enzyme into proximity, initiating polyubiquitination of the target protein, followed by protease-mediated degradation. To date, PROTACs against dozens of immunological targets have been successfully developed, many of which have been clinically validated drug targets, and several have entered clinical trials for immune-related diseases. This article reviews the role of PROTACs-mediated degradation of critical proteins in immune disorders and cancer immunotherapy. Chemical structures, cellular and in vivo activities, and pharmacodynamics of these PROTACs are summarized. Lastly, we also discuss the prospects and potential limitations that PROTACs face.

Transceiver Optimization for mmWave Line-of-Sight MIMO Systems Using Hybrid Arrays.

The performance of millimeter wave (mmWave) line-of-sight multiple input multiple output (LOS MIMO) systems using hybrid arrays of planar subarrays was studied. We characterized the achievable maximum spatial multiplexing gain for such LOS MIMO systems by the measures of spectral efficiency and effective degree of freedom (EDoF). By proposing a joint plane-wave and spherical-wave-based general 3D channel model, we derived the optimal design parameters in the analog domain, i.e., the optimal subarray separation products, and analyzed their sensitivity on the system performance. We also gave analytical eigenvalue expressions of the equivalent LOS MIMO channel matrix, which are applicable to the case of a non-optimal design, as well as the upper and lower bounds of the EDoF for system performance evaluation. A piecewise uniform quantization codebook was further designed for quantizing phase shifter values in practical applications. The numerical and simulation results show that planar subarrays are superior to traditional arrays in terms of spectral efficiency and EDoF in Ricean fading channels because they are more robust to the change in the communication distance and the deviation from the optimal design. The use of hybrid arrays of planar subarrays effectively removes the limitation of mmWave LOS MIMO systems using traditional arrays, through which, the conventional Rayleigh distance criterion has to be satisfied to achieve the optimal performance.

Clinical utility of peripheral blood laboratory testing in the diagnostic workup of prurigo nodularis: A multicenter cohort study.

Background: Prurigo nodularis (PN) is a chronic inflammatory skin disease associated with several systemic comorbidities. However, there is lack of evidence supporting specific laboratory testing in the diagnostic workup of PN patients. Objective: To characterize the frequency and severity of clinical laboratory abnormalities in PN patients compared to controls. Methods: Cross-sectional study of adult patients between October, 2015 and August, 2021 using TriNetX, a global health records database encompassing over 74 million patients. Results: A total of 12,157 PN patients were matched to 12,157 controls. Significantly, greater proportions of PN patients had moderate-to-severely decreased hemoglobin, elevated transaminases, decreased albumin, increased bilirubin, increased serum creatinine, decreased estimated glomerular filtration rate, higher hemoglobin A1c levels, and alterations in thyroid stimulating hormone. Limitations: Our data identifies associated laboratory abnormalities in PN patients but is unable to support a causal relationship. Conclusion: PN patients are more likely to have laboratory abnormalities on renal, hepatic, hematologic, endocrine, and metabolic laboratory testing, demonstrating a role for systemic testing in the diagnostic workup of PN patients.

Long non-coding RNA LOC103222771 promotes infection of porcine reproductive and respiratory syndrome virus in Marc-145 cells by downregulating Claudin-4.

Porcine reproductive and respiratory syndrome (PRRS) is an important swine disease caused by infection of porcine reproductive and respiratory syndrome virus (PRRSV), which leads to huge loss in swine industry. How to effectively control PRRS is challenging. Long non-coding RNA (lncRNA) are key regulator of viral infections and anti-virus immunological responses, therefore, further understanding of lncRNAs will aid to identification of novel regulators of viral infections and better design of prevention and control strategies to viral infection related diseases and immune disorders. We demonstrated that PRRSV infection upregulated the expression of lncRNA LOC103222771 in Marc-145 cells and porcine alveolar macrophage cells (PAMs) and that LOC103222771 is mainly located in cytoplasm. Knockdown of LOC103222771 could inhibit the PRRSV infection in Marc-145 cells. RNA-seq analysis and subsequent validation revealed increased expression of Claudin-4 (CLDN4) in Marc-145 when LOC103222771 was specifically downregulated，suggesting that LOC103222771 might be an upstream regulator of CLDN4, an important component of tight junctions for establishment of the paracellular barrier that controls the flow of molecules in the intercellular space between epithelial cells. We and others showed that Downregulation of CLDN4 could boost the infection of PRRSV. Collectively, LOC103222771/CLDN4 signal axis might be a novel mechanism of PRRSV pathogenesis, implying a potential therapeutic target against PRRSV infection.