Distinct Serum Immune Profiles Define the Spectrum of Acute and Chronic Pancreatitis From the Multicenter Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) Study.

BACKGROUND & AIMS: Pancreatitis is a disease continuum, starting with acute pancreatitis (AP) and progressing in some cases to recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Currently, there are no approved therapies or early diagnostic or prognostic biomarkers for pancreatitis. The current study examined whether patient serum immune profiling could identify noninvasive biomarkers and provide mechanistic insight into the disease continuum of pancreatitis. METHODS: Using Olink immunoassay, we assessed the protein levels of 92 immune markers in serum samples from participants enrolled in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) study of the Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) consortium. Samples (N = 231) were obtained from individuals without pancreatic disease (n = 56) and from those with chronic abdominal pain (CAP) (n = 24), AP (n = 38), RAP (n = 56), and CP (n = 57). RESULTS: A total of 33 immune markers differentiated the combined pancreatitis groups from controls. Immune markers related to interleukin (IL) 17 signaling distinguished CP from AP and RAP. Similarly, the serum level of IL17A and C-C motif chemokine ligand 20 differentiated CP from CAP, suggesting the involvement of T helper 17 cells in CP pathogenesis. The receiver operator characteristic curve with 2 immune markers (IL17A and sulfotransferase 1A1) could differentiate CP from CAP (optimistic area under the curve = 0.78). The macrophage classical activation pathway elevated along the continuum of pancreatitis, suggesting an accumulation of proinflammatory signals over disease progression. Several immune markers were associated with smoking, alcohol, and diabetes status. CONCLUSIONS: Immune profiling of serum samples from a large pancreatitis cohort led to identifying distinct immune markers that could serve as potential biomarkers to differentiate the varying pancreatitis disease states. In addition, the finding of IL17 signaling in CP could provide insight into the immune mechanisms underlying disease progression.

A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.

The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3ß), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

Preventive effect of peptides derived from fermented milk on chronic stress-induced brain damage and intestinal dysfunction in mice.

This study investigated the preventive effects of peptides derived from milk fermented with the probiotic strain Lactobacillus gasseri 505 (505) against stress-related brain damage and anxiety-like behavior. The peptides MKPWIQPKTKVIPYVRYL (Pep14) and VYQHQKAMKPWIQPKTKVIPYVRYL (Pep21), which exhibit high antioxidant and anti-inflammatory activities, were administered to stressed mice. The results showed that the stress mechanism in the gut-brain axis was regulated by pretreatment with both peptides, leading to inhibition of neurodevelopment and neuroinflammation through the hypothalamic-pituitary-adrenal (HPA) axis, based on the expression of related mRNA and proteins. The expression of colonic inflammation-related mRNA and proteins was also reduced. Moreover, anxiety-like behavior was significantly reduced in mice treated with Pep14 and Pep21. These results indicate that the bioactive peptides Pep14 and Pep21, derived from milk fermented with 505, may prevent stress-induced brain damage and anxiety-like behavior via regulation of the HPA axis.

Single-cell sequencing unveils distinct immune microenvironments with CCR6-CCL20 crosstalk in human chronic pancreatitis.

OBJECTIVE: Chronic pancreatitis (CP) is a potentially fatal disease of the exocrine pancreas, with no specific or effective approved therapies. Due to difficulty in accessing pancreas tissues, little is known about local immune responses or pathogenesis in human CP. We sought to characterise pancreatic immune responses using tissues derived from patients with different aetiologies of CP and non-CP organ donors in order to identify key signalling molecules associated with human CP. DESIGN: We performed single-cell level cellular indexing of transcriptomes and epitopes by sequencing and T-cell receptor (TCR) sequencing of pancreatic immune cells isolated from organ donors, hereditary and idiopathic patients with CP who underwent total pancreatectomy. We validated gene expression data by performing flow cytometry and functional assays in a second patient with CP cohort. RESULTS: Deep single-cell sequencing revealed distinct immune characteristics and significantly enriched CCR6+ CD4+ T cells in hereditary compared with idiopathic CP. In hereditary CP, a reduction in T-cell clonality was observed due to the increased CD4+ T (Th) cells that replaced tissue-resident CD8+ T cells. Shared TCR clonotype analysis among T-cell lineages also unveiled unique interactions between CCR6+ Th and Th1 subsets, and TCR clustering analysis showed unique common antigen binding motifs in hereditary CP. In addition, we observed a significant upregulation of the CCR6 ligand (CCL20) expression among monocytes in hereditary CP as compared with those in idiopathic CP. The functional significance of CCR6 expression in CD4+ T cells was confirmed by flow cytometry and chemotaxis assay. CONCLUSION: Single-cell sequencing with pancreatic immune cells in human CP highlights pancreas-specific immune crosstalk through the CCR6-CCL20 axis, a signalling pathway that might be leveraged as a potential future target in human hereditary CP.

A self-assembled nanoparticle cluster array fabricated using nematic-isotropic phase separation on a functionalized surface.

The manipulation of a large number of nanoparticles (NPs) is an interesting but challenging task. Here, we demonstrate a new method to fabricate an NP cluster array, in which the shape and size of each NP cluster can be controlled. The method involves the use of the solubility contrast of NPs in the isotropic and nematic liquid crystal (LC) media, and the isotropic-preference difference depending on the types of the surfaces. The former mechanism is used to trap NPs within the isotropic domain, the size of which is simply manipulated by adjusting temperature. The latter mechanism is used to control the location of isotropic pockets in the continuous nematic phase. By controlling the volume and location of the isotropic pocket, one can simply create various types of NP cluster arrays. This method does not involve the use of any external field, and may be applicable to other types of NPs, including ferroelectric or ferromagnetic materials, thereby expanding its applicability.

Switchable dielectrophoresis of defect-free droplets in an anisotropic liquid crystal medium.

Dielectrophoresis (DEP) is widely used in nanoscience and biology to control small particles but its applicability is significantly limited by its one-way impetus characteristics along the square field gradient (∇E2) direction, that is, DEP force, FDEP ∼ ∇E2. Here, switchable DEP (SDEP) using the anisotropic property of a nematic medium is demonstrated; FDEP does not need to be parallel to ∇E2 but is arbitrarily changeable depending on the permittivity tensor orientation of the medium. To effectively demonstrate the SDEP phenomenon, isotropic droplets with infinitesimal surface anchoring in a nematic medium are introduced, in which topological defects of the nematic medium around dispersed objects are effectively eliminated. The experimental behaviours are well explained by theoretical and simulation results. To emphasize the applicability of SDEP, switchable arrays of isotropic droplets and an isotropic pocket carrier system containing micro-particles are demonstrated. The results reveal a new dimension of DEP and provide a novel approach for manipulating nano- or micro-materials in colloids.

Identification of quantitative trait loci associated with flowering time in perilla using genotyping-by-sequencing.

Understanding the transition to the reproductive period is important for crop breeding. This information can facilitate the production of novel varieties that are better adapted to local environments or changing climatic conditions. Here, we report the development of a high-density linkage map based on genotyping-by-sequencing (GBS) for the genus perilla. Through GBS library construction and Illumina sequencing of an F2 population, a total of 9607 single-nucleotide polymorphism (SNP) markers were developed. The ten-group linkage map of 1309.39 cM contained 2518 markers, with an average marker density of 0.56 cM per linkage group (LG). Using this map, a total of six QTLs were identified. These quantitative trait loci (QTLs) are associated with three traits related to flowering time: days to visible flower bud, days to flowering, and days to maturity. Ortholog analysis conducted with known genes involved in the regulation of flowering time among different crop species identified GI, CO and ELF4 as putative perilla orthologs that are closely linked to the QTL regions associated with flowering time. These results provide a foundation that will be useful for future studies of flowering time in perilla using fine mapping, and marker-assisted selection for the development of new varieties of perilla.

Clinical Characteristics of Oral Allergy Syndrome in Children with Atopic Dermatitis and Birch Sensitization: a Single Center Study.

BACKGROUND: Oral allergy syndrome (OAS) is an immunoglobulin E (IgE)-mediated hypersensitivity that occurs frequently in older children with pollen sensitization. This study focused on the clinical characteristics of OAS in children with atopic dermatitis (AD) and birch sensitization. METHOD: s: A total of 186 patients aged 2-18 years with AD and birch sensitization were enrolled in this study between January 2016 and March 2017. Their levels of serum total IgE and birch- and ragweed-specific IgE (sIgE) were measured using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden). Information regarding causative foods and symptoms were obtained via interviews. The patients were divided into 3 groups according to their ages (group 1, 2-6 years; group 2, 7-12 years; and group 3, 13-18 years). RESULTS: Eighty-one of the 186 (43.5%) children with AD who were sensitized to birch pollen were diagnosed as having OAS. The prevalence of OAS in group 1 (the children who had AD and birch sensitization aged 2-6 years) was 36.6%. A greater predominance of men was noted in the non-OAS group (77.1%) compared to the OAS group (60.5%). Apples were the most common causative food in group 2 and 3 while kiwis were the most common cause of OAS in group 1. There was a statistically significant correlation between birch-sIgE levels and the prevalence of OAS (P = 0.000). The cut-off value was 6.77 kUA/L with 55.6% sensitivity and 79.0% specificity (area under the curve 0.653). CONCLUSION: In our study, the prevalence of OAS in children with AD and birch sensitization was 43.5%. Even in the preschool age group, the prevalence of OAS was considerable. Patients with high levels of birch-sIgE were more likely to have OAS. Clinicians should therefore be vigilant about OAS in patients with a high degree of sensitization to birch pollen and even young children if they have birch sensitization.

Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling.

All-trans Retinoic acid (RA) and its derivatives are potent therapeutics for immunological functions including wound repair. However, the molecular mechanism of RA modulation in innate immunity is poorly understood, especially in macrophages. We found that topical application of RA significantly improves wound healing and that RA and IL-4 synergistically activate Arg1, a critical gene for tissue repair, in M2 polarized macrophages. This involves feed forward regulation of Raldh2, a rate-limiting enzyme for RA biosynthesis, and requires Med25 to coordinate RAR, STAT6 and chromatin remodeler, Brg1 to remodel the +1 nucleosome of Arg1 for transcription initiation. By recruiting elongation factor TFIIS, Med25 also facilitates transcriptional initiation-elongation coupling. This study uncovers synergistic activation of Arg1 by RA and IL-4 in M2 macrophages that involves feed forward regulation of RA synthesis and dual functions of Med25 in nucleosome remodeling and transcription initiation-elongation coupling that underlies robust modulatory activity of RA in innate immunity.

Immunology of pancreatitis and environmental factors.

PURPOSE OF REVIEW: This report reviews recent aspects of pancreatitis immunology and environmental factors that link to development and progression of disease. RECENT FINDINGS: Limited human and animal model studies have recently attempted to understand immune mechanisms that lead to the pathogenesis of acute and chronic pancreatitis. Based on these studies innate immune responses emerge as critical elements in disease pathogenesis and severity of inflammation. The immune basis for environmental factors such as smoking, which are highly associated with disease progression highlight novel cross talk mechanisms between immune and nonimmune pancreatic cells such as the pancreatic stellate cells. SUMMARY: Better understanding of immune responses and signaling pathways are emerging as important contributors in pancreatitis development and progression. Such mechanisms are likely to offer future targetable therapies that can either halt or reverse disease progression.

Guided Electro-Optical Switching of Small Graphene Oxide Particles by Larger Ones in Aqueous Dispersion.

Although the large Kerr coefficient of aqueous graphene oxide (GO) dispersions is quite attractive for electro-optical applications with low power consumption, the maximum birefringence of GO dispersions is not sufficiently high for actual display applications. Here we report that adding a small amount of larger GO particles (about 4 µm) into a high-concentration dispersion of small GO (about 0.2 µm) can improve the electro-optical sensitivity to an electric field and also the maximum birefringence. Large GOs induce the ordering of small particles and enhance the electro-optical switching. Large GOs have higher polarizability and are easily driven under an applied electric field, and the rotational motion of large GO particles leads to switching of surrounding small GO particles, improving the electro-optical performance. The binary mixture can overcome the limitations of pure dispersions of large GO or small GO particles; the former has high interparticle interaction, and the latter has low sensitivity to an electric field.

Adsorption Behavior of Extracellular Polymeric Substances on Graphene Materials Explored by Fluorescence Spectroscopy and Two-Dimensional Fourier Transform Infrared Correlation Spectroscopy.

Adsorption isotherms of extracellular polymeric substances (EPS) on graphene oxide (GO) and reduced GO (rGO) were studied using fluorescence excitation-emission matrix-parallel factor analysis (EEM-PARAFAC) and two-dimensional correlation spectroscopy (2D-COS) combined with Fourier transform infrared spectroscopy (FTIR). Chemical reduction of GO resulted in a greater extent of carbon adsorption with a higher degree of isotherm nonlinearity, suggesting that heterogeneous adsorption sites were additionally created by GO reduction. Two protein-like and two humic-like components were identified from EPS by EEM-PARAFAC. Adsorption of protein-like components was greater than that of humic-like components, and the preferential adsorption was more pronounced for GO versus rGO. Adsorption of protein-like components was more governed by site-limiting mechanisms than humic-like components as shown by the higher isotherm nonlinearity. 2D-COS provided further information on the adsorption of secondary protein structures. Adsorption of the EPS structures related to amide I and aromatic C-C bands was greater for rGO versus GO. Protein structures of EPS were more favorable for adsorption in the order of α-helix → amide II → ß-sheet structures with increasing site limitation. Our results revealed successful applicability of EEM-PARAFAC and 2D-COS in examining the adsorption behavior of heterogeneous biological materials on graphene materials.

Effects of an Early Exercise Program with Cryotherapy on Range of Motion, Pain, Swelling, and Gait in Patients with Total Knee Arthroplasty: A Randomized Controlled Trial.

Background: This study aimed to investigate the effects of cryotherapy on range of motion, pain, swelling, and gait in patients who underwent total knee arthroplasty. Methods: Forty-three patients who underwent TKA (total knee arthroplasty) and met the inclusion criteria were randomly divided into two groups. The experimental (n = 21) and control (n = 22) groups underwent cryotherapy and non-cryotherapy treatments, respectively, six times a week for two weeks, and once each before and after exercise for 3 min. Both groups followed a similar initial rehabilitation exercise program using a continuous passive motion device. Results: The results showed a significant difference in knee flexion range of motion, pain, edema, and 10 MWT comparisons from pre- to post-test (p < 0.001). The above values were also significantly different in the comparison between the two groups (p < 0.05). Conclusions: Therefore, this study confirmed that an initial rehabilitation exercise program accompanied by cryotherapy could be an effective intervention method for range of motion, pain, edema, and walking in patients undergoing total knee arthroplasty.

Corydalis ternata Nakai Alleviates Cognitive Decline in Alzheimer's Disease by Reducing ß-Amyloid and Neuroinflammation.

Recently, natural herbs have gained increasing attention owing to their comparatively low toxicity levels and the abundance of historical medical documentation regarding their use. Nevertheless, owing to a lack of knowledge regarding these herbs and their compounds, attempts to find those that could be beneficial for treating diseases have often been ad hoc; thus, there is now a growing demand for an in silico method to identify beneficial herbs. In this study, we present a computational approach for identifying natural herbs specifically effective in treating cognitive decline in Alzheimer's disease (AD) sufferers, which analyzes the similarities between herbal compounds and known drugs targeting AD-related proteins. Our in silico method suggests that Corydalis ternata can improve cognitive decline in AD sufferers. Behavioral tests with an AD mouse model for the confirmation of the in silico prediction reveals that C. ternata significantly alleviated the cognitive decline (memory and motor functions) caused by neurodegeneration. Further pathology analyses reveal that C. ternata decreases the level of Aß plaques, reduces neuroinflammation, and promotes autophagy flux, and thus C. ternata can be clinically effective for preventing mild cognitive impairment during the early stages of AD. These findings highlight the potential utility of our in silico method and the potential clinical application of the identified natural herb in treating and preventing AD.

Fermented mixed grain ameliorates chronic stress-induced depression-like behavior and memory deficit.

Fermented mixed grain (FG) has beneficial anti-cancer, antioxidant, and anti-inflammatory effects. In this study, we investigated the effects of FG on gut inflammation, brain dysfunction, and anxiety/depression-like behavior induced by unpredictable chronic mild stress (UCMS) in mice. Mice were administered mixed grain or FG for 3 weeks and were then exposed to UCMS for 4 weeks. FG administration ameliorated stress-induced anxiety/despair-like behavior. FG administration also prevented UCMS-induced memory impairment. Additionally, the mRNA levels of 5-HTR1A and IL-6 were restored to normal levels in the brains of FG-administered mice. FG administration also inhibited intestinal damage in stressed mice compared with that in the UCMS (without FG) group. These results suggest that FG can alleviate stress-induced intestinal damage, brain dysfunction, and cognitive impairment.

Cardiovascular hardware simulator and artificial aorta-generated central blood pressure waveform database according to various vascular ages for cardiovascular health monitoring applications.

This study presents a database of central blood pressure waveforms according to cardiovascular health conditions, to supplement the lack of clinical data in cardiovascular health research, constructed by a cardiovascular simulator. Blood pressure (BP) is the most frequently measured biomarker, and in addition to systolic and diastolic pressure, its waveform represents the various conditions of cardiovascular health. A BP waveform is formed by overlapping the forward and reflected waves, which are affected by the pulse wave velocity (PWV). The increase in vascular stiffness with aging increases PWV, and the PWV-age distribution curve is called vascular age. For cardiovascular health research, extensive data of central BP waveform is essential, but the clinical data published so far are insufficient and imbalanced in quantity and quality. This study reproduces the central BP waveform using a cardiovascular hardware simulator and artificial aortas, which mimic the physiological structure and properties of the human. The simulator can adjust cardiovascular health conditions to the same level as humans, such as heart rate of 40-100 BPM, stroke volume of 40-100 mL, and peripheral resistance of 12 steps. Also, 6 artificial aortas with vascular ages in the 20-70 were fabricated to reproduce the increase in vascular stiffness due to aging. Vascular age calculated from measured stiffness of artificial aorta and central BP waveform showed an error of less than 3 years from the clinical value. Through this, a total of 636 waveforms were created to construct a central BP waveform database according to controlled various cardiovascular health conditions.

Selective requirement of H2B N-Terminal tail for p14ARF-induced chromatin silencing.

The N-terminal tail of histone H2B is believed to be involved in gene silencing, but how it exerts its function remains elusive. Here, we report the biochemical characterization of p14ARF tumor suppressor as a transcriptional repressor that selectively recognizes the unacetylated H2B tails on nucleosomes. The p14ARF-H2B tail interaction is functional, as the antagonistic effect of p14ARF on chromatin transcription is lost upon deletion or acetylation of H2B tails. Gene expression profiling and chromatin immunoprecipitation studies emphasize the significance of H2B deacetylation and p14ARF recruitment in establishing a repressive environment over the cell cycle regulatory genes. Moreover, HDAC1-mediated H2B deacetylation, especially at K20, constitutes an essential step in tethering p14ARF near target promoters. Our results thus reveal a hitherto unknown role of p14ARF in the regulation of chromatin transcription, as well as molecular mechanisms governing the repressive action of p14ARF.

Reproduction of human blood pressure waveform using physiology-based cardiovascular simulator.

This study presents a cardiovascular simulator that mimics the human cardiovascular system's physiological structure and properties to reproduce the human blood pressure waveform. Systolic, diastolic blood pressures, and its waveform are key indicators of cardiovascular health. The blood pressure waveform is closely related to the pulse wave velocity and the overlap of the forward and reflected pressure waves. The presented cardiovascular simulator includes an artificial aorta made of biomimetic silicone. The artificial aorta has the same shape and stiffness as the human standard and is encased with a compliance chamber. The compliance chamber prevents distortion of the blood pressure waveform from strain-softening by applying extravascular pressure. The blood pressure waveform reproduced by the simulator has a pressure range of 80-120 mmHg, a pulse wave velocity of 6.58 m/s, and an augmentation index of 13.3%. These values are in the middle of the human standard range, and the reproduced blood pressure waveform is similar to that of humans. The errors from the human standard values are less than 1 mmHg for blood pressure, 0.05 m/s for pulse wave velocity, and 3% for augmentation index. The changes in blood pressure waveform according to cardiovascular parameters, including heart rate, stroke volume, and peripheral resistance, were evaluated. The same pressure ranges and trends as in humans were observed for systolic and diastolic blood pressures according to cardiovascular parameters.