Tai Ji on Cognitive Function Improvement in Parkinson's Disease: A Meta-Analysis.

BACKGROUND: Tai Ji (TJ) can improve cognitive function, which in turn brings life quality to Parkinson's disease (PD) patients. Cognitive function is thus important for PD patients. Analyzing the cognitive function and obtaining precise TJ exercise prescriptions are effective in treating PD patients. OBJECTIVES: The purpose of this review was to discuss the current Randomized Controlled Trials (RCTs) of TJ and cognitive function improvement in PD. MATERIALS AND METHODS: Databases, including PubMed, Web of Science, Scopus, Cochrane Library, EBSCOhost, Wan Fang, and CNKI, were searched. Cochrane systematic evaluation method was adopted wherein 6 RCTs met the final inclusion criteria. RESULTS: Among the 6 included RCTs, 3 were of high quality, and the rest were of medium quality. Quantitative analysis exhibited that TJ intervention improved the cognitive function of PD patients. TJ promoted the global cognitive function (p < 0.05) and the executive function (p = 0.09) compared with the control. However there was no significant improvement in cognitive motor. TJ training intervention doses of two times a week with 45-60 min sessions over ≤12 weeks could improve the cognitive function of PD patients. CONCLUSIONS: TJ affects the cognitive function of PD patients. However, this effect may have a reduced or no significant impact as the disease increases. PD patients can choose TJ as an intervention for 45-60 min twice a week for at least 12 weeks to accomplish maximum improvement in cognitive function.

Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure.

Absence of early outcome biomarkers for Pediatric Acute Liver Failure (PALF) hinders medical and liver transplant decisions. We sought to define dynamic interactions among circulating inflammatory mediators to gain insights into PALF outcome sub-groups. Serum samples from 101 participants in the PALF study, collected over the first 7 days following enrollment, were assayed for 27 inflammatory mediators. Outcomes (Spontaneous survivors [S, n=61], Non-survivors [NS, n=12], and liver transplant patients [LTx, n=28]) were assessed at 21 days post-enrollment. Dynamic interrelations among mediators were defined using data-driven algorithms. Dynamic Bayesian Network inference identified a common network motif with HMGB1 as a central node in all patient sub-groups. The networks in S and LTx were similar, and differed from NS. Dynamic Network Analysis suggested similar dynamic connectivity in S and LTx, but a more highly-interconnected network in NS that increased with time. A Dynamic Robustness Index calculated to quantify how inflammatory network connectivity changes as a function of correlation stringency differentiated all three patient sub-groups. Our results suggest that increasing inflammatory network connectivity is associated with non-survival in PALF, and may ultimately lead to better patient outcome stratification.

KRAS and TP53 mutations in bronchoscopy samples from former lung cancer patients.

Mutations in the KRAS and TP53 genes have been found frequently in lung tumors and specimens from individuals at high risk for lung cancer and have been suggested as predictive markers for lung cancer. In order to assess the prognostic value of these two genes' mutations in lung cancer recurrence, we analyzed mutations in codon 12 of the KRAS gene and in hotspot codons of the TP53 gene in 176 bronchial biopsies obtained from 77 former lung cancer patients. Forty-seven patients (61.0%) showed mutations, including 35/77 (45.5%) in the KRAS gene and 25/77 (32.5%) in the TP53 gene, among them 13/77 (16.9%) had mutations in both genes. When grouped according to past or current smoking status, a higher proportion of current smokers showed mutations, in particular those in the TP53 gene (P = 0.07), compared with ex-smokers. These mutations were found in both abnormal lesions (8/20 or 40%) and histologically normal tissues (70/156 or 44.9%) (P = 0.812). They consisted primarily of G to A transition and G to T transversion in both the KRAS (41/56 or 73.2%) and TP53 (24/34 or 70.6%) genes, consistent with mutations found in lung tumors of smoking lung cancer patients. Overall, recurrence-free survival (RFS) among all subjects could be explained by age at diagnosis, tumor stage, tumor subtype, and smoking (P < 0.05, Cox proportional hazard). Therefore, KRAS and TP53 mutations were frequently detected in bronchial tissues of former lung cancer patients. However, the presence of mutation of bronchial biopsies was not significantly associated with a shorter RFS time. © 2016 Wiley Periodicals, Inc.

Computational Analysis Supports an Early, Type 17 Cell-Associated Divergence of Blunt Trauma Survival and Mortality.

OBJECTIVE: Blunt trauma patients may present with similar demographics and injury severity yet differ with regard to survival. We hypothesized that this divergence was due to different trajectories of systemic inflammation and utilized computational analyses to define these differences. DESIGN: Retrospective clinical study and experimental study in mice. SETTING: Level 1 trauma center and experimental laboratory. PATIENTS: From a cohort of 493 victims of blunt trauma, we conducted a pairwise, retrospective, case-control study of patients who survived over 24 hours but ultimately died (nonsurvivors; n = 19) and patients who, after ICU admission, went on to be discharged(survivors; n = 19). INTERVENTIONS: None in patients. Neutralizing anti-interleukin-17A antibody in mice. MEASUREMENTS AND MAIN RESULTS: Data on systemic inflammatory mediators assessed within the first 24 hours and over 7 days were analyzed with computational modeling to infer dynamic networks of inflammation. Network density among inflammatory mediators in nonsurvivors increased in parallel with organ dysfunction scores over 7 days, suggesting the presence of early, self-sustaining, pathologic inflammation involving high-mobility group protein B1, interleukin-23, and the Th17 pathway. Survivors demonstrated a pattern commensurate with a self-resolving, predominantly lymphoid response, including higher levels of the reparative cytokine interleukin-22. Mice subjected to trauma/hemorrhage exhibited reduced organ damage when treated with anti-interleukin-17A. CONCLUSIONS: Variable type 17 immune responses are hallmarks of organ damage, survival, and mortality after blunt trauma and suggest a lymphoid cell-based switch from self-resolving to self-sustaining inflammation.

Elevated Admission Base Deficit Is Associated with a Complex Dynamic Network of Systemic Inflammation Which Drives Clinical Trajectories in Blunt Trauma Patients.

We hypothesized that elevated base deficit (BD) ≥ 4 mEq/L upon admission could be associated with an altered inflammatory response, which in turn may impact differential clinical trajectories. Using clinical and biobank data from 472 blunt trauma survivors, 154 patients were identified after excluding patients who received prehospital IV fluids or had alcohol intoxication. From this subcohort, 84 patients had a BD ≥ 4 mEq/L and 70 patients with BD < 4 mEq/L. Three samples within the first 24 h were obtained from all patients and then daily up to day 7 after injury. Twenty-two cytokines and chemokines were assayed using Luminex™ and were analyzed using two-way ANOVA and dynamic network analysis (DyNA). Multiple mediators of the innate and lymphoid immune responses in the BD ≥ 4 group were elevated differentially upon admission and up to 16 h after injury. DyNA revealed a higher, sustained degree of interconnectivity of the inflammatory response in the BD ≥ 4 patients during the initial 16 h after injury. These results suggest that elevated admission BD is associated with differential immune/inflammatory pathways, which subsequently could predispose patients to follow a complicated clinical course.

Hydrogen Sulfide Inhalation Improves Neurological Outcome via NF-κB-Mediated Inflammatory Pathway in a Rat Model of Cardiac Arrest and Resuscitation.

BACKGROUND/AIMS: The effects of H2S on cerebral inflammatory reaction after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) remain poorly understood. In this study, we investigated the effects of exogenous 40 ppm and 80 ppm H2S gas on inflammatory reaction and neurological outcome after CA/CPR. METHODS: CA was induced by ventricular fibrillation and followed by CPR. Forty or 80 ppm H2S was inhaled for 1 h immediately following CPR. The levels of IL-1ß, IL-6 and TNF-α, the myeloperoxidase (MPO) activity, the expression of iNOS and ICAM-1, and the phosphorylation and translocation of NF-κB were evaluated at 24 h after CA/ CPR. The tape removal test, survival rate and hippocampal neuronal counts were investigated at 14 d after CA/CPR. RESULTS: CA/CPR induced significant increases in IL-1ß, IL-6, TNF-α and MPO activity. The phosphorylation and translocation of NF-κB, and the expression of iNOS and ICAM-1 were increased significantly. Inhalation of 40 or 80 ppm H2S gas decreased these inflammatory cytokines. Furthermore, 40 or 80 ppm H2S inhibited the activation of NF-κB and the downstream proinflammatory mediators iNOS and ICAM-1. H2S inhalation also improved neurological function, 14-d survival rate, and reduced hippocampal neuronal loss. CONCLUSION: These results indicated that inhalation of H2S protected against brain injury after CA/CPR. The mechanisms underlying protective effects of H2S were associated with the inhibition of CA/ CPR-induced inflammation reactions by reducing IL-1ß, IL-6 and TNF-α, and concomitantly inhibiting the activation and infiltration of neutrophils. The beneficial effects of H2S might be mediated by downregulation of NF-κB and the downstream proinflammatory signaling pathway.

Preparation of Expanded Graphite-VO2 Composite Cathode Material and Performance in Aqueous Zinc-Ion Batteries.

Due to safety problems caused by the use of organic electrolytes in lithium-ion batteries and the high production cost brought by the limited lithium resources, water-based zinc-ion batteries have become a new research focus in the field of energy storage due to their low production cost, safety, efficiency, and environmental friendliness. This paper focused on vanadium dioxide and expanded graphite (EG) composite cathode materials. Given the cycling problem caused by the structural fragility of vanadium dioxide in zinc-ion batteries, the feasibility of preparing a new composite material is explored. The EG/VO2 composites were prepared by a simple hydrothermal method, and compared with the aqueous zinc-ion batteries assembled with a single type of VO2 under the same conditions, the electrode materials composited with high-purity sulfur-free expanded graphite showed more excellent capacity, cycling performance, and multiplicity performance, and the EG/VO2 composites possessed a high discharge ratio of 345 mAh g-1 at 0.1 A g-1, and the Coulombic efficiency was close to 100%. The EG/VO2 composite has a high specific discharge capacity of 345 mAh g-1 at 0.1 A g-1 with a Coulombic efficiency close to 100%, a capacity retention of 77% after 100 cycles, and 277.8 mAh g-1 with a capacity retention of 78% at a 20-fold increase in current density. The long cycle test data demonstrated that the composite with expanded graphite effectively improved the cycling performance of vanadium-based materials, and the composite maintained a stable Coulombic efficiency of 100% at a high current density of 2 A/g and still maintained a specific capacity of 108.9 mAh/g after 2000 cycles.

Dual carbon engineering enabling 1T/2H MoS2 with ultrastable potassium ion storage performance.

Potassium-ion batteries (PIBs) as a promising and low-cost battery technology offer the advantage of utilizing abundant and cost-effective K-salt sources. However, the effective adoption of PIBs necessitates the identification of suitable electrode materials. The 1T phase of MoS2 exhibits enhanced electronic conductivity and greater interlayer spacing compared to the 2H phase, leading to a capable potassium ion storage ability. Herein, we fabricated dual carbon engineered 1T/2H MoS2via a secure and straightforward ammonia-assisted hydrothermal method. The 1T/2H MoS2@rGO@C structure demonstrated an expanded interlayer spacing (9.3 Å). Additionally, the sandwich-like structural design not only enhanced material conductivity but also effectively curbed the agglomeration of nanosheets. Remarkably, 1T/2H MoS2@rGO@C exhibited impressive potassium storage ability, delivering capacities of 351.0 mA h g-1 at 100 mA g-1 and 233.8 mA h g-1 at 1000 mA g-1 following 100 and 1000 cycles, respectively. Moreover, the construction of a K-ion full cell was successfully achieved, utilizing perylene tetracarboxylic dianhydride (PTCDA) as the cathode, and manifesting a capacity of 294.3 mA h g-1 at 100 mA g-1 after 160 cycles. This underscores the substantial potential of employing the 1T/2H MoS2@rGO@C electrode material for PIBs.

Implications of an Altered Gut Microbiome in Rat Experimental Vascularized Composite Transplantation.

OBJECTIVES: Vascularized composite allotransplantation is a reconstructive option after severe injury but is fraught with complications, including transplant rejection due to major histocompatibility complex mismatch in the context of allogeneic transplant, which in turn is due to altered immuno-inflammation secondary to transplant. The immunosuppressant tacrolimus can prevent rejection. Because tacrolimus is metabolized predominantly by the gut, this immunosuppressant alters the gut microbiome in multiple ways, thereby possibly affecting immunoinflammation. MATERIALS AND METHODS: We performed either allogeneic or syngeneic transplant with or without tacrolimus in rats. We quantified protein-level inflammatory mediators in the skin, muscle, and plasma and assessed the diversity of the gut microbiome through 16S RNA analysis at several timepoints over 31 days posttransplant. RESULTS: Statistical analysis highlighted a complex interaction between major histocompatibility complex and tacrolimus therapy on the relative diversity of the microbiome. Time-interval principal component analysis indicated numerous significant differences in the tissue characteristics of inflammation and gut microbiome that varied over time and across experimental conditions. Classification and regression tree analysis suggested that both inflammatory mediators in specific tissues and changes in the gut microbiome are useful in characterizing the temporal dynamics of posttransplant inflammation. Dynamic network analysis highlighted unique changes in Methanosphaera that were correlated with Peptococcusin allogeneic transplants with and without tacrolimus versus Prevotella in syngeneic transplant with tacrolimus, suggesting that alterations in Methanosphaera might be a biomarker of vascularized composite allotransplant rejection. CONCLUSIONS: Our results suggest a complex interaction among major histocompatibility complex, local and systemic immuno-inflammation, and tacrolimus therapy and highlight the potential for novel insights into vascularized composite allotransplant from computational approaches.

Unraveling the complex relationship between mRNA and protein abundances: a machine learning-based approach for imputing protein levels from RNA-seq data.

The correlation between messenger RNA (mRNA) and protein abundances has long been debated. RNA sequencing (RNA-seq), a high-throughput, commonly used method for analyzing transcriptional dynamics, leaves questions about whether we can translate RNA-seq-identified gene signatures directly to protein changes. In this study, we utilized a set of 17 widely assessed immune and wound healing mediators in the context of canine volumetric muscle loss to investigate the correlation of mRNA and protein abundances. Our data reveal an overall agreement between mRNA and protein levels on these 17 mediators when examining samples from the same experimental condition (e.g. the same biopsy). However, we observed a lack of correlation between mRNA and protein levels for individual genes under different conditions, underscoring the challenges in converting transcriptional changes into protein changes. To address this discrepancy, we developed a machine learning model to predict protein abundances from RNA-seq data, achieving high accuracy. Our approach also effectively corrected multiple extreme outliers measured by antibody-based protein assays. Additionally, this model has the potential to detect post-translational modification events, as shown by accurately estimating activated transforming growth factor ß1 levels. This study presents a promising approach for converting RNA-seq data into protein abundance and its biological significance.

Synergistic enhancement of oxygen vacancy enrichment and morphology regulation in CeO2-NiCo2O4 heterostructure catalysts for high-performance cathodes in direct borohydride-hydrogen peroxide fuel cells.

Hydrogen peroxide (H2O2) emerges as a viable oxidant for fuel cells, necessitating the development of an efficient and cost-effective electrocatalyst for the hydrogen peroxide reduction reaction (HPRR). In this study, we synthesized a self-supporting, highly active HPRR electrocatalyst comprising two morphologically distinct components: CeO2-NiCo2O4 nanowires and CeO2-NiCo2O4 metal organic framework derivatives, via a two-step hydrothermal process followed by air calcination. X-ray diffraction and transmission electron microscopy analysis confirmed the presence of CeO2 and NiCo2O4, revealing the amalgamated interface between them. CeO2 exhibits multifunctionality in regulating the surface electronic configuration of NiCo2O4, fostering synergistic connections, and introducing oxygen deficiencies to enhance the catalytic efficacy in HPRR. Electrochemical measurements demonstrate a reduction current density of 789.9 mA·cm-2 at -0.8 V vs. Ag/AgCl. The assembly of direct borohydride-hydrogen peroxide fuel cell (DBHPFC) exhibits a peak power density of 45.2 mW·cm-2, demonstrating durable stability over a continuous operation period of 120 h. This investigation providing evidence that the fabrication of heterostructured catalysts based on CeO2 for HPRR is a viable approach for the development of high-efficiency electrocatalysts in fuel cell technology.

A Self-Healing PVA-Linked Phytic Acid Hydrogel-Based Electrolyte for High-Performance Flexible Supercapacitors.

Flexible supercapacitors can be ideal flexible power sources for wearable electronics due to their ultra-high power density and high cycle life. In daily applications, wearable devices will inevitably cause damage or short circuit during bending, stretching, and compression. Therefore, it is necessary to develop proper energy storage devices to meet the requirements of various wearable electronic devices. Herein, Poly(vinyl alcohol) linked various content of phytic acid (PVA-PAx) hydrogels are synthesized with high transparency and high toughness by a one-step freeze-thaw method. The effects of different raw material ratios and agents on the ionic conductivity and mechanical properties of the hydrogel electrolyte are investigated. The PVA-PA21% with 2 M H2SO4 solution (PVA-PA21%-2 M H2SO4) shows a high ionic conductivity of 62.75 mS cm-1. Based on this, flexible supercapacitors fabricated with PVA-PA21%-2 M H2SO4 hydrogel present a high specific capacitance at 1 A g-1 after bending at 90° (64.8 F g-1) and for 30 times (67.3 F g-1), respectively. Moreover, the device shows energy densities of 13.5 Wh kg-1 and 14.0 Wh kg-1 at a power density of 300 W kg-1 after bending at 90° and for 30 times during 10,000 cycles. It provides inspiration for the design and development of electrolytes for related energy electrochemical devices.

Hierarchical CoNiO2 Microflowers Assembled by Mesoporous Nanosheets as Efficient Electrocatalysts for Hydrogen Evolution Reaction.

In order to alleviate the energy crisis and propel a low-carbon economy, hydrogen (H2) plays an important role as a renewable cleaning resource. To break the hydrogen evolution reaction (HER) bottleneck, we need high-efficiency electrocatalysts. Based on the synergistic effect between bimetallic oxides, hierarchical mesoporous CoNiO2 nanosheets can be fabricated. Combining physical representations with electrochemical measurements, the resultant CoNiO2 catalysts present the hierarchical microflowers morphology assembled by mesoporous nanosheets. The ultrathin two-dimensional nanosheets and porous surface characteristics provide the vast channels for electrolyte injection, thus endowing CoNiO2 the outstanding HER performance. The excellent performance with a fewer onset potential of 94 mV, a smaller overpotential at 10 mA cm-2, a lower Tafel slope of 109 mV dec-1 and better stability after 1000 cycles makes CoNiO2 better than that of metallic Co and metallic Ni.

Peripheral nerve repair is associated with augmented cross-tissue inflammation following vascularized composite allotransplantation.

Introduction: Vascularized composite allotransplantation (VCA), with nerve repair/coaptation (NR) and tacrolimus (TAC) immunosuppressive therapy, is used to repair devastating traumatic injuries but is often complicated by inflammation spanning multiple tissues. We identified the parallel upregulation of transcriptional pathways involving chemokine signaling, T-cell receptor signaling, Th17, Th1, and Th2 pathways in skin and nerve tissue in complete VCA rejection compared to baseline in 7 human hand transplants and defined increasing complexity of protein-level dynamic networks involving chemokine, Th1, and Th17 pathways as a function of rejection severity in 5 of these patients. We next hypothesized that neural mechanisms may regulate the complex spatiotemporal evolution of rejection-associated inflammation post-VCA. Methods: For mechanistic and ethical reasons, protein-level inflammatory mediators in tissues from Lewis rats (8 per group) receiving either syngeneic (Lewis) or allogeneic (Brown-Norway) orthotopic hind limb transplants in combination with TAC, with and without sciatic NR, were compared to human hand transplant samples using computational methods. Results: In cross-correlation analyses of these mediators, VCA tissues from human hand transplants (which included NR) were most similar to those from rats undergoing VCA + NR. Based on dynamic hypergraph analyses, NR following either syngeneic or allogeneic transplantation in rats was associated with greater trans-compartmental localization of early inflammatory mediators vs. no-NR, and impaired downregulation of mediators including IL-17A at later times. Discussion: Thus, NR, while considered necessary for restoring graft function, may also result in dysregulated and mis-compartmentalized inflammation post-VCA and therefore necessitate mitigation strategies. Our novel computational pipeline may also yield translational, spatiotemporal insights in other contexts.

A common single nucleotide polymorphism is associated with inflammation and critical illness outcomes.

Acute inflammation is heterogeneous in critical illness and predictive of outcome. We hypothesized that genetic variability in novel, yet common, gene variants contributes to this heterogeneity and could stratify patient outcomes. We searched algorithmically for significant differences in systemic inflammatory mediators associated with any of 551,839 SNPs in one derivation (n = 380 patients with blunt trauma) and two validation (n = 75 trauma and n = 537 non-trauma patients) cohorts. This analysis identified rs10404939 in the LYPD4 gene. Trauma patients homozygous for the A allele (rs10404939AA; 27%) had different trajectories of systemic inflammation along with persistently elevated multiple organ dysfunction (MOD) indices vs. patients homozygous for the G allele (rs10404939GG; 26%). rs10404939AA homozygotes in the trauma validation cohort had elevated MOD indices, and non-trauma patients displayed more complex inflammatory networks and worse 90-day survival compared to rs10404939GG homozygotes. Thus, rs10404939 emerged as a common, broadly prognostic SNP in critical illness.

Research on Optimization of Process Parameters of Traditional Chinese Medicine Based on Data Mining Technology.

Data mining technology and methods are used to effectively optimize manufacturing process parameters due to the complexity and uniqueness of the process parameters. The data-mining-based optimization method for traditional Chinese medicine (TCM) process parameters is presented, along with a list of process parameters that have shown to be effective in actual production. The influencing factors of process parameters are analyzed and modeled using an attribute weight analysis and classification analysis algorithm. The optimization scheme of process parameters that meet the requirements is selected, and an example is given for verification, by selecting data records that fall within a certain error range and incorporating the rules of association knowledge discovery. The support vector classification algorithm has a higher accuracy, despite the algorithm's results being understandable. The support vector regression algorithm developed a reliable process optimization model.

Inferring Tissue-Specific, TLR4-Dependent Type 17 Immune Interactions in Experimental Trauma/Hemorrhagic Shock and Resuscitation Using Computational Modeling.

Trauma/hemorrhagic shock followed by resuscitation (T/HS-R) results in multi-system inflammation and organ dysfunction, in part driven by binding of damage-associated molecular pattern molecules to Toll-like Receptor 4 (TLR4). We carried out experimental T/HS-R (pseudo-fracture plus 2 h of shock followed by 0-22 h of resuscitation) in C57BL/6 (wild type [WT]) and TLR4-null (TLR4-/-) mice, and then defined the dynamics of 20 protein-level inflammatory mediators in the heart, gut, lung, liver, spleen, kidney, and systemic circulation. Cross-correlation and Principal Component Analysis (PCA) on data from the 7 tissues sampled suggested that TLR4-/- samples express multiple inflammatory mediators in a small subset of tissue compartments as compared to the WT samples, in which many inflammatory mediators were localized non-specifically to nearly all compartments. We and others have previously defined a central role for type 17 immune cells in human trauma. Accordingly, correlations between IL-17A and GM-CSF (indicative of pathogenic Th17 cells); between IL-17A and IL-10 (indicative of non-pathogenic Th17 cells); and IL-17A and TNF (indicative of memory/effector T cells) were assessed across all tissues studied. In both WT and TLR4-/- mice, positive correlations were observed between IL-17A and GM-CSF, IL-10, and TNF in the kidney and gut. In contrast, the variable and dynamic presence of both pathogenic and non-pathogenic Th17 cells was inferred in the systemic circulation of TLR4-/- mice over time, suggesting a role for TLR4 in efflux of these cells into peripheral tissues. Hypergraph analysis - used to define dynamic, cross compartment networks - in concert with PCA-suggested that IL-17A was present persistently in all tissues at all sampled time points except for its absence in the plasma at 0.5h in the WT group, supporting the hypothesis that T/HS-R induces efflux of Th17 cells from the circulation and into specific tissues. These analyses suggest a complex, context-specific role for TLR4 and type 17 immunity following T/HS-R.

Inflammatory signals and network connections implicate cell-mediated immunity in chronic venous insufficiency.

BACKGROUND: The role of inflammation in superficial venous reflux in varicose veins (VVs) is unknown. Computational network modeling has deduced inflammation in experimental and clinical settings. We measured immune mediators in plasma from competent and incompetent leg veins inferring the role of cellular immunity based on cytokine networks. METHODS: Temperature was assessed using infrared thermography (IRT) to measure inflammation. Blood was obtained during sclerotherapy or endovenous thermal ablation for VVs. Control subjects underwent phlebotomy from saphenous and forearm veins. Vein segments were harvested during surgery. Demographics, clinical, etiology, anatomy and pathophysiology classification, venous clinical severity scores (VCSSs), and body mass index (BMI) were collected. Twenty-five mediators were measured in serum and vein segments. Means were compared using Mann-Whitney U test. Pearson correlations equaling or exceeding a threshold prompted connections among nodes, and mapped as networks. Spearman correlations were performed between interleukin (IL)-17A and both granulocyte macrophage colony stimulation factor, and IL-10 as indicators of pathogenic and nonpathogenic Th17 cell involvement. RESULTS: Age, BMI, and VCSSs differed significantly between groups. Temperatures were higher over diseased veins. Plasma concentrations of 20 cytokines differed between control and patient subjects (P<0.05), and most were lower in patients. C-X-C motif chemokine ligand-9 (aka monokine-induced by gamma interferon), C-X-C motif chemokine ligand 10 (aka IFNγ induced protein 10), and soluble IL-2 receptor-alpha were higher in patients, but not connected to other mediators in networks. In contrast, IL-17A, IL-12p70, and interferon gamma were the only mediators that were more highly interconnected in venous insufficiency. IL-17A and granulocyte macrophage colony stimulating factor (GM-CSF) were highly correlated in chronic venous insufficiency (CVI) but not in controls. In tissue, refluxing VVs significantly higher IL-15 expression than competent saphenous veins. CONCLUSIONS: Venous insufficiency associates with age, BMI, skin temperature, and plasma cytokines associated with interferon gamma and possibly IL-17A signaling. The vein wall may be a source of activation of cellular activation, given elevated IL-15 expression. Correlations between IL-17A and GM-CSF suggested a potential role for pathogenic Th17 cells in VVs. Differentially expressed inflammatory networks induced by venous hypertension may reflect or drive venous damage and ulceration.

The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation.

Systems-level insights into inflammatory events after vascularized composite allotransplantation (VCA) are critical to the success of immunomodulatory strategies of these complex procedures. To date, the effects of tacrolimus (TAC) immunosuppression on inflammatory networks in VCA, such as in acute rejection (AR), have not been investigated. We used a systems biology approach to elucidate the effects of tacrolimus on dynamic networks and principal drivers of systemic inflammation in the context of dynamic tissue-specific immune responses following VCA. Lewis (LEW) rat recipients received orthotopic hind limb VCA from fully major histocompatibility complex-mismatched Brown Norway (BN) donors or matched LEW donors. Group 1 (syngeneic controls) received LEW limbs without TAC, and Group 2 (treatment group) received BN limbs with TAC. Time-dependent changes in 27 inflammatory mediators were analyzed in skin, muscle, and peripheral blood using Principal Component Analysis (PCA), Dynamic Bayesian Network (DyBN) inference, and Dynamic Network Analysis (DyNA) to define principal characteristics, central nodes, and putative feedback structures of systemic inflammation. Analyses were repeated on skin + muscle data to construct a "Virtual VCA", and in skin + muscle + peripheral blood data to construct a "Virtual Animal." PCA, DyBN, and DyNA results from individual tissues suggested important roles for leptin, VEGF, various chemokines, the NLRP3 inflammasome (IL-1ß, IL-18), and IL-6 after TAC treatment. The chemokines MCP-1, MIP-1α; and IP-10 were associated with AR in controls. Statistical analysis suggested that 24/27 inflammatory mediators were altered significantly between control and TAC-treated rats in peripheral blood, skin, and/or muscle over time. "Virtual VCA" and "Virtual Animal" analyses implicated the skin as a key control point of dynamic inflammatory networks, whose connectivity/complexity over time exhibited a U-shaped trajectory and was mirrored in the systemic circulation. Our study defines the effects of TAC on complex spatiotemporal evolution of dynamic inflammation networks in VCA. We also demonstrate the potential utility of computational analyses to elucidate nonlinear, cross-tissue interactions. These approaches may help define precision medicine approaches to better personalize TAC immunosuppression in VCA recipients.

A putative "chemokine switch" that regulates systemic acute inflammation in humans.

Systemic inflammation is complex and likely drives clinical outcomes in critical illness such as that which ensues following severe injury. We obtained time course data on multiple inflammatory mediators in the blood of blunt trauma patients. Using dynamic network analyses, we inferred a novel control architecture for systemic inflammation: a three-way switch comprising the chemokines MCP-1/CCL2, MIG/CXCL9, and IP-10/CXCL10. To test this hypothesis, we created a logical model comprising this putative architecture. This model predicted key qualitative features of systemic inflammation in patient sub-groups, as well as the different patterns of hospital discharge of moderately vs. severely injured patients. Thus, a rational transition from data to data-driven models to mechanistic models suggests a novel, chemokine-based mechanism for control of acute inflammation in humans and points to the potential utility of this workflow in defining novel features in other complex diseases.