Imbalanced Activation Research Articles

Age-related unstable transient states and imbalanced activation proportion of brain networks in people with autism spectrum disorder: A resting-state fMRI study using coactivation pattern analyses

ABSTRACT The atypical static brain functions related to the executive control network (ECN), default mode network (DMN), and salience network (SN) in people with autism spectrum disorder (ASD) has been widely reported. However, their transient functions in ASD are not clear. We aim to identify transient network states (TNSs) using coactivation pattern (CAP) analysis to characterize the age-related atypical transient functions in ASD. CAP analysis was performed on a resting-state fMRI dataset (78 ASD and 78 healthy control (CON) juveniles, 54 ASD and 54 CON adults). Six TNSs were divided into the DMN-TNSs, ECN-TNSs, and SN-TNSs. The DMN-TNSs were major states with the highest stability and proportion, and the ECN-TNSs and SN-TNSs were minor states. Age-related abnormalities on spatial stability and TNS proportion were found in ASD. The spatial stability of DMN-TNSs was found increasing with age in CON, but was not found in ASD. A lower proportion of DMN-TNSs was found in ASD compared with CON of the same age, and ASD juveniles had a higher proportion of SN-TNSs while ASD adults had a higher proportion of ECN-TNSs. The abnormalities on spatial stability and TNS proportion were related to social deficits. Our results provided new evidence for atypical transient brain functions in people with ASD.

Asymmetric triangular body-cover model of the vocal folds with bilateral intrinsic muscle activation.

Many voice disorders are linked to imbalanced muscle activity and known to exhibit asymmetric vocal fold vibration. However, the relation between imbalanced muscle activation and asymmetric vocal fold vibration is not well understood. This study introduces an asymmetric triangular body-cover model of the vocal folds, controlled by the activation of bilateral intrinsic laryngeal muscles, to investigate the effects of muscle imbalance on vocal fold oscillation. Various scenarios were considered, encompassing imbalance in individual muscles and muscle pairs, as well as accounting for asymmetry in lumped element parameters. Measurements of amplitude and phase asymmetries were employed to match the oscillatory behavior of two pathological cases: unilateral paralysis and muscle tension dysphonia. The resulting simulations exhibit muscle imbalance consistent with expectations in the composition of these voice disorders, yielding asymmetries exceeding 30% for paralysis and below 5% for dysphonia. This underscores the relevance of muscle imbalance in representing phonatory scenarios and its potential for characterizing asymmetry in vocal fold vibration.

Pixel-Level Domain Adaptation: A New Perspective for Enhancing Weakly Supervised Semantic Segmentation.

Recent attention has been devoted to the pursuit of learning semantic segmentation models exclusively from image tags, a paradigm known as image-level Weakly Supervised Semantic Segmentation (WSSS). Existing attempts adopt the Class Activation Maps (CAMs) as priors to mine object regions yet observe the imbalanced activation issue, where only the most discriminative object parts are located. In this paper, we argue that the distribution discrepancy between the discriminative and the non-discriminative parts of objects prevents the model from producing complete and precise pseudo masks as ground truths. For this purpose, we propose a Pixel-Level Domain Adaptation (PLDA) method to encourage the model in learning pixel-wise domain-invariant features. Specifically, a multi-head domain classifier trained adversarially with the feature extraction is introduced to promote the emergence of pixel features that are invariant with respect to the shift between the source (i.e., the discriminative object parts) and the target (i.e., the non-discriminative object parts) domains. In addition, we come up with a Confident Pseudo-Supervision strategy to guarantee the discriminative ability of each pixel for the segmentation task, which serves as a complement to the intra-image domain adversarial training. Our method is conceptually simple, intuitive and can be easily integrated into existing WSSS methods. Taking several strong baseline models as instances, we experimentally demonstrate the effectiveness of our approach under a wide range of settings.

Evaluation of change in heart rate variability due to different soundscapes

Abstract Soundscapes affect the health and quality of life of humans. Noisy soundscapes have a negative impact on humans causing annoyance, sleep disturbance and cardiovascular issues. This paper analyses the change in heart rate variability (HRV) due to exposure of different soundscape stimuli. A total of 40 soundscape stimuli were collected from New Delhi India, which were grouped into three clusters, ‘Loud’, ‘Active’ and ‘Silent’, based on psychoacoustic indicators. Listening experiments were conducted with 25 healthy participants, during which electro-cardiography responses were collected as response variable. HRV analysis was performed to analyse the change in time domain (Heart rate, SDNN, NN50, pNN50) and frequency domain (VLF, LF, HF, LF/LF ratio) parameters. A significant change in heart rate is observed with an increase in loudness of stimuli. The change in HRV is analysed by considering noise sensitivity level of participants. A significant decrease in SDNN is noted for participants with high noise sensitivity. Frequency domain parameters of HRV did not exhibit a significant change due to noise exposure. A significant decrease in SDNN suggests imbalanced autonomic nervous system activation, which increases the risk of cardiovascular diseases, particularly for people with high noise sensitivity.

Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation.

Homeostatic perturbation caused by infection fosters two major defense strategies, resistance and tolerance, which promote the host’s survival. Resistance relates to the ability of the host to restrict the pathogen load. Tolerance minimizes collateral tissue damage without directly affecting pathogen fitness. These concepts have been explored mechanistically in murine models of malaria but only superficially in human disease. Indeed, individuals infected with Plasmodium vivax may present with asymptomatic malaria, only mild symptoms, or be severely ill. We and others have reported a diverse repertoire of immunopathological events that potentially underly susceptibility to disease severity in vivax malaria. Nevertheless, the combined epidemiologic, clinical, parasitological, and immunologic features associated with defining the disease outcomes are still not fully understood. In the present study, we perform an extensive outlining of cytokines and inflammatory proteins in plasma samples from a cohort of individuals from the Brazilian Amazon infected with P. vivax and presenting with asymptomatic (n = 108) or symptomatic (n = 134) disease (106 with mild presentation and 28 with severe malaria), as well as from uninfected endemic controls (n = 128) to elucidate these gaps further. We employ highly multidimensional Systems Immunology analyses using the molecular degree of perturbation to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity as well as with other clinical and epidemiologic characteristics. Additionally, our findings reveal that the main factor associated with severe cases of P. vivax infection was the number of symptoms, despite of a lower global inflammatory perturbation and parasitemia. In these participants, the number of symptoms directly correlated with perturbation of markers of inflammation and tissue damage. On the other hand, the main factor associated with non-severe infections was the parasitemia values, that correlated only with perturbation of inflammatory markers, such as IL-4 and IL-1β, with a relatively lower number of symptoms. These observations suggest that some persons present severe vivax regardless of pathogen burden and global inflammatory perturbation. Such patients are thus little tolerant to P. vivax infection and show higher susceptibility to disrupt homeostasis and consequently exhibit more clinical manifestations. Other persons are capable to tolerate higher parasitemia with lower inflammatory perturbation and fewer symptoms, developing non-severe malaria. The analytical approach presented here has capability to define in more details the determinants of disease tolerance in vivax malaria.

SARS-CoV-2 Protease-Dependent Human Cell Infection Induces Immunological Response Imbalance and Neutrophils “Proteolytic Storm”. Proteolysis Inhibitors can Prevent and Treat Covid-19

Based on Chinese CDCP report on COVID-19, 14% of patients presented severe disease and 5% critical conditions. The average case-fatality rate was 2.3%, but mortality was as high as 49% in patients with critical illness. Serious life threatening thromboembolic complications have been found in 71•4% of non survivors and micro/macro angiopathic coagulopathy has been found, at autopsy also, with highly increased neutrophil number, fibrinogen, concentrations of D-dimer and FDPs and NETs, ATIII decrease and normal number of platelets. A cytokine storm and interaction between inflammation and coagulation has been advocated as explanation of hypercoagulability. It has been shown that SARS-CoV-2 infection of alveolar cells is driven by the S-protein by engaging ACE2 and TMPRSS2 cell receptors. whose activation depends on the activity of various host proteases. Full inhibition of SARS-CoV-2 entry was observed when serine proteases inhibitor camostat mesylate was coupled with Cathepsin B/L inhibitor E-64d. In addition multiple proteases are involved in host immune response against viral invasion and immunopathology related to imbalanced immune activation. In this paper it’s hypothesised that the severity of Covid-19 is induced by recruitment of innate responder neutrophils, which release proteases and NETs inducing endothelial damage and imbalance of the four major proteolytic cascades (coagulation, complement, fibrinolysis and kallikrein) with prevalence of activators over inhibitors and consequent thrombotic complications. Platelets adhesion to damaged endothelium and vWFVIII multimers presence, due to loss of ADAMTS13, contributes to hypercoagulability state. Human plasma or serine protease inhibitors like aprotinin can help to control neutrophil induced “proteolytic storm”. The goal of this paper is to support the view that, in SARS-CoV-2 infection, proteases have a key role and exceeding imbalanced neutrophil innate “unfriendly fire” response can be identified as the trigger of a “proteolytic storm”, responsible for subsequent well known hypercoagulation and “cytokine storm” and human plasma, in adequate volumes, together with serine proteases inhibitors can be an effective therapeutic strategy.

Metformin: a novel promising option for fertility preservation during cyclophosphamide-based chemotherapy.

Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP + metformin, CP + sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was 4 weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP + metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; P = 0.027). CP + metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP + metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in-vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace.

Цитокины в иммунопатогенезе аллергии

Allergy is characterized by inadequate hyperimmune response to one or several antigens with the properties of allergens. A specific pattern of abnormal synthesis of some cytokines (principal molecular mediators of the initiation, development, and regulation of allergic inflammation) has an important pathogenic role in allergy. In recent years, it is generally accepted that allergic disorders are accounted for by impaired immune regulation resulting from increased imbalanced activation of allergen-specific T helper 2 cell clones. Allergic type of immune response is currently referred to as type 2 immune response which normally provides humoral immunity, anthelmintic protection etc. However, pathological response results in allergy. Studies on immune pathogenesis of allergic disorders have improved our understanding of the role of altered synthesis of some cytokines (key mediators of allergic inflammation). Cytokines involved in the initiation and regulation of allergy are produced by epithelial cells, various subsets of leukocytes, innate lymphoid cells, and allergen-activated T helper cell clones. Analysis of the associations of the changes in immune reactivity and clinical manifestations has established pathogenic heterogeneity and identified asthma phenotypes and endotypes. These findings have provided a basis for more reasonable, successful, and personalized approach to biological anti-cytokine treatment for allergic disorders. KEYWORDS: allergy, cytokines, T helper cell clones, phenotype, asthma, anti-cytokine therapy. FOR CITATION: Simbirtsev A.S. Cytokines and their role in immune pathogenesis of allergy. Russian Medical Inquiry. 2021;5(1):32–37. DOI: 10.32364/2587-6821-2021-5-1-32-37.

Signaling pathways and effectors of aging.

Aging leads to and is associated with aberrant function of multiple signaling pathways and a host of factors that maintain cellular health. Under normal conditions, the prolongevity, 5' AMP-activated protein kinase (AMPK), is dedicated to the homeostasis of metabolism and autophagy for removal of damaged cellular compartments and molecules. A host of sirtuin family of molecules, that extend life-span, regulate metabolism and repair DNA damage, and possess either mono-ADP-ribosyltransferase, or deacylase activity. Another group of pro-longevity factors, include FOX (forkhead box) proteins, a family of transcription factors that regulate the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt) catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide (NMN), a requisite step for production of NAD+, which is known to increase longevity. Loss of Klotho, a transmembrane enzyme that controls the sensitivity of the organism to insulin and suppresses oxidative stress and inflammation, leads to premature aging in mice. Hydrogen sulfide and transsulfuration pathways are crucial to the long life and are required in protection of cells against damage. Aging also leads to the imbalanced activation of other pathways and factors including p53, insulin and IGF signaling, P13K/AKT, mTOR, PKA, RAS, RTK, MEK, ERK, MAPK, CRTC-1/CREB and NFkB. Such aberrant cellular functions, disturb cell metabolism, derail autophagy and other housekeeping actions, inhibit cell division, induce inflammaging and immunosenecence, cause stem cell exhaustion and induce either senescence, apoptosis or cancer.

SARS-CoV-2 Infection is Protease-Dependent and Induces Neutrophils “Proteolytic Storm” Triggering Clinical Worsening and Viral Sepsis. Proteolysis and Inhibitors of Neutrophil Release Can Prevent and Treat Covid-19

Based on Chinese CDCP report on COVID-19, 14% of patients presented severe disease and 5% critical conditions. The average case-fatality rate was 2.3%, but mortality was as high as 49% in patients with critical illness. Serious life threatening thromboembolic complications have been found in 71.4% of non-survivors and micro/macro angiopathic coagulopathy has been found, at autopsy also, with highly increased neutrophil number, fibrinogen, concentrations of D-dimer and FDPs and NETs, ATIII decrease and normal number of platelets. A cytokine storm and interaction between inflammation and coagulation has been advocated as explanation of hypercoagulability. It has been shown that SARS-CoV-2 infection of alveolar cells is driven by the S-protein by engaging ACE2 and TMPRSS2 cell receptors. Whose activation depends on the activity of various host proteases. Full inhibition of SARS-CoV-2 entry was observed when serine proteases inhibitor camostat mesylate was coupled with Cathepsin B/L inhibitor E-64d. In addition multiple proteases are involved in host immune response against viral invasion and immunopathology related to imbalanced immune activation. In this paper it’s hypothesized that the severity of Covid-19 is induced by recruitment of innate responder neutrophils, which release proteases and NETs inducing endothelial damage and imbalance of the four major proteolytic cascades (coagulation, complement, fibrinolysis and kallikrein) with prevalence of activators over inhibitors and consequent thrombotic complications. Platelets adhesion to damaged endothelium and vWFVIII multimers presence, due to loss of ADAMTS13, contributes to hypercoagulability state. Human plasma or serine protease inhibitors like aprotinin can help to control neutrophil induced “proteolytic storm”. The goal of this paper is to support the view that, in SARS-CoV-2 infection, proteases have a key role and exceeding imbalanced neutrophil innate “unfriendly fire” response can be identified as the trigger of a “proteolytic storm”, responsible for subsequent well known hyper coagulation and “cytokine storm” and human plasma, in adequate volumes, together with serine proteases inhibitors can be an effective therapeutic strategy.

Role of Nivolumab in Hodgkin Lymphoma: A Review of Case Reports and Case Series

INTRODUCTION The patients with refractory/ relapsing classical Hodgkin lymphoma (ref/rel cHL) are usually treated with salvage chemotherapy and autologous stem cell transplantation (autoSCT). The ones who fail the treatment with autoSCT are subsequently treated with Brentuximab vedotin (BV) [1]. Use of nivolumab (an immune checkpoint inhibitor) has been approved in the ones who fail the treatments of autoSCT and BV. Because of the high success rate observed with BV and immune checkpoint inhibitors in ref/ rel cHL, they are now often initiated early in management [1]. METHODS We searched case reports and case series in the PubMed database, from 2014 to 2020, by using the keywords 'Nivolumab' and 'Hodgkin lymphoma' in combination. Forty-eight studies were retrieved. Twenty- eight studies were excluded after reading their abstracts. Subsequently, a study was excluded because it emphasised on the use of Pembrolizumab, and another study was rejected because it was done on a patient of Metastatic squamous cell carcinoma. In the end, eighteen studies were finalized to be included in this review. RESULTS Table 1 highlights the course of treatment in twenty one patients. While six (29%) patients achieved complete resolution of disease, seven (33%) demonstrated marked improvement in their clinical status. Four (19%) went on to accomplish a partial response, whereas one died. Two patients witnessed progressive disease, and one only moderate tumor shrinkage. Nivolumab induced adverse events (NIAEs) were seen in fifteen (71%) patients. Table 2 mentions the abbreviations used in table 1. DISCUSSION Nivolumab is a high affinity, a human monoclonal antibody with a half-life approximately 15 days. It received approval by the Federal Drug Administration (FDA) on May 17th, 2016, for patients with rel/ ref cHL [20]. Biomarkers directly correlating with higher progression free survival (PFS) includes a higher degree of 9p24.1 molecular alteration, which is associated with increased expression of PD-L1 and some degree of expression (positive or decreased) of MHC II and CD4+ mediated T-cell response [21]. The adverse reactions that most patients experienced were GVHD involving the skin (most common), pneumonitis, hepatitis, infusion reaction, colitis, and encephalitis or meningitis [22]. These are managed with drug discontinuation, systemic steroids, and tacrolimus. These reactions mostly develop due to imbalanced immune activation and often present as subtle and easily missable features, thus requiring a high degree of suspicion [20]. CONCLUSION Nivolumab, earlier tried in patients with ref/rel cHL, only is associated with better clinical outcomes. Drug discontinuation can occur as a result of mild-moderate NIAEs. Hence, a high degree of suspicion and prompt management can ensure continued compliance by patients and a better overall prognosis. REFERENCES 1) Vassilakopoulos TP, et al. Cancers (Basel). 2019 2) Serrao A, et al. Ann Hematol. 2019 3) Foran AE, et al. J Pediatr Hematol Oncol. 2017 4) Tardy MP, et al. Oncol. 2017 5) Onizuka M, et al. Int J Hematol. 2017 6) Oliveira DS et al. Rev Assoc Med Bras (1992). 2019 7) Hwang YY, et. Ann Hematol. 2017 8) Chang E, et al. Clin Lymphoma Myeloma Leuk. 2018 9) Dada R, et al. J Oncol Pharm Pract. 2018 10) de Forceville L, et al. Cancer Radiother. 2019 11) Yared JA, et al. Bone Marrow Transplant. 2016 12) Shad AT, et al. Pediatr Blood Cancer. 2017 13) Tchapyjnikov D, et al. J Immunother. 2017 14) Munakata W, et al. Int J Hematol. 2017 15) Godfrey J,et al. J Immunother Cancer. 2017 16) Wight JC, et al. Leuk Lymphoma. 2018 17) Ding J,et al. Acta Haematol. 2020 18) Ono K, et al. Ann Hematol. 2019 19) Wada F, et al. Ann Hematol. 2020 20) Allen PB, et al. Expert Rev Hematol. 2016 21) Roemer MGM, et al. J Clin Oncol. 2018 22) Bair SM, et al.Oncologist. 2019 Disclosures No relevant conflicts of interest to declare.

Cancer Cachexia: Definition, Staging, and Emerging Treatments.

Cachexia is a multifactorial disease characterized by weight loss via skeletal muscle and adipose tissue loss, an imbalance in metabolic regulation, and reduced food intake. It is caused by factors of catabolism produced by tumors in the systemic circulation as well as physiological factors such as the imbalanced inflammatory activation, proteolysis, autophagy, and lipolysis that may occur with gastric, pancreatic, esophageal, lung cancer, liver, and bowel cancer. Cancer cachexia not only negatively affects the quality of life of patients with cancer but also reduces the effectiveness of anti-cancer chemotherapy and increases its toxicity, leading to increased cancer-related mortality and expenditure of medical resources. Currently, there are no effective medical interventions to completely reverse cachexia and no approved drugs. Adequate nutritional support is the main method of cachexia treatment, while drugs that target the inhibition of catabolism, cell damage, and excessive activation of inflammation are under study. This article reviews recent advances in the diagnosis, staging, and evaluation of cancer cachexia.

Newborns With Zika Virus-Associated Microcephaly Exhibit Marked Systemic Inflammatory Imbalance.

Zika virus (ZIKV) is an emergent flavivirus initially considered a benign and self-limited exanthematic illness. In 2015, a new epidemic emerged in northeastern of Brazil with increased incidence of a previously rare clinical outcome, microcephaly, in newborns from mothers who were infected during pregnancy. Little is known about the immunopathogenesis of ZIKV-associated microcephaly. Understanding the inflammatory profile and degree of inflammation of persons affected with such condition is an important step towards development of innovative therapeutic strategies. A case-control study compared plasma levels of several inflammatory biomarkers from newborns with ZIKV microcephaly, asymptomatic ZKV infection, or uninfected controls. Plasma biomarkers were assessed using Luminex. A series of multidimensional analysis was performed to characterize the systemic immune activation profile of the clinical groups. We identified an inflammatory signature associated with ZIKV microcephaly that suggested an increased inflammation. Network analysis suggested that ZIKV microcephaly is associated with imbalanced immune activation and inflammation. The cephalic perimeter was inversely proportional with the degree of inflammatory perturbation. Furthermore, a combination of plasma inflammatory biomarkers could discriminate ZIKV with microcephaly from those with ZIKV without microcephaly or uninfected neonates. An intense inflammatory imbalance that is proportional to the disease severity hallmarks ZIKV microcephaly.

The Abilities of Salidroside on Ameliorating Inflammation, Skewing the Imbalanced Nucleotide Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3/Autophagy, and Maintaining Intestinal Barrier Are Profitable in Colitis.

Salidroside (Sal), as a major glycoside extracted from Rhodiola rosea L., has exhibited its mighty anti-aging, anti-oxidant, anti-cancer, anti-inflammation, and neuroprotective effects in many diseases. Recently, it has showed its protective effect in colitis mice by activating the SIRT1/FoxOs pathway. Whereas, it is not known whether Sal has other protective mechanisms on dextran sulfate sodium (DSS)-induced colitis in mice. In this study, we investigated the protective effects and mechanisms of Sal on DSS-induced colitis in mice. The results demonstrated Sal was a competent candidate in the treatment of ulcerative colitis (UC). Sal remitted DSS-induced disease activity index (DAI), colon length shortening, and colonic pathological damage. Simultaneously, Sal alleviated excessive inflammation by reversing the IL-1β, TNF-α, and IL-10 protein levels in DSS-treated mice. Western blot analysis revealed that Sal inhibited p65 and p38 activation together with peroxisome proliferator-activated receptor (PPARγ) up-regulation. In addition, Sal skewed the imbalanced activation of nucleotide oligomerization domain-like receptor family pyrin domain containing 3 inflammasome and autophagy contributing to colitis recovery. The damaged intestinal barrier induced by DSS was also alleviated along with plasma lipopolysaccharides (LPS) reduction after Sal treatment. In vitro, Sal showed PPARγ-dependent anti-inflammatory effect in LPS-stimulated RAW264.7 cells. In summary, our results demonstrated that Sal might be an effective factor for UC treatment and its pharmacological value deserved further development.

SIV infection aggravates malaria in a Chinese rhesus monkey coinfection model

BackgroundThe co-occurrence of human immunodeficiency virus (HIV) infection and malaria in humans in endemic areas raises the question of whether one of these infections affects the course of the other. Although epidemiological studies have shown the impact of HIV infection on malaria, the mechanism(s) are not yet fully understood. Using a Chinese rhesus macaque coinfection model with simian immunodeficiency virus (SIV) and Plasmodium cynomolgi (Pc) malaria, we investigated the effect of concurrent SIV infection on the course of malaria and the underlying immunological mechanism(s).MethodsWe randomly assigned ten Chinese rhesus monkeys to two groups based on body weight and age. The SIV-Pc coinfection animals (S + P group) were infected intravenously with SIVmac251 eight weeks prior to malaria infection, and the control animals (P group) were infected intravenously with only Pc-infected red blood cells. After malaria was cured with chloroquine phosphate, we also initiated a secondary malaria infection that lasted 4 weeks.We monitored body weight, body temperature and parasitemia, measured SIV viral loads, hemoglobin and neopterin, and tracked the CD4+, CD8+, and CD4+ memory subpopulations, Ki67 and apoptosis by flow cytometry. Then, we compared these parameters between the two groups.ResultsThe animals infected with SIV prior to Pc infection exhibited more severe malaria symptoms characterized by longer episodes, higher parasitemia, more severe anemia, greater body weight loss and higher body temperature than the animals infected with Pc alone. Concurrent SIV infection also impaired immune protection against the secondary Pc challenge infection. The coinfected animals showed a reduced B cell response to Pc malaria and produced lower levels of Pc-specific antibodies. In addition, compared to the animals subjected to Pc infection alone, the animals coinfected with SIV and Pc had suppressed total CD4+ T cells, CD4+CD28highCD95high central memory T cells, and CD4+CD28lowCD95− naïve T cells, which may result from the imbalanced immune activation and faster CD4+ T cell turnover in coinfected animals.ConclusionsSIV infection aggravates malaria physiologically and immunologically in Chinese rhesus monkeys. This nonhuman primate SIV and Pc malaria coinfection model might be a useful tool for investigating human HIV and malaria coinfection and developing effective therapeutics.

IMMU-35. COMPLEMENT SYSTEM AND GLIOBLASTOMA: AN INTRICATE RELATIONSHIP

Abstract The complement system is a vital part of the innate immune system which plays a critical role in immune surveillance and inflammatory processes. Malignant and host cells express various complement inhibitory proteins on their surface to protect against complement mediated cytotoxicity. Imbalanced complement activation triggers inflammation and alters the tumor microenvironment. Complement activation has been shown to induce proliferation and migration of breast, ovarian and lung cancer cells. At this time, the expression and functional role of the complement cascade in glioblastoma (GBM) remain elusive. Here, we investigated the role of complement proteins and their receptor expression in human primary glioma stem-like cells (GSCs) and human GBM tissues. Western blot data demonstrated a high level of expression of central complement components and their receptors in GSCs. RT-PCR data further confirmed the high expression of complement genes which was similar or higher to normal human astrocytes (HA), a cell with high baseline expression levels of complement genes. Flow cytometry analysis revealed that almost 95% of GSCs expressed the anaphylatoxin complement receptors C3aR and C5aR on their cell surfaces which was consistent with our immunohistochemistry analysis of freshly resected GBM tissues. Furthermore, anaphylatoxin C5a exposure increased the proliferation of a subgroup of GSCs while reduced in another subset. Interestingly, C5a exposure was found to increase the expression of various pro-inflammatory markers in GSCs with reduced proliferation. Fluorescence-activated cell sorting (FACS) analysis of freshly isolated human GBM tissue revealed predominant expression of C5aR on cancer cells (CD11b-/CD45- cells) rather than on immune cells. RT-PCR analysis also demonstrated high expression levels of complement genes with concomitant decrease in complement inhibitory genes in human GBM tissue. Evaluation of the differential role of the complement system in GSCs along with their role in in vivo glioma models is ongoing.

The Abilities of Salidroside on Ameliorating Inflammation, Skewing the Imbalanced NLRP3/Autophagy and Maintaining Intestinal Barrier Are Profitable in Colitis

Salidroside (Sal), as a major glycoside extracted from Rhodiola rosea L, has exhibited its mighty anti-aging, anti-oxidant, anti-cancer, anti-inflammation and neuroprotective effects in many diseases. Whereas, it is not known whether salidroside has a protective effect on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). In this study, we investigated the protective effects and mechanisms of Sal on DSS-induced colitis in mice. The results demonstrated Sal was a competent candidate in the treatment of UC. Sal remitted DSS-induced disease activity index (DAI), colon length shortening and colonic pathological damage. Simultaneously, Sal alleviated excessive inflammation by reversing the IL-1β, TNF-α and IL-10 protein levels in DSS-treated mice. Western blot analysis revealed that Sal inhibited p65 and p38 activation together with PPARγ up-regulation. In addition, Sal skewed the imbalanced activation of NLRP3 inflammasome and autophagy contributing to colitis recovery. The damaged intestinal barrier induced by DSS was also alleviated along with plasma LPS reduction after Sal treatment.In vitro, Sal showed PPARγdependent anti-inflammatory effect in LPS-stimulated RAW264.7 cells. In summary, our results demonstrated that Sal might be an effective factor for UC treatment and its pharmacological value deserved further development. Funding Statement: This work was supported by the Key Project of Chinese National Programs for Research and Development (no. 2016YFD0501009) and National Natural Science Foundation of China (nos. 31572582 and 31472248). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: All animal experiments were performed in strict accordance with regulations of the Administration of Affairs Concerning Experimental Animals in China. The protocol was approved by the Institutional Animal Care and Use Committee of Jilin University (20170318).

Epicardial injection of nanoformulated calcium into cardiac ganglionic plexi suppresses autonomic nerve activity and postoperative atrial fibrillation

Imbalanced activation of the cardiac autonomic nervous system triggers postoperative atrial fibrillation (POAF). Neuronal calcium overload induces apoptosis. We hypothesize that epicardial injection of timed-release nanoformulated CaCl2 (nCaCl2) into left atrial ganglionic plexi (GP) modulates autonomic function and suppresses POAF. The purpose of this study was to determine whether nCaCl2 GP therapy suppresses POAF. We used a novel canine model of POAF with implanted radiotelemetry to record nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus nerve, and GP. At week 3, nCaCl2 (n = 7) or vehicle control (sham; n = 3) was injected into left pulmonary vein GP (LGP), followed by right pulmonary vein GP at week 4. Atrial effective refractory period (AERP) and atrial fibrillation vulnerability (AFV) were assessed invivo. Resting and exercise NA and heart rate (HR) were assessed before and after LGP treatment. AERP decreased (P < .0001) and AFV increased (P=.008) at week 3 vs baseline. However, nCaCl2-LGP treatment reversed these changes and restored them to baseline after 1week (P = .04). Subsequent nCaCl2-right pulmonary vein GP treatment further reduced AFV (P = .03). In contrast, AFV increased (P=.001) and AERP remained decreased (P = .01) 1 week after sham-LGP treatment vs baseline. nCaCl2-LGP treatment reduced NA from GP (P < .02) and NA from the left cardiac vagus nerve (P<.05) and increased SNA (P < .02). Despite increased SNA, HR was decreased (P < .01) with loss of HR-SNA correlation (R=0.62). After sham-LGP treatment, NA was unchanged and HR-SNA remained correlated (R = 0.95). Histology confirmed nCaCl2-GP colocalization, apoptosis, and loss of immunoreactivity in nCaCl2-treated somas. Epicardial injection of nCaCl2 into left atrial GP induced neuroapoptosis and modulated autonomic function. This reversed a postoperative reduction in AERP and suppressed POAF.

QSAR modelling of a large imbalanced aryl hydrocarbon activation dataset by rational and random sampling and screening of 80,086 REACH pre-registered and/or registered substances.

The Aryl hydrocarbon receptor (AhR) plays important roles in many normal and pathological physiological processes, including endocrine homeostasis, foetal development, cell cycle regulation, cellular oxidation/antioxidation, immune regulation, metabolism of endogenous and exogenous substances, and carcinogenesis. An experimental data set for human in vitro AhR activation comprising 324,858 substances, of which 1,982 were confirmed actives, was used to test an in-house-developed approach to rationally select Quantitative Structure-Activity Relationship (QSAR) training set substances from an unbalanced data set. In the first iteration, active and inactive substances were selected by random to make QSAR models. Then, more inactive substances were added to the training set in two further iterations based on incorrect or out-of-domain predictions to produce larger models. The resulting ‘rational’ model, comprising 832 actives and four times as many inactives, i.e. 3,328, was compared to a model with a training set of same size and proportion of inactives chosen entirely by random. Both models underwent robust cross-validation and external validation showing good statistical performance, with the rational model having external validation sensitivity of 85.1% and specificity of 97.1%, compared to the random model with sensitivity 89.1% and specificity 91.3%. Furthermore, we integrated the training sets for both models with the 93 external validation test set actives and 372 randomly selected inactives to make two final models. They also underwent external validations for specificity and cross-validations, which confirmed that good predictivity was maintained. All developed models were applied to predict 80,086 EU REACH substances. The rational and random final models had 63.1% and 56.9% coverage of the REACH set, respectively, and predicted 1,256 and 3,214 substances as actives. The final models as well as predictions for AhR activation for 650,000 substances will be published in the Danish (Q)SAR Database and can, for example, be used for priority setting, in read-across predictions and in weight-of-evidence assessments of chemicals.

Th17 cells: a promising therapeutic target for Parkinson’s disease?

ABSTRACTIntroduction: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder caused by the progressive loss of neurons in the midbrain and other brain regions. Only symptomatic treatment is currently available. Mounting evidence suggests that T cells are a key contributor to PD pathogenesis and neurodegeneration by a mechanism that requires further elucidation.Areas covered: We discuss the evidence of imbalanced activation of effector T cell populations in PD and summarize the data of Th17 involvement and Th17-regulated mechanisms in PD pathology. Moreover, possible Th17-related molecular targets as possible neuroprotective immunomodulatory therapeutic targets for PD are examined.Expert Opinion: Existing data show that Th17 cells, their effector molecules, and signaling pathways are potentially effective therapeutic targets for neuroprotective immunomodulation in PD treatment. However, specificity of action within Th17-mediated signaling pathways for PD requires careful consideration.