STING Signaling Drives Production of Innate Cytokines, Generation of CD8+ T Cells and Enhanced Protection Against Trypanosoma cruzi Infection

A variety of signaling pathways are involved in the induction of innate cytokines and CD8+ T cells, which are major players in protection against acute Trypanosoma cruzi infection. Previous data have demonstrated that a TBK-1/IRF3-dependent signaling pathway promotes IFN-β production in response to Trypanosoma cruzi, but the role for STING, a main interactor of these proteins, remained to be addressed. Here, we demonstrated that STING signaling is required for production of IFN-β, IL-6, and IL-12 in response to Trypanosoma cruzi infection and that STING absence negatively impacts activation of IRF-dependent pathways in response to the parasite. We reported no significant activation of IRF-dependent pathways and cytokine expression in RAW264.7 macrophages in response to heat-killed trypomastigotes. In addition, we showed that STING is essential for T. cruzi DNA-mediated induction of IFN-β, IL-6, and IL-12 gene expression in RAW264.7 macrophages. We demonstrated that STING-knockout mice have significantly higher parasitemia from days 5 to 8 of infection and higher heart parasitism at day 13 after infection. Although we observed similar heart inflammatory infiltrates at day 13 after infection, IFN-β, IL-12, CXCL9, IFN-γ, and perforin gene expression were lower in the absence of STING. We also showed an inverse correlation between parasite DNA and the expression of CXCL9, IFN-γ, and perforin genes in the hearts of infected animals at day 13 after infection. Finally, we reported that STING signaling is required for splenic IFN-β and IL-6 expression early after infection and that STING deficiency results in lower numbers of splenic parasite-specific IFN-γ and IFN-γ/perforin-producing CD8+ T cells, indicating a pivotal role for STING signaling in immunity to Trypanosoma cruzi.

Investigating the Cortical Correlates of Singing: Potential Neural Benefits of Choir for Persons With Dementia

Through leveraging the known advantages of musical engagement and socialization, choir interventions are known to facilitate psychological and cognitive benefits for persons with dementia (PwD). Surprisingly, no research has explored whether social singing may also confer neurological advantages. In this study, we employed functional near infrared spectroscopy (fNIRS) to investigate the cortical correlates of both social and solo singing in PwD (n=13). Paired-sample t-tests were used to evaluate within-person differences in frontal cortical activation between the social vs solo singing. Results showed significant activation differences in three frontal channels, with social singing requiring comparatively less frontocortical activation. These findings indicate potential neural benefits of social singing – with less frontal activation being a proxy for greater reliance on intact proceduralized systems – and serve to highlight the utility of fNIRS in better understanding the neural correlates underlying the benefits of social singing interventions for PwD.

Contribution of Ascorbate and Glutathione in Endobacteria Bacillus subtilis-Mediated Drought Tolerance in Two Triticum aestivum L. Genotypes Contrasting in Drought Sensitivity

We evaluated the effect of endobacteria Bacillus subtilis (strain 10–4) as a co-inoculant for promoting plant growth and redox metabolism in two contrasting genotypes of Triticum aestivum L. (wheat): Ekada70 (drought tolerant (DT)) and Salavat Yulaev (drought susceptible (DS)) in early stages of adaptation to drought (12% PEG–6000). Results revealed that drought reduced growth and dramatically augmented oxidative stress markers, i.e., hydrogen peroxide (H2O2) and lipid peroxidation (MDA). Furthermore, the depletion of ascorbate (AsA) and glutathione (GSH), accompanied by a significant activation of ascorbate peroxidase (APX) and glutathione reductase (GR), in both stressed wheat cultivars (which was more pronounced in DS genotype) was found. B. subtilis had a protective effect on growth and antioxidant status, wherein the stabilization of AsA and GSH levels was revealed. This was accompanied by a decrease of drought-caused APX and GR activation in DS plants, while in DT plants additional antioxidant accumulation and GR activation were observed. H2O2 and MDA were considerably reduced in both drought-stressed wheat genotypes because of the application of B. subtilis. Thus, the findings suggest the key roles in B. subtilis-mediated drought tolerance in DS cv. Salavat Yulaev and DT cv. Ekada70 played are AsA and GSH, respectively; which, in both cases, resulted in reduced cell oxidative damage and improved growth in seedlings under drought.

PECULIARITIES OF THE WOUND PROCESS DEVELOPMENT IN PATIENTS WITH THERMAL INJURY WHEN USED SILVER PREPARATIONS IN BURN WOUNDS SURGICAL TREATMENT

Fundamental research in the field of burn wound development process highlights new pathogenetic mechanisms that underlie the improvement of medical practice, the main purpose of which is to create optimal conditions for early regeneration of the affected skin, as well as to eliminate the development of local and general complications. Irrational general and local treatment of wounds contribute to the slowing down of regenerative processes, thereby worsening the prognosis and consequences of thermal injury. It was found out that in patients of both study groups in the first period of the study the characteristics of the cellular composition of the wound impressions of the wound bottom of the area of thermal damage correspond to the degenerative type. In patients of the main group in the second term of the study in the area of thermal damage cells with high levels of functional and metabolic activity begin to appear, which increase antimicrobial resistance and reduce the risk of generalization of the infectious process which is the main source of burns. In patients of the main group, an increase in the activity of neutrophilic granulocytes in the induced test was found in the second term of the study, which, in our opinion, indicates the involvement of neutrophilic granulocytes with high functional and metabolic activity. Under conditions of significant activation of resident monocytes in response to injury in patients of the main group in the second and third term, the area of thermal damage migrates functionally effective monocytes. In patients of the main group the preservation of the activity of myeloperoxidase - the main enzyme of the oxygen-dependent phase of phagocytosis at the minimum subcompensated level, which leads to the preservation of the oxygen-dependent metabolic reaction of neutrophilic granulocytes in the subsequent study, Increases in the content of PAS-positive substances in neutrophilic granulocytes indicate the preservation of the functional reserve for activation and completion of the oxygen-independent phase of phagocytosis. The use of the developed treatment promotes the involvement of functionally active phagocytic cells in the burn wound, reduces the toxic load on monocytes and neutrophils, which helps to maintain their functional activity at the subcompensated level. These trends in patients of the main group reduce the risk of both local and general infectious complications of burn disease. It was found that the level of spontaneous functional activity in the HCT test is associated with the activity of resident monocytes. They form the primary barrier that protects the body from infection or harmful macromolecular complexes. Monocytes - "inflammatory", which constantly come from the free pool and their functional activity against microbial antigens is much higher than resident monocytes. An indicator of the activity of monocytes - "inflammatory" is an indicator of functional activity in the induced HCT test. The results of the study indicate that under conditions of significant activation of resident monocytes in response to injury in patients of the main group in the second and third terms of the area of thermal damage migrate functionally effective monocytes.

p47phox-Dependent Oxidant Signalling through ASK1, MKK3/6 and MAPKs in Angiotensin II-Induced Cardiac Hypertrophy and Apoptosis

The p47phox is a key regulatory subunit of Nox2-containing NADPH oxidase (Nox2) that by generating reactive oxygen species (ROS) plays an important role in Angiotensin II (AngII)-induced cardiac hypertrophy and heart failure. However, the signalling pathways of p47phox in the heart remains unclear. In this study, we used wild-type (WT) and p47phox knockout (KO) mice (C57BL/6, male, 7-month-old, n = 9) to investigate p47phox-dependent oxidant-signalling in AngII infusion (0.8 mg/kg/day, 14 days)-induced cardiac hypertrophy and cardiomyocyte apoptosis. AngII infusion resulted in remarkable high blood pressure and cardiac hypertrophy in WT mice. However, these AngII-induced pathological changes were significantly reduced in p47phox KO mice. In WT hearts, AngII infusion increased significantly the levels of superoxide production, the expressions of Nox subunits, the expression of PKCα and C-Src and the activation of ASK1 (apoptosis signal-regulating kinase 1), MKK3/6, ERK1/2, p38 MAPK and JNK signalling pathways together with an elevated expression of apoptotic markers, i.e., γH2AX and p53 in the cardiomyocytes. However, in the absence of p47phox, although PKCα expression was increased in the hearts after AngII infusion, there was no significant activation of ASK1, MKK3/6 and MAPKs signalling pathways and no increase in apoptosis biomarker expression in cardiomyocytes. In conclusion, p47phox-dependent redox-signalling through ASK1, MKK3/6 and MAPKs plays a crucial role in AngII-induced cardiac hypertrophy and cardiomyocyte apoptosis.

Visual-Spatial and Verbal Remote Association: An fMRI Study

Although idea connections at verbal and conceptual levels have been explored by remote associates tests, the visual-spatial level is much less researched. This study investigated the visual-spatial ability via Chinese Radical Remote Associates Test (CRRAT), wherein respondents consider the positions of the stimulus and target Chinese radicals. Chinese Compound Remote Associates Test (CCRAT) questions also feature stimuli of a single Chinese character; therefore, it was adopted for comparison to distinguish the roles played by verbal and visual-spatial associations in a remote associative process. Thirty-six adults responded to CRRAT and CCRAT; their brain activities were analyzed. Upon excluding the influence of age, verbal comprehension, and working memory, it was found that the caudate, posterior cingulate cortex, postcentral gyrus, and medial frontal gyrus were activated when the respondents answered CCRAT, but only the caudate showed significant activation when they answered CRRAT. The Chinese radical remote association minus the Chinese compound remote association showed that the middle frontal gyrus, inferior parietal lobule, and precuneus demonstrated significant activation. Therefore, this study demonstrated differences in brain mechanisms between visual-spatial and verbal remote associations.

Autophagy-Related LC3 Accumulation Interacted Directly With LIR Containing RIPK1 and RIPK3, Stimulating Necroptosis in Hypoxic Cardiomyocytes

The exact relationships and detailed mechanisms between autophagy and necroptosis remain obscure. Here, we demonstrated the link between accumulated autophagosome and necroptosis by intervening with autophagic flux. We first confirmed that the LC3 interacting region (LIR) domain is present in the protein sequences of RIPK1 and RIPK3. Mutual effects among LC3, RIPK1, and RIPK3 have been identified in myocardium and cardiomyocytes. Direct LC3-RIPK1 and LC3-RIPK3 interactions were confirmed by pull-down assays, and their interactions were deleted after LIR domain mutation. Moreover, after disrupting autophagic flux under normoxia with bafilomycin A1 treatment, or with LC3 or ATG5 overexpression adenovirus, RIPK1, RIPK3, p-RIPK3, and p-MLKL levels increased, suggesting necroptosis activation. Severe disruptions in autophagic flux were observed under hypoxia and bafilomycin A1 co-treated cardiomyocytes and myocardium and led to more significant activation of necroptosis. Conversely, after alleviating hypoxia-induced autophagic flux impairment with LC3 or ATG5 knockdown adenovirus, the effects of hypoxia on RIPK1 and RIPK3 levels were reduced, which resulted in decreased p-RIPK3 and p-MLKL. Furthermore, necroptosis was inhibited by siRNAs against RIPK1 and RIPK3 under hypoxia or normoxia. Based on our results, LIR domain mediated LC3-RIPK1 and LC3-RIPK3 interaction. Besides, autophagosome accumulation under hypoxia lead to necrosome formation and, in turn, necroptosis, while when autophagic flux was uninterrupted, RIPK1 and RIPK3 were cleared through an autophagy-related pathway which inhibited necroptosis. These findings provide novel insights for the role of LC3 in regulating cardiomyocyte necroptosis, indicating its therapeutic potential in the prevention and treatment of hypoxic myocardial injury and other hypoxia-related diseases.

Are There Any Differences in Abdominal Activation between Women and Men during Hypopressive Exercises?

This study analyzes the effects of hypopressive exercises on the abdominal thickness of healthy subjects and compares the performance between women and men. We conducted a transversal observational study in 98 subjects (63% women). The muscle thickness is analyzed in transversus abdominis, internal oblique, external oblique, and rectus abdominis with ultrasound imaging at rest and during the hypopressive exercise (HE) in supine and standing position. Comparisons between rest and hypopressive exercise are carried out in the two different positions and between women and men. In the supine position, there is a significant activation of the transversus abdominis and internal oblique during hypopressive exercise (p < 0.001), and it is similar in both sexes, the external oblique is only activated significantly by men (p < 0.001) and rectus abdominis had no significant activation (p > 0.05). Our results show that standing transversus abdominis and external oblique significantly increased their thickness during HE with higher effects in men. Internal oblique also increased significantly, but with higher effects in women, and rectus abdominis had no significant increase. Men had similar effects to women during HE, with an activation of the deepest abdominal muscles. The unequal anatomy and the position could explain the different results obtained between the sexes.

Neural asymmetry during memory encoding and its association with markers of preclinical Alzheimers Disease

Background: Alzheimers Disease (AD) is the most common form of dementia and is characterized by cognitive dysfunction that impacts daily functioning. Beta-amyloid (Ab) is a cytotoxic protein that deposits in the brain many years prior to the onset of cognitive dysfunction. The preclinical period is a stage of AD in which significant pathology is present without clinical symptoms. Ab has been shown to deposit asymmetrically early in the AD trajectory, which has shown to have functional consequences (e.g., asymmetric hypometabolism). We aimed to investigate whether markers of AD and cognitive function were correlated with neural activation asymmetry during memory encoding tasks. Methods: We recruited participants who were cognitively normal to undergo functional magnetic resonance imaging (fMRI), positron emission tomography (PET) imaging, and cognitive testing. We conducted analyses to identify regions of significant activation during a well-established face-name pair memory encoding task, and to identify regions of significant asymmetry. We then computed hemispheric asymmetry (negative/positive values indicate left/right asymmetry, respectively) and absolute asymmetry (greater values indicate greater asymmetry in either hemisphere) and investigated their associations with age, sex, education, global cerebral amyloid, global cerebral metabolism, memory encoding task performance, white matter hyperintensities, and multiple domains of cognitive function. Results: We identified expected regions of significant activation, including the hippocampus, and identified four regions with significant left-hemisphere asymmetry: superior medial frontal gyrus, middle frontal gyrus, supplemental motor area, and medial orbitofrontal gyrus, and two regions with significant right hemisphere asymmetry: putamen and ventral posterolateral nucleus of the thalamus. We found that greater left-hemisphere asymmetry in the middle frontal gyrus was correlated with greater global cerebral glucose metabolism. We also found that better performance in memory, learning, and executive attention was associated with greater absolute symmetry in the thalamus, while better visuospatial performance was associated with greater putamen absolute symmetry. Discussion: Functional asymmetry is correlated with functional markers (e.g., glucose metabolism) in older cognitively normal adults and may reflect metabolic and cognitive changes. Longitudinal studies may help us better understand these associations and the causal impact of neural activation asymmetry.

Allergy to Polyethilenglicole of Anti-SARS CoV2 Vaccine Recipient: A Case Report of Young Adult Recipient and the Management of Future Exposure to SARS-CoV2

The main contraindication to the anti-SARS CoV2 vaccine is an anaphylactic reaction to a vaccine component. The need to vaccinate allergic people who are at higher risk can be of public health interest and this report shows a case of an allergic reaction to PEG of a HCW who had received the first dose of anti-SARS CoV2 vaccine. For 5 h after the administration of the vaccine, she had the appearance of erythematous spots on the face and neck, and a feeling of a slurred mouth and hoarseness. In order to treat the event, she was administered 8 mg intravenous dexamethasone, 1 vial intravenous chlorphenamine maleate, 250 mL intravenous 0.9% NaCl, and conventional oxygen therapy (2 L/min) with complete resolution of the suspected adverse drug reaction. According to the contraindication to the cutaneous test for this patient, BAT was used for further investigations. The patient who suffered the adverse reaction to the COVID-19 vaccine and other five allergic patients who did not report any adverse reaction after the vaccination were tested. There was a significant activation of the vaccine-reactive patient’s basophils with 14.79 CD203chigh% at the concentration of 0.2 mg/mL, while other patients were negative. People who have a confirmed reaction to a vaccine component should undergo further investigation to discover other possible cross-reactions and select the right vaccine to immunize them.