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Background & Aims: Ischemia-reperfusion injury (IRI) can cause hepatic failure after liver surgery or transplantation. IRI causes oxidative stress, which injures sinusoidal endothelial cells (SECs), leading to recruitment and activation of Kupffer cells, platelets and microcirculatory impairment. We investigated whether injured SECs and other cell types release microparticles during post-ischemic reperfusion, and whether such microparticles have pro-inflammatory, platelet-activating and pro-injurious effects that could contribute to IRI pathogenesis., Methods: C57BL6 mice underwent 60 min of partial hepatic ischemia followed by 15 min-24 hrs of reperfusion. We collected blood and liver samples, isolated circulating microparticles, and determined protein and lipid content. To establish mechanism for microparticle production, we subjected murine primary hepatocytes to hypoxia-reoxygenation. Because microparticles express everted phosphatidylserine residues that are the target of annexin V, we analyzed the effects of an annexin V-homodimer (Diannexin or ASP8597) on post-ischemia microparticle production and function., Results: Microparticles were detected in the circulation 15-30 min after post-ischemic reperfusion, and contained markers of SECs, platelets, natural killer T cells, and CD8+ cells; 4 hrs later, they contained markers of macrophages. Microparticles contained F2-isoprostanes, indicating oxidative damage to membrane lipids. Injection of mice with TNF-α increased microparticle formation, whereas Diannexin substantially reduced microparticle release and prevented IRI. Hypoxia-re-oxygenation generated microparticles from primary hepatocytes by processes that involved oxidative stress. Exposing cultured hepatocytes to preparations of microparticles isolated from the circulation during IRI caused injury involving mitochondrial membrane permeability transition. Microparticles also activated platelets and induced neutrophil migration in vitro. The inflammatory properties of microparticles involved activation of NF-κB and JNK, increased expression of E-selectin, P-selectin, ICAM-1 and VCAM-1. All these processes were blocked by coating microparticles with Diannexin., Conclusions: Following hepatic IRI, microparticles circulate and can be taken up by hepatocytes, where they activate signaling pathways that mediate inflammation and hepatocyte injury. Diannexin prevents microparticle formation and subsequent inflammation.

Background: Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents., Methodology/principal Findings: We created CCR2-red fluorescent protein (RFP) knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C(hi)/CCR2(hi) monocytes. Surprisingly, neutrophils, not Ly6C(lo) monocytes, largely replaced Ly6C(hi) cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia., Conclusion/significance: These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations.

Introduction: Administration of spinal cord stimulation to individuals with PSPS-T1/2 may induce supraspinal descending activation. Similarly, exercise is recognized as a fundamental aspect of spinal pain management. Studies have demonstrated its impact on neurophysiological factors, including the release of spinal and supraspinal beta-endorphins, which activate μ-opioid receptors. Therefore, the purpose of this study will be to examine the effect of SCS in combination with lumbo-pelvic stability core training on perceived low back pain, quality of life and disability in PSPS-T2 patients. Methods/Materials: A double-blind randomized clinical trial (RCT) has been designed. All participants will be randomized from a pre-set sequence. The intervention design has been elaborated from the CONSORT guidelines. This study has been registered at Clinicaltrial.gov (NCT06272539). Sample size was calculated using G Power® Sample size software (University of Düsseldorf). The calculation was based on a moderate effect size of 0.7 (partial η2 = 0.70, α =.05, power = 0.95), resulting in a total of 40 patients. Assuming a 30% dropout rate, 52 participants will be recruited in total. Two sessions per week will be scheduled for 8 weeks with a total of 16 sessions. Each work session will have a duration of 60 minutes. The exercise will be adapted according to the phases based on the results already published, limiting in each phase the degrees of flexion and extension of the spine to avoid the risk of electrode migration. Primary outcomes will be functionality, satisfaction, strength, psychosocial variables, quality of life and pain perception. [ABSTRACT FROM AUTHOR]

Background: In diabetes, high blood glucose induces glucotoxicity, resulting in the further damage of pancreatic beta-cells and then precipitating diabetic complications. This study was aimed to investigate the relationship between glucotoxicity with the level of adipokines, diabetic cardiomyopathy, and hematological markers. Moreover, the study examined the potential modulatory effect of coenzyme Q10 (CoQ10) on the aforementioned markers associated with the sequelae of diabetes mellitus. Material and methods: Twenty-four male rats were randomly assigned to receive an injection of STZ to induce diabetes (n = 16) or to remain uninduced (n = 8). The hyperglycemic status was induced in fasting rats by single intraperitoneal injection of STZ (45 mg /kg b.w.) dissolved in citrate buffer (pH 4.5). Three days after STZ injection, rats were divided into three groups; Normal control group (A), Diabetic control group (B), and CoQ10- treated diabetic group (C). The group (C) was fed with the basal diet supplemented with 5 g of CoQ10 per kilogram of diet for three weeks after the diabetes induction. After 21 days, the blood and serum samples were taken to conduct biochemical analyses. Blood glucose was determined by Blood Glucose Monitoring System. Adipokines or cytokines were evaluated by ELISA from a serum sample. Cardiac myopathy biomarkers were estimated by UP-Converting Phosphor Immunoassay Analyzer, and hematological parameters were measured by automatic hematology analyzer. Results: In hyperglycemic rats, the level of fasting blood glucose, and serum level of resistin, omentin, TNF-α, and cardiomyopathy biomarkers significantly increased (P < 0.05). The treatment with CoQ10 significantly decreased the profile of adipokines and cardiomyopathy markers (cardiac enzymes and LPPLA2) in diabetic rats and also reduced glucose levels (P < 0.05). Lymphocyte percentages significantly decreased while significant increases were observed in granulocytes and MID percentages in hyperglycemic rats. Conclusion: Diabetic rats had higher serum levels of adipokines and cardiomyopathy markers. Among the hematological markers, GRA% and MID% increased while LYM% decreased. The profile of adipokines and cardiomyopathy markers improved when CoQ10 was supplemented. The study suggests that CoQ10 may have a beneficial effect on improving diabetic complications. [ABSTRACT FROM AUTHOR]

Background: Virtual Reality (VR) is an immersive computer-generated environment that provides a multi-sensory experience for the user. Modern technology allows the user to explore and interact with the virtual environment, offering opportunities for rehabilitation. The use of immersive VR in the management of musculoskeletal shoulder pain is relatively new and research is required to demonstrate its feasibility and effectiveness in this field. Aim: The aims of this study were, firstly, to explore physiotherapists' beliefs and perspectives of immersive VR as a platform for rehabilitation in patients with musculoskeletal shoulder pain, secondly, to identify potential barriers and facilitators to using VR in a musculoskeletal setting and thirdly, to gain insight from clinicians that would inform the development of a VR intervention for the rehabilitation of musculoskeletal shoulder pain. Methods: This study used qualitative descriptive design methodology. A series of three focus group interviews were carried out, via Microsoft Teams. Physiotherapists received an Oculus Quest™ headset to use at home prior to the focus group interviews. A six-phase process of reflexive thematic analysis was carried out to identify themes within the data. Atlas Ti Qualitative Data Analysis software was used to facilitate thematic analysis. Results: Five themes were identified within the data. They reflected physiotherapists beliefs that VR provides novel opportunities for shoulder rehabilitation and may offer new avenues for managing movement-related fear and improving concordance with rehabilitation. However, barriers related to safety and practical considerations associated with using VR were also identified in the final themes. Conclusion: These findings provide valuable insight into clinician acceptability of immersive VR as a platform for rehabilitation and the need for further research to answer the questions posed by physiotherapists in the current study. This research will contribute to human-centered design of VR-supported interventions for managing musculoskeletal shoulder pain. [ABSTRACT FROM AUTHOR]

Western mothers use more mental state talk with children than do Chinese mothers (e.g., "think", "like", "happy"). The present study aimed to examine whether Western mothers not only produced a greater amount of mental state talk, but also used a wider range of mental state terms (i.e., greater lexical variety) compared to Chinese mothers. We compared maternal mental state talk in 271 mother-child dyads from New Zealand, Australia and China, and coded both quantity (i.e., frequency) and quality (i.e., type, variety, valence) of mothers' mental state talk to their 2.5- to 5-year-olds. Western mothers produced more talk about cognitions and emotions, as well as modulations of assertions, but a similar amount of desire talk, compared to Chinese mothers, with the same patterns found in the variety of talk. Western mothers produced an overall higher amount of mental state talk and a greater variety of mental state terms, but crucially, still produced more MS talk after controlling for the variety. Neither the amount nor the variety of maternal MS talk was correlated with children's theory of mind. These findings shed light on the diverse ways that mothers construe and describe mental states in different cultures, and highlight the importance of examining different aspects of maternal mental state talk and their impact on children's theory of mind in future longitudinal studies. [ABSTRACT FROM AUTHOR]

Dairy products are important constituents of a healthy and balanced diet, but their association with health outcomes remains to be established. We investigated the association of total dairy, total fermented dairy, and different dairy subtypes (including total/high-fat/low-fat milk, yogurt, cheese, butter, and cream) and the risk of cardiovascular disease (CVD), coronary heart disease (CHD), bone fracture and all-cause mortality among 1746 Danish healthy men and women (30–60 years, 52%female). Hazard ratios (HRs) and 95% CIs were estimated using the multivariable Cox proportional hazard models. During a mean follow-up of 30 years, incident cases of CVD (n = 904), CHD (n = 332), fracture (n = 447) and all-cause mortality (n = 680) were reported. High intake of total fermented dairy was associated with lower fracture risk (HR 0.67, 95% CI: 0.51–0.90, P = 0.02) than observed in the lowest tertile of the fermented dairy group. Furthermore, high intake of low-fat milk was associated with lower risks of CVD (HR 0.84, 95% CI: 0.68–1.03, P = 0.03), CHD (HR 0.82, 95% CI: 0.59–1.16, P = 0.04), and all-cause mortality (HR 0.77, 95% CI: 0.61–0.97, P = 0.004) compared with the lowest tertile of low-fat milk group. No associations were found with other dairy subtypes. The findings from this prospective cohort study suggest an inverse association between total fermented dairy and fracture risk, and also inverse associations were found between low-fat milk consumption and risk of CVD, CHD and all-cause mortality. [ABSTRACT FROM AUTHOR]

Learning from others provides the foundation for culture and the advancement of knowledge. Learning a new visuospatial skill from others represents a specific challenge—overcoming differences in perspective so that we understand what someone is doing and why they are doing it. The "what" of visuospatial learning is thought to be easiest from a shared 0° first-person perspective and most difficult from a 180° third-person perspective. However, the visual disparity at 180° promotes face-to-face interaction, which may enhance learning by scaffolding social perspective taking, the "why" of visuospatial learning. We tested these potentially conflicting hypotheses in child and young adult learners. Thirty-six children (4–6 years) and 57 young adults (18–27 years) observed a live model open a puzzle box from a first-person (0°) or third-person (90° or 180°) perspective. The puzzle box had multiple solutions, only one of which was modelled, which allowed for the assessment of imitation and goal emulation. Participants had three attempts to open the puzzle box from the model's perspective. While first-person (0°) observation increased imitation relative to a 180° third-person perspective, the 180° observers opened the puzzle box most readily (i.e., fastest). Although both age groups were excellent imitators and able to take the model's perspective, adults were more faithful imitators, and children were more likely to innovate a new solution. A shared visual perspective increased imitation, but a shared mental perspective promoted goal achievement and the social transmission of innovation. "Perfection of means and confusion of goals—in my opinion—seem to characterize our age" Einstein (1973) pg 337, Ideas and Opinions [ABSTRACT FROM AUTHOR]

Understanding how we see the world is different from how other people see it is a crucial part of social cognition and is known as visual perspective-taking. Although previous studies have demonstrated that 14-month-old infants have the capacity to compute the visual perspectives of others, it remains unknown whether infants under 12 months also have this ability. In this study, we modified a conventional gaze-following experimental setting in which one toy was placed in front of a model and was hidden by a barrier (Blocked Line of Sight Condition), and another toy was placed without a barrier (Clear Line of Sight Condition). We examined the visual perspective-taking abilities of 48 infants aged 7 and 12 months by measuring the infants' gaze shift towards the gaze-cued toy object with and without a barrier. The results demonstrated that 12-month-old infants could correctly follow a model's gaze if the model's line of sight was clear. In contrast, 7-month-old infants showed no evidence of such capacity. Our findings indicate that 12-month-old infants seem to have the capacity to compute the visual perspective of others. [ABSTRACT FROM AUTHOR]

Visual perspective taking is inferring how the world looks to another person. To clarify this process, we investigated whether employing a humanoid avatar as the viewpoint would facilitate an imagined perspective shift in a virtual environment, and which factor of the avatar is effective for the facilitation effect. We used a task that involved reporting how an object looks by a simple direction judgment, either from the avatar's position or from the position of an empty chair. We found that the humanoid avatar's presence improved task performance. Furthermore, the avatar's facilitation effect was observed only when the avatar was facing the visual stimulus to be judged; performance was worse when it faced backwards than when there was only an empty chair facing forwards. This suggests that the avatar does not simply attract spatial attention, but the posture of the avatar is crucial for the facilitation effect. In addition, when the directions of the head and the torso were opposite (i.e., an impossible posture), the avatar's facilitation effect disappeared. Thus, visual perspective taking might not be facilitated by the avatar when its posture is biomechanically impossible because we cannot embody it. Finally, even when the avatar's head of the possible posture was covered with a bucket, the facilitation effect was found with the forward-facing avatar rather than the backward-facing avatar. That is, the head/gaze direction cue, or presumably the belief that the visual stimulus to be judged can be seen by the avatar, was not required. These results suggest that explicit perspective taking is facilitated by embodiment towards humanoid avatars. [ABSTRACT FROM AUTHOR]

Level-2 visuo-spatial perspective-taking is an embodied process during which the perspective-taker mentally simulates a movement of his or her body into the location of the target. Evidence for the embodiment of this process so far exclusively stems from congruency effects in visuo-spatial perspective-taking experiments. Here, additional triangulation for the embodiment of this process is provided from an interindividual differences perspective. In a cross-sectional observational study, participants completed a behavioral level-2 visuo-spatial perspective-taking task and the heartbeat tracking task, which measures interoceptive accuracy and sensibility. Interoceptive accuracy is the objective ability to accurately perceive signals from within the body. In the present study, interoceptive accuracy was quantified by comparing the number of actual heartbeats observed via electrocardiographic recording to subjectively perceived heartbeats during that time. This measure was related to faster perspective-taking and better overall perspective-taking performance. Interoceptive sensibility refers to subjective beliefs about interoceptive abilities. Here, confidence in the estimated number of heartbeats served as a measure if interoceptive sensibility. Finally, the correspondence between interoceptive accuracy and sensibility is referred to as interoceptive awareness. Interoceptive sensibility and awareness were unrelated to perspective-taking. The study is a demonstration of the role interindividual differences in different facets of interoception play for embodied cognition. Implications for future research on links between embodied cognition and interoception are outlined and critically discussed. [ABSTRACT FROM AUTHOR]

The current research explored toddlers’ gaze fixation during a scene showing a person expressing sadness after a ball is stolen from her. The relation between the duration of gaze fixation on different parts of the person’s sad face (e.g., eyes, mouth) and theory of mind skills was examined. Eye tracking data indicated that before the actor experienced the negative event, toddlers divided their fixation equally between the actor’s happy face and other distracting objects, but looked longer at the face after the ball was stolen and she expressed sadness. The strongest predictor of increased focus on the sad face versus other elements of the scene was toddlers’ ability to predict others’ emotional reactions when outcomes fulfilled (happiness) or failed to fulfill (sadness) desires, whereas toddlers’ visual perspective-taking skills predicted their more specific focusing on the actor’s eyes and, for boys only, mouth. Furthermore, gender differences emerged in toddlers’ fixation on parts of the scene. Taken together, these findings suggest that top-down processes are involved in the scanning of emotional facial expressions in toddlers. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease is the most common form of age-related dementia. At least 15 mutations in the human gene PRESENILIN 2 (PSEN2) have been found to cause familial Alzheimer’s disease (fAD). Zebrafish possess an orthologous gene, psen2, and present opportunities for investigation of PRESENILIN function related to Alzheimer’s disease. The most prevalent and best characterized fAD mutation in PSEN2 is N141I. The equivalent codon in zebrafish psen2 is N140. We used genome editing technology in zebrafish to target generation of mutations to the N140 codon. We isolated two mutations: psen2N140fs, (hereafter “N140fs”), causing truncation of the coding sequence, and psen2T141_L142delinsMISLISV, (hereafter “T141_L142delinsMISLISV”), that deletes the two codons immediately downstream of N140 and replaces them with seven codons coding for amino acid residues MISLISV. Thus, like almost every fAD mutation in the PRESENILIN genes, this latter mutation does not truncate the gene’s open reading frame. Both mutations are homozygous viable although N140fs transcripts are subject to nonsense-mediated decay and lack any possibility of coding for an active γ-secretase enzyme. N140fs homozygous larvae initially show grossly normal melanotic skin pigmentation but subsequently lose this as they grow while retaining pigmentation in the retinal pigmented epithelium. T141_L142delinsMISLISV homozygotes retain faint skin melanotic pigmentation as adults, most likely indicating that the protein encoded by this allele retains weak γ-secretase activity. Null mutations in the human PRESENILIN genes do not cause Alzheimer’s disease so these two mutations may be useful for future investigation of the differential effects of null and fAD-like PRESENILIN mutations on brain aging. [ABSTRACT FROM AUTHOR]

The metabolic health benefits of fermented milks have already been investigated using clinical biomarkers but the development of transcriptomic analytics in blood offers an alternative approach that may help to sensitively characterise such effects. We aimed to assess the effects of probiotic yoghurt intake, compared to non-fermented, acidified milk intake, on clinical biomarkers and gene expression in peripheral blood. To this end, a randomised, crossover study was conducted in fourteen healthy, young men to test the two dairy products. For a subset of seven subjects, RNA sequencing was used to measure gene expression in blood collected during postprandial tests and after two weeks daily intake. We found that the postprandial response in insulin was different for probiotic yoghurt as compared to that of acidified milk. Moreover changes in several clinical biomarkers were associated with changes in the expression of genes representing six metabolic genesets. Assessment of the postprandial effects of each dairy product on gene expression by geneset enrichment analysis revealed significant, similar modulation of inflammatory and glycolytic genes after both probiotic yoghurt and acidified milk intake, although distinct kinetic characteristics of the modulation differentiated the dairy products. The aryl hydrocarbon receptor was a major contributor to the down-regulation of the inflammatory genesets and was also positively associated with changes in circulating insulin at 2h after yoghurt intake (p = 0.05). Daily intake of the dairy products showed little effect on the fasting blood transcriptome. Probiotic yoghurt and acidified milk appear to affect similar gene pathways during the postprandial phase but differences in the timing and the extent of this modulation may lead to different physiological consequences. The functional relevance of these differences in gene expression is supported by their associations with circulating biomarkers. [ABSTRACT FROM AUTHOR]

Obesity-related skeletal muscle changes include muscle atrophy, slow-to-fast fiber-type transformation, and impaired mitochondrial oxidative capacity. These changes relate with increased risk of insulin resistance. Mangiferin, the major component of the plant Mangifera indica, is a well-known anti-inflammatory, anti-diabetic, and antihyperlipidemic agent. This study tested the hypothesis that mangiferin treatment counteracts obesity-induced fiber atrophy and slow-to-fast fiber transition, and favors an oxidative phenotype in skeletal muscle of obese rats. Obese Zucker rats were fed gelatin pellets with (15 mg/kg BW/day) or without (placebo group) mangiferin for 8 weeks. Lean Zucker rats received the same gelatin pellets without mangiferin and served as non-obese and non-diabetic controls. Lesser diameter, fiber composition, and histochemical succinic dehydrogenase activity (an oxidative marker) of myosin-based fiber-types were assessed in soleus and tibialis cranialis muscles. A multivariate discriminant analysis encompassing all fiber-type features indicated that obese rats treated with mangiferin displayed skeletal muscle phenotypes significantly different compared with both lean and obese control rats. Mangiferin significantly decreased inflammatory cytokines, preserved skeletal muscle mass, fiber cross-sectional size, and fiber-type composition, and enhanced muscle fiber oxidative capacity. These data demonstrate that mangiferin attenuated adverse skeletal muscle changes in obese rats. [ABSTRACT FROM AUTHOR]

Background: Recent epidemiological evidence has linked hypoxia with the development of Alzheimer disease (AD). A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-β peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-β precursor protein, the β-secretase Bace1, or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes. Objectives: To investigate the effects of acute and chronic sustained hypoxia in Aβ generation in vivo. Methods: 2–3 month-old C57/Bl6J wild-type mice were exposed to either normoxia (21% O2) or hypoxia (9% O2) for either 4 to 72 h (acute) or 21–30 days (chronic sustained) in a hermetic chamber. Brain mRNA levels of Aβ-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AβPP, and its C-terminal fragments (C99/C88 ratio) were measured by Western blot. In addition, 8 and 14-month-old APP/PS1 transgenic mice were subjected to 9% O2 for 21 days and levels of Aβ40, Aβ42, full length AβPP, and soluble AβPPα (sAβPPα) were measured by ELISA or WB. Results: Hypoxia (either acute or chronic sustained) did not impact the transcription of any of the Aβ-related genes in young wild-type mice. A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length AβPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AβPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Aβ40, Aβ42, full length AβPP, or sAβPPα in either young or aged APP/PS1 mice. Discussion: Our results argue against a hypoxia-induced shift of AβPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies. [ABSTRACT FROM AUTHOR]

Background: Lipopolysaccharide (LPS) preconditioning is known to attenuate hepatic ischemia/reperfusion injury (I/RI); however, the precise mechanism remains unclear. This study investigated the role of receptor-interacting protein 140 (RIP140) on the protective effect of LPS preconditioning in hepatic I/RI involving Kupffer cells (KCs). Methods: Sprague—Dawley rats underwent 70% hepatic ischemia for 90 minutes. LPS (100 μg/kg) was injected intraperitoneally 24 hours before ischemia. Hepatic injury was observed using serum and liver samples. The LPS/NF-κB (nuclear factor-κB) pathway and hepatic RIP140 expression in isolated KCs were investigated. Results: LPS preconditioning significantly inhibited hepatic RIP140 expression, NF-κB activation, and serum proinflammatory cytokine expression after I/RI, with an observation of remarkably reduced serum enzyme levels and histopathologic scores. Our experiments showed that protection effects could be effectively induced in KCs by LPS preconditioning, but couldn’t when RIP140 was overexpressed in KCs. Conversely, even without LPS preconditioning, protective effects were found in KCs if RIP140 expression was suppressed with siRNA. Conclusions: Down-regulated RIP140 is involved in LPS-induced inactivation of KCs and hepatic I/RI attenuation. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a devastating complication of bone fracture. Bone fracture shortly after stroke enhances stroke injury by augmenting inflammation. We hypothesize that bone fracture shortly before ischemic stroke also exacerbates ischemic cerebral injury. Tibia fracture was performed 6 or 24 hours before permanent middle cerebral artery occlusion (pMCAO) on C57BL/6J mice or Ccr2RFP/+Cx3cr1GFP/+ mice that have the RFP gene knocked into one allele of Ccr2 gene and GFP gene knocked into one allele of Cx3cr1 gene. Behavior was tested 3 days after pMCAO. Infarct volume, the number of CD68+ cells, apoptotic neurons, bone marrow-derived macrophages (RFP+), and microgila (GFP+) in the peri-infarct region were quantified. Compared to mice subjected to pMCAO only, bone fracture 6 or 24 hours before pMCAO increased behavioral deficits, the infarct volume, and the number of CD68+ cells and apoptotic neurons in the peri-infarct area. Both bone marrow-derived macrophages (CCR2+) and microglia (CX3CR1+) increased in the peri-infarct regions of mice subjected to bone fracture before pMCAO compared to stroke-only mice. The mice subjected to bone fracture 6 hours before pMCAO had more severe injury than mice that had bone fracture 24 hours before pMCAO. Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury. Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke. [ABSTRACT FROM AUTHOR]

Ischemia / reperfusion injury (IRI) during the course of liver transplantation enhances the immunogenicity of allografts and thus impacts overall graft outcome. This sterile inflammatory insult is known to activate innate immunity and propagate organ damage through the recognition of damage-associate molecular pattern (DAMP) molecules. The purpose of the present study was to investigate the role of mitochondrial DAMPs (MTDs) in the pathogenesis of hepatic IRI. Using in vitro models we observed that levels of MTDs were significantly higher in both transplantation-associated and warm IR, and that co-culture of MTDs with human and rat hepatocytes significantly increased cell death. MTDs were also released in an in vivo rat model of hepatic IRI and associated with increased secretion of inflammatory cytokines (TNF-α, IL-6, and IL-10) and increased liver injury compared to the sham group. Our results suggest that hepatic IR results in a significant increase of MTDs both in vitro and in vivo suggesting that MTDs may serve as a novel marker in hepatic IRI. Co-culture of MTDs with hepatocytes showed a decrease in cell viability in a concentration dependent manner, which indicates that MTDs is a toxic mediator participating in the pathogenesis of liver IR injury. [ABSTRACT FROM AUTHOR]

The objective of this study is to transport and deliver resveratrol to intracellular sites using apolipoprotein E3 (apoE3). Reconstituted high-density lipoprotein (rHDL) bearing resveratrol (rHDL/res) was prepared using phospholipids and the low-density lipoprotein receptor (LDLr)-binding domain of apoE3. Biophysical characterization revealed that resveratrol was partitioned into the phospholipid bilayer of discoidal rHDL/res particles (~19 nm diameter). Co-immunoprecipitation studies indicated that the LDLr-binding ability of apoE3 was retained. Cellular uptake of resveratrol to intracellular sites was evaluated in glioblastoma A-172 cells by direct fluorescence using chemically synthesized NBD-labeled resveratrol (res/NBD) embedded in rHDL/res. Competition and inhibition studies indicate that the uptake is by receptor mediated endocytosis via the LDLr, with co-localization of apoE3 and res/NBD in late endosomes/lysosomes. We propose that rHDL provides an ideal hydrophobic milieu to sequester resveratrol and that rHDL containing apoE3 serves as an effective “nanovehicle” to transport and deliver resveratrol to targeted intracellular sites. [ABSTRACT FROM AUTHOR]

Aim: To compare the mean of anteroposterior (AP) measurements of the uterus in longitudinal and oblique transverse planes, and the pulsatility index (PI) and resistive index (RI) of the uterine artery and superficial skin wound artery between patients taking Channa striatus and placebo. Background: Channa striatus, also known as haruan, is a fresh water snakehead fish consumed in many parts of Southeast Asia. Channa striatus is also normally consumed by women postpartum to promote wound healing as well as to reduce post-operative pain. Methodology: This study is a randomised, double blind, placebo-controlled study conducted in women after Lower Segment Caesarean Section (LSCS). Subjects were randomised to either a Channa striatus or a placebo group and were given a daily dosage of 500 mg of Channa striatus extract or 500 mg maltodextrin, respectively, for six weeks post LSCS. The anteroposterior measurements of the uterus in the longitudinal and oblique transverse planes, and the pulsatility index (PI) and resistive index (RI) of the uterine and superficial skin wound arteries were assessed using pelvic Gray-scale ultrasound and Doppler ultrasound at baseline (Day 3) and at two weeks, four weeks and six weeks post-operatively. Results: Sixty-six subjects were randomised into the study with 33 in the Channa striatus group and 33 in the placebo group. No significant differences were detected in terms of the pulsatility index (PI) and the resistive index (RI) of the uterine and superficial skin wound arteries between the Channa striatus and placebo groups. However, in the Channa striatus group, the AP measurements of the uterus on the longitudinal and oblique transverse planes were significantly lower compared to the placebo group (p<0.05 and p<0.001, respectively). Conclusion: Daily intake of Channa striatus extract results in marked differences compared to placebo in terms of uterine involution and recovery in women post LSCS. Trial Registration: [ABSTRACT FROM AUTHOR]

In the current study we investigated the effect of a brief personalised feedback intervention (BPI), compared to an active control intervention, on outcome measures of (i) alcohol consumption (ii) frequency of binge drinking and (iii) readiness to change (RTC). A sample of 103 college students (mean age=23.85) who consumed alcohol regularly provided baseline measures of drinking behaviour and readiness to change before completing an alcohol-related quiz on the UK Department of Health’s Change4Life website (active control). The study was a between subjects design and half the participants were randomly allocated to the BPI group (N=52), who received 10 minutes personalised feedback on their drinking in addition to the alcohol-related quiz. At a two-week follow-up, participants (N=103) repeated the questionnaire battery, and attempted to recall the answers to the alcohol quiz. Results indicated that both groups significantly reduced their alcohol consumption and frequency of binge drinking but there were no significant group differences in either of these measures. We conclude that the provision of generalised information can be as efficient as a BPI for the reduction of alcohol consumption in students. [ABSTRACT FROM AUTHOR]

Quercetin is one of the most abundant polyphenolic flavonoids found in fruits and vegetables and has anti-oxidative and anti-obesity effects. Because the small intestine is a major absorptive organ of dietary nutrients, it is likely that highly concentrated food constituents, including polyphenols, are present in the small intestinal epithelial cells, suggesting that food factors may have a profound effect in this tissue. To identify novel targets of quercetin in the intestinal enterocytes, mRNA profiling using human intestinal epithelial Caco-2 cells was performed. We found that mRNA levels of some apolipoproteins, particularly apolipoprotein B (apoB), are downregulated in the presence of quercetin. On the exposure of Caco-2 cells to quercetin, both mRNA and protein levels of apoB were decreased. Promoter analysis of the human apoB revealed that quercetin response element is localized at the 5′-proximal promoter region, which contains a conserved CCAAT enhancer-binding protein (C/EBP)-response element. We found that quercetin reduces the promoter activity of apoB, driven by the enforced expression of C/EBPβ. Quercetin had no effect on either mRNA or protein levels of C/EBPβ. In contrast, we found that quercetin inhibits the transcriptional activity of C/EBPβ but not its recruitment to the apoB promoter. On the exposure of Caco-2 cells to quercetin 3-O-glucuronide, which is in a cell-impermeable form, no notable change in apoB mRNA was observed, suggesting an intracellular action of quercetin. In vitro interaction experiments using quercetin-conjugated beads revealed that quercetin binds to C/EBPβ. Our results describe a novel regulatory mechanism of transcription of apolipoprotein genes by quercetin in the intestinal enterocytes. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate chemokine profiles and their functional roles in the early phase of fracture healing in mouse models. Methods: The expression profiles of chemokines were examined during fracture healing in wild-type (WT) mice using a polymerase chain reaction array and histological staining. The functional effect of monocyte chemotactic protein-1 (MCP-1) on primary mouse bone marrow stromal cells (mBMSCs) was evaluated using an in vitro migration assay. MCP-1−/− and C-C chemokine receptor 2 (CCR2)−/− mice were fractured and evaluated by histological staining and micro-computed tomography (micro-CT). RS102895, an antagonist of CCR2, was continuously administered in WT mice before or after rib fracture and evaluated by histological staining and micro-CT. Bone graft exchange models were created in WT and MCP-1−/− mice and were evaluated by histological staining and micro-CT. Results: MCP-1 and MCP-3 expression in the early phase of fracture healing were up-regulated, and high levels of MCP-1 and MCP-3 protein expression observed in the periosteum and endosteum in the same period. MCP-1, but not MCP-3, increased migration of mBMSCs in a dose-dependent manner. Fracture healing in MCP-1−/− and CCR2−/− mice was delayed compared with WT mice on day 21. Administration of RS102895 in the early, but not in the late phase, caused delayed fracture healing. Transplantation of WT-derived graft into host MCP-1−/− mice significantly increased new bone formation in the bone graft exchange models. Furthermore, marked induction of MCP-1 expression in the periosteum and endosteum was observed around the WT-derived graft in the host MCP-1−/− mouse. Conversely, transplantation of MCP-1−/− mouse-derived grafts into host WT mice markedly decreased new bone formation. Conclusions: MCP-1/CCR2 signaling in the periosteum and endosteum is essential for the recruitment of mesenchymal progenitor cells in the early phase of fracture healing. [ABSTRACT FROM AUTHOR]

Brain trauma is known to activate inflammatory cells via various chemokine signals although their interactions remain to be characterized. Mice deficient in Ccl3, Ccr2 or Cxcl10 were compared with wildtype mice after controlled cortical impact injury. Expression of Ccl3 in wildtypes was rapidly upregulated in resident, regularly spaced reactive microglia. Ccl3-deficiency enhanced endothelial expression of platelet selectin and invasion of peripheral inflammatory cells. Appearance of Ccr2 transcripts, encoding the Ccl2 receptor, reflected invasion of lysozyme 2-expressing phagocytes and classical antigen-presenting dendritic cells expressing major histocompatibility complex class II. Ccr2 also directed clustered plasmacytoid dendritic cells positive for the T-cell attracting chemokine Cxcl10. A reduction in Ccr2 and dendritic cells was found in injured wildtype cortex after cyclophosphamide treatment resembling effects of Ccr2-deficiency. The findings demonstrate the feasibility to control inflammation in the injured brain by regulating chemokine-dependent pathways. [ABSTRACT FROM AUTHOR]

Therapeutic irradiation is commonly used to treat primary or metastatic central nervous system tumors. It is believed that activation of neuroinflammatory signaling pathways contributes to the development of common adverse effects, which may ultimately contribute to cognitive dysfunction. Recent studies identified the chemokine (C-C motif) receptor (CCR2), constitutively expressed by cells of the monocyte-macrophage lineage, as a mediator of cognitive impairments induced by irradiation. In the present study we utilized a unique reporter mouse (CCR2RFP/+CX3CR1GFP/+) to accurately delineate the resident (CX3CR1+) versus peripheral (CCR2+) innate immune response in the brain following cranial irradiation. Our results demonstrate that a single dose of 10Gy cranial γ-irradiation induced a significant decrease in the percentage of resident microglia, while inducing an increase in the infiltration of peripherally derived CCR2+ macrophages. Although reduced in percentage, there was a significant increase in F4/80+ activated macrophages in irradiated animals compared to sham. Moreover, we found that there were altered levels of pro-inflammatory cytokines, chemokines, adhesion molecules, and growth factors in the hippocampi of wild type irradiated mice as compared to sham. All of these molecules are implicated in the recruitment, adhesion, and migration of peripheral monocytes to injured tissue. Importantly, there were no measureable changes in the expression of multiple markers associated with blood-brain barrier integrity; implicating the infiltration of peripheral CCR2+ macrophages may be due to inflammatory induced chemotactic signaling. Cumulatively, these data provide evidence that therapeutic levels of cranial radiation are sufficient to alter the brain’s homeostatic balance and permit the influx of peripherally-derived CCR2+ macrophages as well as the regional susceptibility of the hippocampal formation to ionizing radiation. [ABSTRACT FROM AUTHOR]

Recent studies have shown that monocytes possess pluripotent plasticity. We previously reported that monocytes could differentiate into hepatic stellate cells. Although stellate cells are also present in the pancreas, their origin remains unclear. An accumulation of enhanced green fluorescent protein (EGFP)+CD45– cells was observed in the pancreases and livers of chimeric mice, which were transplanted with a single hematopoietic stem cell isolated from EGFP-transgenic mice and treated with carbon tetrachloride (CCl4). Because the vast majority of EGFP+CD45– cells in the pancreas expressed stellate cell-associated antigens such as vimentin, desmin, glial fibrillary acidic protein, procollagen-I, and α-smooth muscle actin, they were characterized as pancreatic stellate cells (PaSCs). EGFP+ PaSCs were also observed in CCl4-treated mice adoptively transferred with monocytes but not with other cell lineages isolated from EGFP-transgenic mice. The expression of monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) increased in the pancreas of CCl4-treated mice and their respective receptors, C-C chemokine receptor 2 (CCR2) and Ang II type 1 receptor (AT1R), were expressed on Ly6Chigh monocytes isolated from EGFP-transgenic mice. We examined the effect of an AT1R antagonist, irbesartan, which is also a CCR2 antagonist, on the migration of monocytes into the pancreas. Monocytes migrated toward MCP-1 but not Ang II in vitro. Irbesartan inhibited not only their in vitro chemotaxis but also in vivo migration of adoptively transferred monocytes from peripheral blood into the pancreas. Irbesartan treatment significantly reduced the numbers of EGFP+F4/80+CCR2+ monocytic cells and EGFP+ PaSCs in the pancreas of CCl4-treated chimeric mice receiving EGFP+ bone marrow cells. A specific CCR2 antagonist RS504393 inhibited the occurrence of EGFP+ PaSCs in injured mice. We propose that CCR2+ monocytes migrate into the pancreas possibly via the MCP-1/CCR2 pathway and give rise to PaSCs. [ABSTRACT FROM AUTHOR]

The present study examined effects of role-play experience on reading the mind of people with different perception. It is normally difficult but very important in daily life to understand people with different characteristics, including those with restricted color vision. We explored the mechanisms of reading the mind of people with different perception. Forty university students were introduced to a communication task in which the use of mindreading was essential. During each trial, participants viewed a shelf, presented on a laptop computer, which contained several familiar objects, and they were instructed to touch an object on the shelf following an instruction issued by a partner who stood at the opposite side of the shelf. There were two partners: one was a monkey with normal color vision and the other was a dog with restricted color vision. The monkey could see all the objects in the same colors as the participants, whereas the dog saw some objects in different colors (e.g., he saw as yellow objects that the participants saw as red). Participants were required to respond according to the partner's instruction. In the restricted color vision condition, the dog saw the colors of objects differently; thus, participants had to work out his intentions (i.e., mind read), according to his different perspective. In the normal color vision condition, all objects were in the same colors as those seen by the monkey. Before the test phase, the role-play group had a role-play experience in which participants assumed the role of people with restricted color vision. No-role-play participants made significantly more errors in the restricted color vision condition than in the normal color vision condition, whereas among role-play participants, there was no difference between conditions. These results suggest that role-play experience facilitates reading the mind of people with perceptual experiences different from our own. [ABSTRACT FROM AUTHOR]

Background: Grapes (Vitis species) are economically the most important fruit crop worldwide. However, the complexity of molecular and biochemical events that lead to ripening of berries as well as how aroma is developed are not fully understood. Methodology/Principal Findings: In an attempt to identify the common mechanisms associated with the onset of ripening independently of the cultivar, grapes of Portuguese elite cultivars, Trincadeira, Aragonês, and Touriga Nacional, were studied. The mRNA expression profiles corresponding to veraison (EL35) and mature berries (EL36) were compared. Across the three varieties, 9,8% (2255) probesets corresponding to 1915 unigenes were robustly differentially expressed at EL 36 compared to EL 35. Eleven functional categories were represented in this differential gene set. Information on gene expression related to primary and secondary metabolism was verified by RT-qPCR analysis of selected candidate genes at four developmental stages (EL32, EL35, EL36 and EL 38). Gene expression data were integrated with metabolic profiling data from GC-EI-TOF/MS and headspace GC-EI-MS platforms. Conclusions/Significance: Putative molecular and metabolic markers of grape pre-ripening and ripening related to primary and secondary metabolism were established and revealed a substantial developmental reprogramming of cellular metabolism. Altogether the results provide valuable new information on the main metabolic events leading to grape ripening. Furthermore, we provide first hints about how the development of a cultivar specific aroma is controlled at transcriptional level. [ABSTRACT FROM AUTHOR]

Objective:Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome. Methods:High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM. Results:We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype. Significance:These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention. [ABSTRACT FROM AUTHOR]