Notes

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f Rhubarb on DEN-induced hepatocarcinogenesis.

Rhubarb promoted DEN-induced hepatocarcinogenesis by activating the PPP, indicating that the efficacy and safety of Rhubarb in the treatment of liver cancer deserve to be deliberated.
Rhubarb promoted DEN-induced hepatocarcinogenesis by activating the PPP, indicating that the efficacy and safety of Rhubarb in the treatment of liver cancer deserve to be deliberated.
The present study was designed to investigate the regulation of the redox signaling and inflammation by ethanolic leaf extract of Terminalia myriocarpaVan Heurck & Müller (ETM), inspired by the reported antioxidant potential of the plant bark and the anti-edema effect of the same genus.

HPLC-DAD dereplication study was conducted to detect the major polyphenolic secondary metabolites. In-vitro DPPH free radical scavenging assay, nitric oxide (NO) scavenging assay, Fe
ion chelating ability assay and reducing power assay were conducted to evaluate the antioxidant capacity. The molecular mechanism of anti-inflammation was investigated via assessing the NO and NF-ĸB inhibiting properties in different cell lines. In-vivo carrageenan and histamine-induced edema tests were conducted using established animal models. Pro-inflammatory proteins iNOS and NF-κB were docked against the major metabolites of ETM in the in-silico study.

HPLC dereplication analysis revealed the presence of considerable amount of ellthe anti-inflammatory and antioxidant potentials of ETM which might be correlated with its NF-ĸB inhibiting properties.
Mentionable basis was found on behalf of the anti-inflammatory and antioxidant potentials of ETM which might be correlated with its NF-ĸB inhibiting properties.
Huyang Yangkun Formula(HYF) is a traditional Chinese medicine formula based on the traditional theory of Yin and Yang. It could consolidate the Qi of Yin and Yang, adjust the balance of Qi and blood. It has shown clinical efficacy for patients with Premature Ovarian Insufficiency(POI).

Aim to access the effect of Huyang Yangkun formula (HYF) on premature ovarian insufficiency rat model and explores the mechanism related to aquaporins(AQPs) and apoptosis.

Female SD rats were injected with 4-vinylcyclonhexenediepoxide(VCD, 160mg/kg/day) for 15 days. Then, HYF (0.297g/kg)/estradiol valerate (0.1mg/kg) was administered for 105 days in the HYF/estradiol valerate treatment(EVT) group. Serum AMH, FSH and E
were detected by ELISA, and the developing follicles were counted in each group.The TUNEL assay was used to detect positive apoptotic signals. IHC and western blots were used to verify differentially expressed AQPs and apoptosis-related regulators potentially associated with HYF.

Total follicles were incated the treatment effect of HYF on POI in rats. It showed that HYF could promote the follicles development by regulating AQP8/Bcl-2 family-related mitochondrial apoptosis, which provides basic evidence for TCM as an alternative therapy for POI.
This study evaluated the treatment effect of HYF on POI in rats. It showed that HYF could promote the follicles development by regulating AQP8/Bcl-2 family-related mitochondrial apoptosis, which provides basic evidence for TCM as an alternative therapy for POI.Background Since December 2019, the newly emerged SARS-CoV-2 virus continues to infect humans and many people died from severe Covid-19 during the last 2 years worldwide. Different approaches are being used for treatment of this infection and its consequences, but limited results have been achieved and new therapeutics are still needed. One of the most interesting biotherapeutics in this era are Nanobodies which have shown very promising results in recent researches. Scope of review Here, we have reviewed the potentials of Nanobodies in Covid-19 treatment. We have also discussed the properties of these biotherapeutics that make them very suitable for pulmonary drug delivery, which seems to be very important route of administration in this disease. Major conclusion Nanobodies with their special biological and biophysical characteristics and their resistance against harsh manufacturing condition, can be considered as promising, targeted biotherapeutics which can be administered by pulmonary delivery pharmaceutical systems against Covid-19. General significance Covid-19 has become a global problem during the last two years and with emerging mutant strains, prophylactic and therapeutic approaches are still highly needed. Nanobodies with their specific properties can be considered as valuable and promising candidates in Covid-19 therapy.
The endothelial glycocalyx is susceptible to high concentration of glucose and sodium in the blood. These challenges often involve an increase in osmotic pressure which may independently alters the glycocalyx components. The glycocalyx anchors on the cell membrane via core proteins that link with the actin cytoskeleton. This study aims to investigate the role of actomyosin in the osmoregulation of syndecan-1, a core protein that bears abundant sugar chains of the glycocalyx.

Human umbilical vein endothelial cells were incubated with mannitol-based hyperosmotic medium up to 2h. The surface expression of syndecan-1 and the actin cytoskeleton were analysed by confocal microscopy, either without or with cytoskeletal manipulation.

Syndecan-1 expression was compromised when hyperosmotic challenge was prolonged for 2h, with the normalised intensity substantially dropped to 65.78±2.07% at +200mOsm. The reduction is associated with a sustained actin hyper-polymerisation, including significant increases in cortex coverage and cytoskeletal tension. Disassembling the cortex by cytochalasin D restores syndecan-1 in hyperosmosis. Inhibition of ROCK, rather than MLCK and myosin II ATPase activity, prevents the reduction of syndecan-1.

We have demonstrated that prolonged hyperosmotic stress disrupts the integrity of syndecan-1 through an aberrant cortex polymerisation. Our results provide new evidence in the interplay between the glycocalyx and the actin. It helps us better interpret the regulation of the glycocalyx, moving towards a goal of protecting and restoring the glycocalyx under healthy and diseased conditions.
We have demonstrated that prolonged hyperosmotic stress disrupts the integrity of syndecan-1 through an aberrant cortex polymerisation. Our results provide new evidence in the interplay between the glycocalyx and the actin. It helps us better interpret the regulation of the glycocalyx, moving towards a goal of protecting and restoring the glycocalyx under healthy and diseased conditions.Low-intensity transcranial ultrasound stimulation (LITUS) can improve the inflammatory reaction after traumatic brain injury (TBI), and Baicalin also has a good protective effect on TBI. The purpose of this study was to observe the neuroprotective effect of LITUS combined with Baicalin intervention in the TBI rats. Sprague Dawley (SD) rats were randomly divided into 5 groups (n = 15) which were Sham control group, TBI group, LITUS group, Baicalin group, LITUS combined with Baicalin group (LB group). The rats were scanned with 3.0 T magnetic resonance imager, and the apparent diffusion coefficient (ADC) and the fractional anisotropy (FA) of the brain injury cortical area were determined at 3 h, 1, 3, 7 and 10 d after TBI. The ADC value, FA value, neurological function score and Nissl staining were used to assess the level of brain damage of rats. The results showed that on the 10th day after TBI, the ADC values of the TBI group, the LITUS group and the Baicalin group were remarkable greater than that of the L-B group (all adjusted P  less then   0.05), FA values were remarkable smaller than that of the L-B group (all adjusted P  less then   0.05), neurological function scores were remarkable greater than that of the L-B group (all adjusted P  less then   0.05), and Nissl body loss rates were remarkable greater than that of the L-B group (all adjusted P  less then   0.001). This study indicated that compared with the LITUS group and the Baicalin group, the L-B group can more effectively reduce level of brain damage after TBI, and the method of LITUS combined with Baicalin intervention was a more effective neuroprotection for brain injury.Our previous finding suggests that p38 MAPK contributes to the GLT-1 upregulation during induction of brain ischemic tolerance by cerebral ischemic preconditioning (CIP), however, the underlying mechanism is still unclear. Here, we investigated the molecular mechanisms underlying the CIP-induced GLT-1 upregulation by using Western blotting, Co-immunoprecipitation (Co-IP), electrophoretic mobility shift assay (EMSA) and thionin staining in rat hippocampus CA1 subset. We found that application of BAY11-7082 (an inhibitor of NF-κB), or dihydrokainate (an inhibitor of GLT-1), or SB203580 (an inhibitor of p38 MAPK) could attenuate the CIP-induced neuronal protection in hippocampus CA1 region of rats. Moreover, CIP caused rapid activation of NF-κB, as evidenced by nuclear translocation of NF-κB p50 protein, which led to active p50/p65 dimer formation and increased DNA binding activity. GLT-1 was also increased after CIP. Pretreatment with BAY11-7082 blocked the CIP-induced GLT-1 upregulation. The above results suggest that NF-κB participates in GLT-1 up-regulation during the induction of brain ischemic tolerance by CIP. We also found that pretreatment with SB203580 caused significant reduction of NF-κB p50 protein in nucleus, NF-κB p50/p65 dimer nuclear translocation and DNA binding activity of NF-κB. Together, we conclude that p38 MAPK/NF-κB pathway participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance induced by CIP.Chronic low-grade retinal inflammation is an essential contributor to the pathogenesis of diabetic retinopathy (DR). It is characterized by increased retinal cell expression and secretion of a variety of inflammatory cytokines; among these, IL-1β has the reputation of being a major driver of cytokine-induced inflammation. IL-1β and other cytokines drive inflammatory changes that cause damage to retinal cells, leading to the hallmark vascular lesions of DR; these include increased leukocyte adherence, vascular permeability, and capillary cell death. Nuclear factor of activated T-cells (NFAT) is a transcriptional regulator of inflammatory cytokines and adhesion molecules and is expressed in retinal cells. Consequently, it may influence multiple pathogenic steps early in DR. We investigated the NFAT-dependency of IL-1β-induced inflammation in human Müller cells (hMC) and human retinal microvascular endothelial cells (hRMEC). Our results show that an NFAT inhibitor, Inhibitor of NFAT-Calcineurin Association-6 (INCA-6), decreased IL-1β-induced expression of IL-1β and TNFα in hMC, while having no effect on VEGF, CCL2, or CCL5 expression. We also demonstrate that INCA-6 attenuated IL-1β-induced increases of IL-1β, TNFα, IL-6, CCL2, and CCL5 (inflammatory cytokines and chemokines), and ICAM-1 and E-selectin (leukocyte adhesion molecules) expression in hRMEC. INCA-6 similarly inhibited IL-1β-induced increases in leukocyte adhesion in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Finally, INCA-6 rescued IL-1β-induced permeability in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Taken together, these data demonstrate the potential of NFAT inhibition to mitigate retinal inflammation secondary to diabetes.Other than being a physiological process, pregnancy is a condition characterized by major adaptations of maternal endocrine and metabolic homeostasis that are necessary to accommodate the fetoplacental unit. Unfortunately, all these systemic, cellular, and molecular changes in maternal physiology also make the mother and the fetus more prone to adverse outcomes, including numerous alterations arising from viral infections. Common infections during pregnancy that have long been recognized as congenitally and perinatally transmissible to newborns include toxoplasmosis, rubella, cytomegalovirus, and herpes simplex viruses (originally coined as ToRCH infections). In addition, enterovirus, parvovirus B19, hepatitis virus, varicella-zoster virus, human immunodeficiency virus, Zika and Dengue virus, and, more recently, coronavirus infections including Middle Eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) infections (especially the novel SARS-CoV-2 responsible for the ongoing COVID-19 pandemic), constitute relevant targets for current research on maternal-fetal interactions in viral infections during pregnancy. Appropriate maternal education from preconception to the early postnatal period is crucial to promote healthy pregnancies in general and to prevent and/or reduce the impact of viral infections in particular. Specifically, an adequate lifestyle based on proper nutrition plans and feeding interventions, whenever possible, might be crucial to reduce the risk of virus-related gestational diseases and accompanying complications in later life. Here we aim to provide an overview of the emerging literature addressing the impact of nutrition in the context of potentially harmful viral infections during pregnancy.Mammary gland (MG) undergoes critical points of structural changes throughout a woman's life. During the perinatal and pubertal stages, MG develops through growth and differentiation to establish a pre-mature feature. If pregnancy and lactation occur, the epithelial compartment branches and differentiates to create a specialized structure for milk secretion and nurturing of the newborn. However, the ultimate MG modification consists of a regression process aiming to reestablish the smaller and less energy demanding structure until another production cycle happens. The unraveling of these fascinating physiologic cycles has helped the scientific community elucidate aspects of molecular regulation of proliferative and apoptotic events and remodeling of the stromal compartment. However, greater understanding of the hormonal pathways involved in MG developmental stages led to concern that endocrine disruptors such as bisphenol A (BPA), may influence these specific development/involution stages, called "windows of susceptibility". Since it is used in the manufacture of polycarbonate plastics and epoxy resins, BPA is a ubiquitous chemical present in human everyday life, exerting an estrogenic effect. Thus, descriptions of its deleterious effects on the MG, especially in terms of serum hormone concentrations, hormonal receptor expression, molecular pathways, and epigenetic alterations, have been widely published. Therefore, allied to a didactic description of the main physiological mechanisms involved in different critical points of MG development, the current review provides a summary of key mechanisms by which the endocrine disruptor BPA impacts MG homeostasis at different windows of susceptibility, causing short- and long-term effects.Ceramide synthases (CerSs) catalyze the formation of ceramides from sphingoid bases and acyl-CoA substrates. Increasing evidence suggests that cancer cells generally exhibit altered sphingolipid metabolism in the tumorigenesis of multiple cancers. However, there is no evidence that CerSs are associated with pancreatic ductal carcinoma (PDAC). In the present study, we examined CerS expression in clinical tissue and conducted data mining to investigate the clinical significance of CerSs in the TCGA-PAAD database. We found that high CerS6 expression positively correlated with progression and predicted worse prognosis in PDAC patients, establishing CerS6 as a potential biomarker for PDAC. Furthermore, CerS6 promoted cell proliferation, colony formation and invasion by producing C16-ceramide and was required for tumor formation. Mechanistically, AKT1 interacted with and phosphorylated FOXP3 at S418, which decreased the binding of FOXP3 to the CERS6 promoter and in turn induced CerS6 expression by reconstituting an activated state on the CERS6 promoter. The AKT1/FOXP3 axis mediated the CerS6 expression and promoted p53 mutant pancreatic tumorigenesis by producing excessive C16-ceramide, which induced the accumulation of mutant p53. Thus, our study explores the relationship between PI3K/AKT signaling and sphingolipid metabolism, revealing an oncogenic role for CerS6, which may represent a potential target for PDAC treatment.Cell death is a natural process in organismal development, homeostasis and response to disease or infection that eliminates unnecessary or potentially dangerous cells and acts as an innate barrier to oncogenesis. Inactivation of cell death is a key step in tumour development and also impedes effective response to cancer therapy. Precise execution of unwanted cells is achieved through regulated cell death processes including the intrinsic apoptotic pathway that is governed by the BCL-2 (B-cell lymphoma 2) protein family. There is compelling evidence that intrinsic apoptosis is defective in prostate cancer, particularly in metastatic and castration resistant advanced disease, currently a lethal diagnosis. New therapeutics have been developed to target pro-survival BCL-2 proteins (including BCL-2, BCL-XL and MCL-1) and show promise in reinstating apoptosis to destroy tumour cells in haematological cancers. Here we discuss perturbation of cell death in prostate cancer and how new therapeutics could improve treatment outcome in prostate cancer.Recent studies suggest that RRP15 (Ribosomal RNA Processing 15 Homolog) might be a potential target for cancer therapy. However, the role of RRP15 in hepatocarcinogenesis remains poorly delineated. In this study, we aimed to evaluate the expression and biological function of RRP15 in human hepatocellular carcinoma (HCC). We show that RRP15 was up regulated in HCC cell lines and tumours. Up-regulation of RRP15 in HCC tumours was also correlated with unfavorable prognosis. We further show that the frequent up-regulation of RRP15 in HCCs is at least partly driven by recurrent gene copy gain at chromosome 1q41. Functional studies indicated that RRP15 knockdown suppresses HCC proliferation and growth both in vitro and in vivo. Mechanistically, RRP15 depletion in p53-wild-type HepG2 cells induced senescence via activation of the p53-p21 signalling pathway through enhanced interaction of RPL11 with MDM2, as well as inhibition of SIRT1-mediated p53 deacetylation. Moreover, RRP15 depletion in p53-mutant PLC5 and p53-deleted Hep3B cells induced metabolic shift from the glycolytic pentose-phosphate to mitochondrial oxidative phosphorylation via regulating a series of key genes such as HK2 and TIGAR, and thus, promoted the generation of ROS and apoptosis. Taken together, our findings provide evidence for an important role of the RRP15 gene in hepatocarcinogenesis through regulation of HCC proliferation and growth, raising the possibility that targeting RRP15 may represent a potential therapeutic strategy for HCC treatment.
To investigate age-related changes in the intramuscular adipose tissue (IAT) of the tongue and geniohyoid muscle (GHM) and associated factors.

Exploratory cross-sectional study.

This study included 89 participants recruited from a health survey, which included 38 younger adults (age range, 20-63years) and 51 older adults (age range, 65-87years).

Age, body mass index, body fat, lean body mass, skeletal muscle mass index, trunk muscle mass index, tongue pressure, jaw opening force, and oral diadochokinesis were assessed. The cross-sectional area (CSA) and echo intensity (EI) of the tongue and GHM were measured using ultrasonography. IAT was assessed according to EI values. The factors related to the IAT of each muscle were examined using multiple regression analysis. We also investigated the correlation of IAT with factors related to oral function and systemic and morphological factors.

Neither the EI of the tongue nor that of the GHM had a significant correlation with factors related to oral function and systemic factors. In the multiple regression analysis, significant explanatory variables for EI of the tongue and GHM were age (β=0.14, P=0.019; tongue and β=0.13, P=0.017; GHM) and the CSA of each muscle (β=-0.01, P=0.042; tongue and β=-0.04, P=0.003; GHM). EI was positively associated with age and negatively associated with muscle CSA.

Age-related changes in the IAT show the same trend for both the tongue and GHM, unlike age-related changes in muscle mass. The IATs of the tongue and GHM were not significantly correlated with oral function and systemic factors. Therefore, EI may not be a useful index for the functional evaluation of the tongue and GHM.
Age-related changes in the IAT show the same trend for both the tongue and GHM, unlike age-related changes in muscle mass. The IATs of the tongue and GHM were not significantly correlated with oral function and systemic factors. Therefore, EI may not be a useful index for the functional evaluation of the tongue and GHM.
To evaluate the effects of functional and concurrent training on immune function and functional fitness in postmenopausal women.

A randomized controlled trial was performed on 108 women aged 60 or older who were randomly assigned among the groups control group (CG n=40; 63.88±3.64years); functional training (FT n=32; 63.88±3.79years); and concurrent training (CT n=36; 64.83±4.00years). Immune function was measured by the expression of the T-lymphocyte function-related surface markers (CD28 and CD57). Functional fitness was assessed using physical tests similar to daily activities, i.e., five times sit to stand, timed up and go, and gallon-jug shelf-transfer.

Regarding immune function, there was only a time effect, without between-group differences. Specifically, FT and CT show a reduction and increase in CD4
and CD8
T cells, respectively, without impairment in the subpopulations analyzed, while CG showed a reduction in naive T cells (CD8
CD28
). For functional fitness tests, there was a time×group interaction effect for all tests, the FT and CT were superior to the CG, with FT showing differences after the fourth week, while the CT showed this effect after the eighth week of intervention.

FT and CT do not impair immune function and similarly improve functional fitness in postmenopausal women.

RBR-2d56bt.
RBR-2d56bt.Upon awakening from nighttime sleep, the stress hormone cortisol in humans exhibits a robust rise within thirty to forty-five minutes. This cortisol awakening response (CAR), a crucial point of reference within the healthy cortisol circadian rhythm, has been linked to various psychological, psychiatric and health-related conditions. The CAR is thought to prepare the brain for anticipated challenges of the upcoming day to maintain one's homeostasis and promote adaptive responses. Using brain imaging with a prospective design and pharmacological manipulation, we investigate the neurobiological mechanisms underlying this preparation function of the CAR across two studies. In Study 1, a robust CAR is predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions during a demanding task hours later in the afternoon. Reduced prefrontal activity is in turn linked to better working memory performance, implicating that the CAR proactively promotes brain preparedness based on improved neurocognitive efficiency. In Study 2, pharmacologically suppressed CAR using Dexamethasone mirrors this proactive effect, which further causes a selective reduction of prefrontal top-down functional modulation over hippocampal activity. These findings establish a causal link between the CAR and its proactive role in optimizing functional brain networks involved in neuroendocrine control, executive function and memory.Seeing an agent perform an action typically triggers a motor simulation of that action in the observer's Mirror Neuron System (MNS). Over the past few years, it has become increasingly clear that during action observation the patterns and strengths of responses in the MNS are modulated by multiple factors. The first aim of this paper is therefore to provide the most comprehensive survey to date of these factors. To that end, 22 distinct factors are described, broken down into the following sets six involving the action; two involving the actor; nine involving the observer; four involving the relationship between actor and observer; and one involving the context. The second aim is to consider the implications of these findings for four prominent theoretical models of the MNS the Direct Matching Model; the Predictive Coding Model; the Value-Driven Model; and the Associative Model. These assessments suggest that although each model is supported by a wide range of findings, each one is also challenged by other findings and relatively unaffected by still others. Hence, there is now a pressing need for a richer, more inclusive model that is better able to account for all of the modulatory factors that have been identified so far.For several years, a great effort has been devoted to understand how circadian oscillations in physiological processes are determined by the circadian clock system. This system is composed by the master clock at the suprachiasmatic nucleus which sets the pace and tunes peripheral clocks in several organs. It was recently demonstrated that the choroid plexus epithelial cells that compose the blood-cerebrospinal fluid barrier hold a circadian clock which might control their multiple functions with implications for the maintenance of brain homeostasis. However, the choroid plexus activities regulated by its inner clock are still largely unknown. In this review, we propose that several choroid plexus functions might be regulated by the circadian clock, alike in other tissues. We provide evidences that the timing of cerebrospinal fluid secretion, clearance of amyloid-beta peptides and xenobiotics, and the barrier function of the blood-cerebrospinal fluid barrier are regulated by the circadian clock. These data, highlight that the circadian regulation of the blood-cerebrospinal fluid barrier must be taken into consideration for enhancing drug delivery to central nervous system disorders.
Stroke is a major cause of death and disability in the United States. Current acute stroke therapy consists of clot-dissolving drugs, catheter-based interventions and physical rehabilitation. To date, there are no therapies that directly enhance neuronal survival after a stroke. Previous work from our lab demonstrated that Interleukin-15 (IL-15) peptide could rescue cardiomyocytes subjected to hypoxia. We sought to extend these findings to cortical neurons since IL-15 has been implicated to have an important role in neuronal homeostasis.

We have evaluated the effect of IL-15 peptide on primary cortical neurons derived from embryonic rats in vitro under conditions of anoxia and glucose deprivation, and in vivo following middle cerebral artery occlusion.

IL-15 administration rescued neuronal cells subjected to anoxia coupled with glucose deprivation (AGD), as well as with reoxygenation. A hallmark of stroke is the ischemic microenvironment and associated oxidative stress, which results in DNA damage and ER stress, both of which contribute to neuronal cell damage and death. The expression of anoxia, ER stress, and DNA damage factors/markers was evaluated via western blot and correlated with the cellular survival effects of IL-15 in vitro. In addition, IL-15 effect of alleviating ER stress and increasing cell survival was also observed in vivo.

Our data indicate, for the first time, that administration of the pleiotropic factor IL-15 reduces neuronal cell death during AGD, which correlates with modulation of multiple cellular stress pathways.
Our data indicate, for the first time, that administration of the pleiotropic factor IL-15 reduces neuronal cell death during AGD, which correlates with modulation of multiple cellular stress pathways.Understanding the different neural networks that support human language is an ongoing challenge for cognitive neuroscience. Which divisions are capable of distinguishing the functional significance of regions across the language network? A key separation between semantic cognition and phonological processing was highlighted in early meta-analyses, yet these seminal works did not formally test this proposition. Moreover, organization by domain is not the only possibility. Regions may be organized by the type of process performed, as in the separation between representation and control processes proposed within the Controlled Semantic Cognition framework. The importance of these factors was assessed in a series of activation likelihood estimation meta-analyses that investigated which regions of the language network are consistently recruited for semantic and phonological domains, and for representation and control processes. Whilst semantic and phonological processing consistently recruit many overlapping regions, they can be dissociated (by differential involvement of bilateral anterior temporal lobes, precentral gyrus and superior temporal gyri) only when using both formal analysis methods and sufficient data. Both semantic and phonological regions are further dissociable into control and representation regions, highlighting this as an additional, distinct dimension on which the language network is functionally organized. Furthermore, some of these control regions overlap with multiple-demand network regions critical for control beyond the language domain, suggesting the relative level of domain-specificity is also informative. Multiple, distinct dimensions are critical to understand the role of language regions. Here we present a proposal as to the core principles underpinning the functional organization of the language network.Type I interferons (IFN) are central players in the pathogenesis of systemic lupus erythematosus (SLE) and the up-regulation of interferon-stimulated genes (ISGs) in SLE patients is subjected to increasing scrutiny as for its use in diagnosis, stratification and monitoring of SLE patients. Determinants of this immunological phenomenon are yet to be fully charted. The purpose of this systematic review was to characterize expressions of ISGs in blood of SLE patients and to analyze if they associated with core demographic and clinical features of SLE. Twenty cross-sectional, case-control studies comprising 1033 SLE patients and 602 study controls could be included. ISG fold-change expression values (SLE vs controls), demographic and clinical data were extracted from the published material and analyzed by hierarchical cluster analysis and generalized linear modelling. ISG expression varied substantially within each study with IFI27, IFI44, IFI44L, IFIT4 and RSAD2, being the top-five upregulated ISGs. Analysis of inter-study variation showed that IFI27, IFI44, IFI44L, IFIT1, PRKR and RSAD2 expression clustered with the fraction of SLE cases having African ancestry or lupus nephritis. Generalized linear models adjusted for prevalence of lupus nephritis and usage of hydroxychloroquine confirmed the observed association between African ancestry and IFI27, IFI44L, IFIT1, PRKR and RSAD2, whereas disease activity was associated with expression of IFI27 and RNASE2. In conclusion, this systematic review revealed that expression of ISGs often used for deriving an IFN signature in SLE patients were influenced by African ancestry rather than disease activity. This underscores the necessity of taking ancestry into account when employing the IFN signature for clinical research in SLE.Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (rs) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median rs was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples ange and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays.
The purpose of the current study is to compare the outcomes of open subpectoral biceps tenodesis (BT) to arthroscopic repair (AR) for SLAP tears in patients under the age of 30 years.

A retrospective review of patients under the age of 30 years who underwent either isolated BT or AR for a diagnosis of a SLAP tear between 2011 and 2019 was performed. Patients were included if they were >16 years old at the time of surgery, had an isolated SLAP tear involving instability of the biceps-labral anchor (types II-IV), were skeletally mature, and had a minimum follow-up of 12 months. The American Shoulder & Elbow Surgeons score, visual analog scale, Subjective Shoulder Value, patient satisfaction, willingness to undergo surgery again, revisions, and return to play (RTP) were evaluated. A P value of <.05 was considered statistically significant.

Our study included 103 patients in total; 29 patients were treated with BT, and 74 were treated with AR. The mean age was 24.8 years, and the mean follow-up duration was 60 months. At final follow-up, there was no difference between treatment groups in any of the functional outcome measures assessed (P>.05). Overall, there was no significant difference in the total rate of RTP (BT 76.3%, AR 85%; P= .53), timing of RTP (BT 8.8 months, AR 9.4 months; P= .61), and total rate of RTP among overhead athletes (BT 84.2%, AR 83.3%; P>.99). Among those undergoing AR, 9 required a revision procedure (11.5%) compared to none treated with BT (P=.11).

In patients under the age of 30 years with a symptomatic isolated SLAP tear, BT may be a reliable alternative to AR.

Level III, retrospective comparative study.
Level III, retrospective comparative study.
To examine acute postoperative opioid consumption in patients undergoing hip arthroscopy and randomized to either receive a preoperative lateral quadratus lumborum block or sham injection.

This trial randomized 46 subjects undergoing hip arthroscopy with a single surgeon to receive a preoperative lateral quadratus lumborum block (40 mL, ropivacaine 0.25%) or sham injection. The primary outcome was postoperative opioid consumption in patients with and without a block. All opioid medications were converted to morphine milligram equivalents for comparisons. Categorical data were compared with χ
tests and Fisher exact tests where appropriate. Continuous data were compared with 2-sided t-test and Wilcoxon rank-sum tests.

Forty-six subjects scheduled for elective hip arthroscopy were successfully consented and randomized. Demographic and clinical characteristics did not differ. Postoperative opioid consumption decreased 28.3% in patients who received a preoperative lateral quadratus lumborum block (P= .04). Level I, randomized controlled trial.
Level I, randomized controlled trial.
Approximately 73% of children with severe neurological impairment (SNI) can experience episodes of pain and irritability often of unknown origin (PIUO). Limited research exists on how these experiences of PIUO may affect parental caregivers and families. The primary objective of this study was to understand the parental caregiver experience of caring for a child with SNI who experiences persistent PIUO.

We conducted a qualitative study using semi-structured interviews to explore the experience of parental caregivers of children with SNI. Interview guide questions focused on exploring pain behaviours, the diagnostic process, pharmacological and non-pharmacological management, healthcare-team support, discussion surrounding irritability, and family impact. Interviews were conducted until thematic saturation was reached. Interviews were audio-recorded, transcribed verbatim, and coded and analyzed by 2 independent reviewers using thematic analysis.

15 parental caregivers were interviewed, with 93% being motd supportive resources for education and coping for parents.
Patients with advanced cancer often involve family caregivers in health-related decision-making from diagnosis to end-of-life; however, few interventions have been developed to enhance caregiver decision support skills.

Assess the feasibility, acceptability, and potential efficacy of individual intervention components of CASCADE (CAre Supporters Coached to be Adept DEcision Partners), an early telehealth, palliative care coach-led decision support training intervention for caregivers.

Pilot factorial trial using the multiphase optimization strategy (October 2019-October 2020). Family caregivers and their care recipients with newly-diagnosed advanced cancer (n=46 dyads) were randomized to1 of 8 experimental conditions that included a combination of one of the following three CASCADE components 1) effective decision support psychoeducation; 2) decision support communication training; and 3) Ottawa Decision Guide training. Feasibility was assessed by completion of sessions and questionnaires (predefined aswith advanced cancer. CASCADE components were acceptable and the trial design feasible, providing promising future directions for palliative care intervention development and testing. Pilot results will inform a fully-powered trial.
We pilot tested components of CASCADE, an early palliative care decision support training intervention for family caregivers of patients with advanced cancer. CASCADE components were acceptable and the trial design feasible, providing promising future directions for palliative care intervention development and testing. Pilot results will inform a fully-powered trial.
It is important to address fatigue and co-occurring symptoms during chemotherapy to preserve quality of life in patients with gastrointestinal (GI) cancer.

To conduct a randomized controlled pilot study of a Yoga Skills Training (YST) intervention compared to an attention control (AC) among adults diagnosed with GI cancer.

YST consisted of four 30-minute sessions delivered individually during chemotherapy plus home practice. AC provided empathic attention plus home diaries. Patient-reported (PROMIS T-score) assessments of fatigue, depressive symptoms, sleep disturbances, and psychological stress (Perceived Stress Scale) were collected at chemotherapy visits baseline, Week 8, Week 10 and Week 14, and analyzed using a mixed effects model. Inflammatory cytokines were assessed at baseline and Week 10.

Forty-four of 77 adults approached agreed to participate (57%; YST n=23; AC n=21). Participants' mean age was 58 years and 48% were men. Participants randomized to YST reported a larger decline in fatigue (-2.4 difference, d=0.30) and depressive symptoms (-2.5 difference, d=0.30) than AC participants from baseline to Week 10 and sleep disturbances at Week 8 (-3.9 difference, d=0.50). Differences in magnitude of change in symptoms were consistent with or exceeded a minimally important difference. Psychological stress decreased more in the AC at Week 10 (d=0.30). Reductions in inflammatory cytokines (IL-6, sTNF R1) were larger in the YST group than AC.

YST showed promise for improving fatigue, depressive symptoms, sleep disturbances, and inflammation. YST is also feasible and reaches patients underrepresented in yoga research (i.e., GI cancer, men), thus warranting further examination.
YST showed promise for improving fatigue, depressive symptoms, sleep disturbances, and inflammation. YST is also feasible and reaches patients underrepresented in yoga research (i.e., GI cancer, men), thus warranting further examination.Inflammation during pregnancy can disturb brain development and lead to disorders in the progeny, including autism spectrum disorder and schizophrenia. However, the mechanism by which a prenatal, short-lived increase of cytokines results in adverse neurodevelopmental outcomes remains largely unknown. Microglia-the brain's resident immune-cells-stand as fundamental cellular mediators, being highly sensitive and responsive to immune signals, which also play key roles during normal development. The fractalkine signaling axis is a neuron-microglia communication mechanism used to regulate neurogenesis and network formation. Previously, we showed hippocampal reduction of fractalkine receptor (Cx3cr1) mRNA at postnatal day (P) 15 in male offspring exposed to maternal immune activation induced with lipopolysaccharide (LPS) during late gestation, which was concomitant to an increased dendritic spine density in the dentate gyrus, a neurogenic niche. The current study sought to evaluate the origin and impact of this redfractalkine signaling has been recently associated with an increased risk for neurodevelopmental disorders. We show that an acute immune insult during late gestation can alter fractalkine signaling by reducing the microglial CX3CR1 protein expression, highlighting neuron-microglial fractalkine signaling as a relevant target underlying the outcomes of environmental risk factors on neurodevelopmental disorders.While the immune system is essential for survival, an excessive or prolonged inflammatory response, such as that resulting from sustained heavy alcohol use, can damage the host and contribute to psychiatric disorders. A growing body of literature indicates that the immune system plays a critical role in the development and maintenance of alcohol use disorder (AUD). As such, there is enthusiasm for treatments that can restore healthy levels of inflammation as a mechanism to reduce drinking and promote recovery. In this qualitative literature review, we provide a conceptual rationale for immune therapies and discuss progress in medications development for AUD focused on the immune system as a treatment target. This review is organized into sections based on primary signaling pathways targeted by the candidate therapies, namely (a) toll-like receptors, (b) phosphodiesterase inhibitors, (c) peroxisome proliferator-activated receptors, (d) microglia and astrocytes, (e) other immune pharmacotherapies, and (f) behavioral therapies. As relevant within each section, we examine the basic biological mechanisms of each class of therapy and evaluate preclinical research testing the role of the therapy on mitigating alcohol-related behaviors in animal models. To the extent available, translational findings are reviewed with discussion of completed and ongoing randomized clinical trials and their findings to date. An applied and clinically focused approach is taken to identify the potential clinical applications of the various treatments reviewed. We conclude by delineating the most promising candidate treatments and discussing future directions by considering opportunities for immune treatment development and personalized medicine for AUD.Alzheimer's disease (AD) pathology is characterized by amyloid-β (Aβ) deposition and tau hyper-phosphorylation, accompanied by a progressive cognitive decline. Monocytes have been recently shown to play a major role in modulating Aβ pathology, and thereby have been pointed as potential therapeutic targets. However, the main challenge remains in identifying clinically relevant interventions that could modulate monocyte immune functions in absence of undesired off-target effects. Erythropoietin (EPO), a key regulator of erythrocyte production, has been shown to possess immunomodulatory potential and to provide beneficial effects in preclinical models of AD. However, the transition to use recombinant human EPO in clinical trials was hindered by unwanted erythropoietic effects that could lead to thrombosis. Here, we used a recently identified non-erythropoietic analogue of EPO, ARA 290, to evaluate its therapeutic potential in AD therapy. We first evaluated the effects of early systemic ARA 290 administration on ocytes. Our study suggests that ARA 290 early systemic treatment could prevent AD-like progression via modulation of monocyte functions by specifically increasing the ratio of patrolling monocytes.Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard oice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal's ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress.Toll-like receptors (TLRs) participate in the response to infection, stress, and injury by initiating an innate immune response. In addition, these receptors are expressed in many neural cell types and under physiological conditions are implicated in modulating cognitive function and neural plasticity in the adult and aged brain. Knockout of the Toll-like receptor 4 (TLR4) subtype enhances spatial memory and adult hippocampal neurogenesis through increasing proliferation and neuronal differentiation. Currently unknown is whether pharmacological inhibition of TLR4 produces similar enhancements in cognitive function and cell proliferation. The present study evaluated water maze performance, cytokine expression, and cell proliferation in the hippocampus of young and aged male and female C57BL6/J mice following treatment with the TLR4 antagonist, TAK-242. Further, alterations in the response to an acute stressor were evaluated in TAK-242-treated mice. Results showed that TAK-242 selectively enhanced spatial learning and memory in young females. Additionally, TAK-242 treatment reduced thigmotaxis in the water maze and lowered corticosterone levels following acute stress in females. TAK-242 decreased hippocampal interleukin (IL)-1β expression but had no effect on IL-6 or tumor necrosis factor-α (TNFα). Aged mice showed decreased cell proliferation compared to young mice, but TAK-242 administration had minimal effects on estimated Ki67 positive cell numbers. Findings indicate that pharmacological inhibition of TLR4 improves cognitive function in young females likely through attenuating stress reactivity.
To examine whether there was an association of leucocyte telomere length (LTL) with all-cause, cardiovascular (CVD)- and cancer-specific mortality risks among U.S. adults; and whether these associations vary with race and ethnicity and age.

We conducted a retrospective cohort using data from the National Health and Nutrition Examination Survey, 1999 to 2002 and the 2015 Linked Mortality File on adults 25 years or older (n=6,526 and 1,753 deaths). Cox proportional hazards regression was used to quantify the association of LTL with each outcome adjusting for baseline sociodemographic and health-related characteristics. We tested a three-way interaction for LTL, race andethnicity, and age groups.

After adjustment, the rate of dying for all-cause and CVD-specific mortality was at least 24% lower for a 1 kilobase increase in LTL. When compared with adults with the shortest telomere, the rates of dying were at least 17% lower for all-cause and CVD-specific mortality for those with longer telomere. For all-cause mortality, increase LTL was associated with lower rate of dying among non-Hispanic Blacks 45 years or older, and non-Hispanic Whites 65 years or older.

We found that increase telomere length was associated with lower all-cause and CVD-specific mortality rates among U.S. adults. For all-cause mortality, this association varies within racial andethnic groups across age groups.
We found that increase telomere length was associated with lower all-cause and CVD-specific mortality rates among U.S. adults. For all-cause mortality, this association varies within racial andethnic groups across age groups.Antibody-mediated rejection after liver transplantation is an under-recognised cause of allograft injury. While definitions of acute and chronic antibody-mediated rejection have increased clinical awareness, timely identification and management of antibody-mediated rejection remain difficult because of complexities in diagnosis and histopathology, lack of treatment protocols, and unclear long-term outcomes. While recent cohort studies assessing the importance of donor-specific antibodies have aided in its diagnosis, literature on the treatment of antibody-mediated rejection in liver transplantation remain limited to case reports and small series. Further increasing the awareness and timely recognition of antibody-mediated rejection post-liver transplantation is crucial in order to stimulate future research and the development of protocols for its diagnosis and treatment. This review will summarise recent advances in the clinical diagnosis and treatment of antibody-mediated rejection in liver transplantation, as well as some of the histopathologic features (on liver biopsy tissue) of acute and chronic antibody-mediated rejection.The endogenous cannabinoid transmitter system regulates synaptic transmission throughout the nervous system. Unlike conventional transmitters, specific stimuli induce synthesis of endocannabinoids (eCBs) in the postsynaptic neuron, and these travel backwards to modulate presynaptic inputs. In doing so, eCBs can induce short-term changes in synaptic strength and longer-term plasticity. While this eCB regulation is near ubiquitous, it displays major regional and synapse specific variations with different synapse specific forms of short-versus long-term plasticity throughout the brain. These differences are due to the plethora of pre- and postsynaptic mechanisms which have been implicated in eCB signalling, the intricacies of which are only just being realised. In this review, we shall describe the current understanding and highlight new advances in this area, with a focus on the retrograde action of eCBs at CB1 receptors (CB1Rs).
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