Peripheral Lymphoid Volume Expansion and Maintenance Are Controlled by Gut Microbiota via RALDH+ Dendritic Cells.

Lymphocyte homing to draining lymph nodes is critical for the initiation of immune responses. Secondary lymphoid organs of germ-free mice are underdeveloped. How gut commensal microbes remotely regulate cellularity and volume of secondary lymphoid organs remains unknown. We report here that, driven by commensal fungi, a wave of CD45(+)CD103(+)RALDH(+) cells migrates to the peripheral lymph nodes after birth. The arrival of these cells introduces high amounts of retinoic acid, mediates the neonatal to adult addressin switch on endothelial cells, and directs the homing of lymphocytes to both gut-associated lymphoid tissues and peripheral lymph nodes. In adult mice, a small number of these RALDH(+) cells might serve to maintain the volume of secondary lymphoid organs. Homing deficiency of these cells was associated with lymph node attrition in vitamin-A-deficient mice, suggesting a perpetual dependence on retinoic acid signaling for structural and functional maintenance of peripheral immune organs.

The Effects of Carvedilol on Cardiac Function and the AKT/XIAP Signaling Pathway in Diabetic Cardiomyopathy Rats.

OBJECTIVES: Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction, myocardial inflammation, interstitial fibrosis and cardiomyocytes apoptosis. The present study aimed to investigate the effects of carvedilol on cardiac function and the AKT/XIAP signaling pathway in DCM rats. METHODS: Male Wistar rats were randomly divided into 3 groups: the control group, diabetic mellitus (DM) group and DM with carvedilol treatment group. DM rats were induced by streptozotocin accompanied by high energy intake. Carvedilol was orally administered at a dose of 10 mg/kg/day. After 16 weeks, the interrelated blood data were detected by biochemical analysis. Cardiac function was evaluated by echocardiography and the serum NT-proBNP level. The changes of myocardium ultrastructural and fibrosis were determined by electron microscopy and Masson's staining. Apoptotic cells were examined by TUNEL staining and interrelated proteins were measured by immunohistochemical and Western blots. RESULTS: Rats in the DM group showed significant serum elevation of glucose, cholesterol, triglyceride, NT-proBNP, IL-1ß and TNF-α, along with decreased cardiac function. Moreover, in the DM group, the levels of myocardial apoptosis and fibrosis were all increased accompanied by upregulation of caspase-3 and downregulation of phos-AKT and phos-XIAP, whereas carvedilol treatment prevented or reversed all the changes without influencing plasma levels of glucose, cholesterol and triglyceride. CONCLUSIONS: The AKT/XIAP signaling pathway may be involved in DCM. Carvedilol can improve cardiac function, possibly not only by upregulating the AKT/XIAP antiapoptotic signaling pathway and subsequently attenuating myocardial fibrosis, but also through suppressing the myocardial inflammation response.

High glucose exacerbates neuroinflammation and apoptosis at the intermediate stage after post-traumatic brain injury.

Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. In vitro assays were used to assess inflammatory factor expression, apoptotic protein levels and neuronal survival after MEK5 activation in TBI- and/or high-glucose-treated neurons. MEK5/extracellular signal-regulated kinase 5 (ERK5) pathway activation reduced the inflammation, cleaved caspase-3 expression, Bax/Bcl-2 ratio and apoptosis of TBI neurons, even under high-glucose conditions. Thus, high glucose exacerbated neuroinflammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway.

Astrocyte-derived exosomes protect hippocampal neurons after traumatic brain injury by suppressing mitochondrial oxidative stress and apoptosis.

In this study, we investigated the mechanisms through which astrocyte-derived exosomes (AS-Exos) alleviate traumatic brain injury (TBI)-induced neuronal defects in TBI model rats and mice. Treatment with AS-Exos alleviated neurobehavioral deficits, cognitive impairment, and brain edema in TBI rats. AS-Exos also significantly reduced neuronal cell loss and atrophy in the TBI rats. AS-Exos significantly reduced oxidative stress and mitochondrial H2O2 levels by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in the hippocampal neurons of TBI rats. TUNEL-staining assays showed that AS-Exos significantly reduced TBI-induced neuronal apoptosis. Mechanistically, AS-Exos ameliorated oxidative stress by activating Nrf2/HO-1 signaling in the hippocampus of TBI rats. In addition, the neuroprotective effects of AS-Exos were abrogated in brain-specific Nrf2-knockout mice subjected to TBI. These findings demonstrate that AS-Exos protects against TBI-induced oxidative stress and neuronal apoptosis by activating Nrf2 signaling in both rat and mouse models.

Long-term outcomes of non-systematic device reimplantation following lead extraction in selected patients.

Following the removal of cardiovascular implantable electronic devices (CIEDs), reassessment of the need for a new device is vital. Some patients may have exhibited an improvement in rhythm or cardiac function and may thus no longer meet the guideline requirements for reimplantation. However, the long-term outcomes of non-systematic device reimplantation remain unknown. In the present study, it was hypothesized that the implantation of pacing systems in selected patients following lead extraction is safe. In order to confirm this hypothesis, a total of 854 patients (aged between 28 and 82 years) who underwent the removal of a CIED were enrolled in the present study and they were all reassessed to determine whether a new device following lead extraction was necessary. In order to determine which patients would undergo non-systematic device reimplantation, the standard guidelines, the criteria and the wishes of the patient were all taken into consideration. Patients remained device-free unless an adverse clinical event occurred that required reimplantation. The primary study endpoint was the rate of sudden death or reimplantation. Between January, 2014 and December, 2019, 854 consecutive patients underwent pacing system extraction, of whom 210 patients (24.6%) underwent non-systematic device reimplantation following careful reassessment (the non-reimplantation group). Among the 210 patients, 162 (77.1%) were fitted with pacemakers, 26 (12.4%) underwent cardiac resynchronization therapy or cardiac resynchronization therapy-defibrillator and 22 (10.5%) were implanted with a cardioverter-defibrillator. During a mean follow-up period of 40.4 months, 86 patients reached the primary endpoint of the study, including 54 out of 210 patients (25.7%) who experienced an adverse clinical event that required reimplantation and 32 out of 210 patients (15.2%) who experienced sudden death. Reimplantation of a new device was not required in ~25% of the patients. On the whole, the present study demonstrates that following pacing system removal, non-systematic device reimplantation associated with close surveillance is safe for selected patients.

Investigation of sag behaviour for aluminium conductor steel reinforced considering tensile stress distribution.

Sag calculation plays an important role in overhead line design. Since the tensile stress of aluminium conductor steel reinforced (ACSR) is required for the sag calculation, an analysis on sag behaviour when considering the tensile stress distribution can be very useful to improve the accuracy of sag results. First, this paper analyses the ACSR tensile stress distribution arising from the temperature maldistribution through proposing a new calculation formula. A finite-element analysis (FEA) model of ACSR is conducted for the solution of the new formula. By using the results, the error and limitations of the existing sag calculation methods for ACSR are discussed. As the critical point of sag calculation, knee-point temperature is solved iteratively involving the tensile stress maldistribution phenomenon in aluminium wires. Based on this iterative solution, an improved analytical method for the ACSR sag calculation considering the creep effect is presented and also compared with the hybrid sag method. The results show that these two methods are basically coincident without the consideration of creep effect, while there are non-negligible differences between them as the creep strain is involved. Compared with the existing analytical methods, the improved sag calculation method proposed in this paper can be applied in more extensive situations.

Cardiac resynchronization therapy coronary venous left ventricular lead removal and reimplantation: Experience from a single center in China.

The present study aimed to investigate the success rate, methods and associated complications of left ventricular lead (LVL) extraction and venous pathway reimplantation in patients with cardiac resynchronization therapy device/defibrillator (CRT/CRTD). A retrospective analysis was performed in the patients who underwent CRT/CRTD extraction and reimplantation at our hospital from January 2012 to October 2018. The methods, patient complications and success rate of extraction and reimplantation of LVL were analyzed. A total of 54 patients underwent CRT/CRTD removal (pacemaker infection, n=51; LVL dysfunction, n=3; CRT/CRTD, 34/20). A total of 54 LVLs were removed (3 active electrodes and 51 passive electrodes). The average implantation duration of the LVL was 53.5 months (range, 1-204 months), whereas the success rate of the LVL extraction was 100% (94% completely removed and 6% clinically removed. A total of 6 patients (11%) were treated only by manual traction, whereas the remaining patients had their LVL successfully removed using extraction tools. In the peri-operative period, one fatality occurred (2%). The highest complication rate of the lead extraction was 2% and no minor complications were observed. A total of 36 patients were reimplanted on the right side, which was successful in 31 cases (success rate, 86.1%), whereas 3 cases were successfully reimplanted on the left side. The total success rate of LVL reimplantation was 87.2%. The procedure of the LVL removal and reimplantation exhibited a high success rate and a lower incidence of complications compared with that in patients with cardiac devices.

Carvedilol alleviates diabetic cardiomyopathy in diabetic rats.

Diabetic cardiomyopathy (DCM) is characterized by structural and functional changes in the myocardium. Several studies have revealed that myocardial apoptosis and fibrosis occur during DCM. Studies have also indicated that oxidative stress may be a major factor associated with the development of DCM. Protein kinase C (PKC)ß2 has been demonstrated to be activated in diabetic rats, and overexpression of PKCß2 in the myocardium may result in cardiac hypertrophy and fibrosis. The P66shc adaptor protein, which is mediated by PKCß, serves an important role in apoptosis during oxidative stress. The aim of the present study was to investigate whether the PKCß2/P66shc oxidative stress pathway is associated with DCM, and to investigate the role and mechanisms of carvedilol in preserving cardiac function. Experimental diabetic rat models were induced by streptozotocin treatment accompanied by high energy intake. Carvedilol was orally administrated at a dose of 1 or 10 mg/kg/day. Cardiac function was evaluated by serum N-terminal pro-B-type natriuretic peptide level and cardiac ultrasound. Myocardial inflammation, oxidative stress, apoptosis and fibrosis were assessed by histopathological and echocardiographic analyses and tests for oxidative markers. Associated proteins and factors were examined by immunohistochemical and western blot analyses. Rats in the diabetes mellitus group exhibited significantly decreased systolic cardiac function along with elevated expression levels of phosphorylated (p)-PKCß2, phos-P66shc, caspase-3, malondialdehyde, collagen type I, tumor necrosis factor-α and interleukin-1ß, which were accompanied by disorder in metabolic processes. Treatment with carvedilol reversed these changes. Thus, the present results suggest that the PKCß2/P66shc signaling pathway may be associated with diabetic cardiomyopathy; furthermore, carvedilol, as a novel ß-receptor blocker, may protect the myocardium from injury by suppressing the myocardial inflammatory response, fibrosis, P66shc-mediated oxidative stress and subsequent apoptosis in myocardial tissue. Consequently, carvedilol may have potential as a therapy for the treatment of DCM.

Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.

Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.

Strong adhesion by regulatory T cells induces dendritic cell cytoskeletal polarization and contact-dependent lethargy.

Dendritic cells are targeted by regulatory T (T reg) cells, in a manner that operates as an indirect mode of T cell suppression. In this study, using a combination of single-cell force spectroscopy and structured illumination microscopy, we analyze individual T reg cell-DC interaction events and show that T reg cells exhibit strong intrinsic adhesiveness to DCs. This increased DC adhesion reduces the ability of contacted DCs to engage other antigen-specific cells. We show that this unusually strong LFA-1-dependent adhesiveness of T reg cells is caused in part by their low calpain activities, which normally release integrin-cytoskeleton linkage, and thereby reduce adhesion. Super resolution imaging reveals that such T reg cell adhesion causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation, and skews Fascin-1-dependent actin polarization in DCs toward the T reg cell adhesion zone. Although it is reversible upon T reg cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. Our results reveal a dynamic cytoskeletal component underlying T reg cell-mediated DC suppression in a contact-dependent manner.

Multiple characteristics analysis of Alzheimer's electroencephalogram by power spectral density and Lempel-Ziv complexity.

To investigate the electroencephalograph (EEG) background activity in patients with Alzheimer's disease (AD), power spectrum density (PSD) and Lempel-Ziv (LZ) complexity analysis are proposed to extract multiple effective features of EEG signals from AD patients and further applied to distinguish AD patients from the normal controls. Spectral analysis based on autoregressive Burg method is first used to quantify the power distribution of EEG series in the frequency domain. Compared with the control group, the relative PSD of AD group is significantly higher in the theta frequency band while lower in the alpha frequency bands. In order to explore the nonlinear information, Lempel-Ziv complexity (LZC) and multi-scale LZC is further applied to all electrodes for the four frequency bands. Analysis results demonstrate that the group difference is significant in the alpha frequency band by LZC and multi-scale LZC analysis. However, the group difference of multi-scale LZC is much more remarkable, manifesting as more channels undergo notable changes, particularly in electrodes O1 and O2 in the occipital area. Moreover, the multi-scale LZC value provided a better classification between the two groups with an accuracy of 85.7 %. In addition, we combine both features of the relative PSD and multi-scale LZC to discriminate AD patients from the normal controls by applying a support vector machine model in the alpha frequency band. It is indicated that the two groups can be clearly classified by the combined feature. Importantly, the accuracy of the classification is higher than that of any one feature, reaching 91.4 %. The obtained results show that analysis of PSD and multi-scale LZC can be taken as a potential comprehensive measure to distinguish AD patients from the normal controls, which may benefit our understanding of the disease.

[Metagenomic analysis of bat virome in several Chinese regions].

Bats are important reservoir animals and more than 60 viruses have been identified in bats with many of them highly pathogenic to human. In order to understand the natural background, genetic diversity of bat viruses in China and discover potential viral pathogens, Solexa sequencing based viral metagenomics focusing on bats tissues was established and to analyze the virome of bats collected from Jilin, Yunnan and Hunan province. By Solexa sequencing, 116 442 324 useful reads were obtained and assembled into 4 872 contigs, of which 8.2% (4 002/4 4872) were annotated to 36 viral families, including 19 vertebrate virus families, 6 plant virus families, 4 insect virus families and 4 phages. Further contigs analyses showed that some adenovirus, bocavirus, picobirnavirus, parvovirus contigs sequences were similar with known viruses. However, part of them shared limited identities to these viruses implying the discovery of new viruses. Moreover, PCR validation of adenovirus and bocavirus confirmed the results obtained by viral metagenomics. This study aimed to understand bat virome in China by viral metagenomics and could be helpful to establish effective surveillance on wildlife-associate zoonoses.