Background
On the basis of the importance of the enteric nervous system (ENS) in gastrointestinal motility, we hypothesized that the ENS may mediate the therapeutic efficacy of electro‐acupuncture ...(EA) in constipation by regulating the mechanisms underlying the effects of EA on gastrointestinal function.
Methods
Model mice with constipation were generated by gastric instillation of 0‐4°C normal saline. Defecation time and stool (form and wet and dry weight) were assessed. The effect of EA at ST37 or ST25 on colorectal motility and proximal colonic motility was assessed using a water‐filled balloon. The expression of protein gene product 9.5 (PGP9.5), the cholinergic neuron marker acetyltransferase (ChAT) and the anticholinergic neuron marker nitric oxide synthase (nNOS) was detected by immunohistochemistry, real‐time quantitative polymerase chain reaction (qPCR) and western blot analysis.
Key Results
ST37 and ST25 improved colorectal pressure; however, ST37 but not ST25 improved proximal colonic pressure. In the proximal colon, the expression of PGP9.5 returned to normal after EA at ST 37, while EA at ST25 did not have this effect. In addition, qPCR and western blot analysis showed that ST37 could downregulate the expression of nNOS and upregulate the expression of ChAT to normal levels, while ST25 could only downregulate the expression of nNOS to normal levels.
Conclusions and Inferences
Electro‐acupuncture at specific acupoints can improve intestinal motility in constipation by altering the ENS and differentially affecting excitatory and inhibitory neurons, restoring the coordination between contraction and relaxation muscles, and working in concert with the central nervous system and peripheral neural pathways.
EA stimulation at either ST 37 or ST 25 relieves the symptoms of constipation, but has different effects in the proximal colon. ST 37 alters both excitatory and inhibitory enteric neurons, while ST 25 only influences inhibitory neurons.
Psychosocial stress contributes to the development of anxiety and depression. Recent clinical studies have reported increased inflammatory leukocytes in circulation of individuals with stress-related ...psychiatric disorders. Parallel to this, our work in mice shows that social stress causes release of inflammatory monocytes into circulation. In addition, social stress caused the development of prolonged anxiety that was dependent on inflammatory monocytes in the brain. Therefore, we hypothesize that chronic stress drives the production of inflammatory monocytes that are actively recruited to the brain by microglia, and these monocytes augment neuroinflammatory signaling and prolong anxiety. Here we show that repeated social defeat stress in mice activated threat appraisal centers in the brain that spatially coincided with microglial activation and endothelial facilitation of monocyte recruitment. Moreover, microglial depletion with a CSF1R antagonist prior to stress prevented the recruitment of monocytes to the brain and abrogated the development of anxiety. Cell-specific transcriptional profiling revealed that microglia selectively enhanced CCL2 expression, while monocytes expressed the pro-inflammatory cytokine interleukin-1β (IL-1β). Consistent with these profiles, the recruited inflammatory monocytes with stress adhered to IL-1R1
neurovascular endothelial cells and this interaction was blocked by microglial depletion. Furthermore, disruption of IL-1β signaling by caspase-1
specifically within bone marrow-derived cells revealed that monocytes promoted anxiogenesis through stimulation of neurovascular IL-1R1 by IL-1β. Collectively, the development of anxiety during stress was caused by microglial recruitment of IL-1β-producing monocytes, which stimulated brain endothelial IL-1R1. Thus, monocyte IL-1β production represents a novel mechanism that underlies behavioral complications associated with stress-related psychiatric disorders.
Solid tumors often exhibit simultaneously inflammatory and hypoxic microenvironments. The 'signal transducer and activator of transcription-3' (STAT3)-mediated inflammatory response and the ...hypoxia-inducible factor (HIF)-mediated hypoxia response have been independently shown to promote tumorigenesis through the activation of HIF or STAT3 target genes and to be indicative of a poor prognosis in a variety of tumors. We report here for the first time that STAT3 is involved in the HIF1, but not HIF2-mediated hypoxic transcriptional response. We show that inhibiting STAT3 activity in MDA-MB-231 and RCC4 cells by a STAT3 inhibitor or STAT3 small interfering RNA significantly reduces the levels of HIF1, but not HIF2 target genes in spite of normal levels of hypoxia-inducible transcription factor 1α (HIF1α) and HIF2α protein. Mechanistically, STAT3 activates HIF1 target genes by binding to HIF1 target gene promoters, interacting with HIF1α protein and recruiting coactivators CREB binding protein (CBP) and p300, and RNA polymerase II (Pol II) to form enhanceosome complexes that contain HIF1α, STAT3, CBP, p300 and RNA Pol II on HIF1 target gene promoters. Functionally, the effect of STAT3 knockdown on proliferation, motility and clonogenic survival of tumor cells in vitro is phenocopied by HIF1α knockdown in hypoxic cells, whereas STAT3 knockdown in normoxic cells also reduces cell proliferation, motility and clonogenic survival. This indicates that STAT3 works with HIF1 to activate HIF1 target genes and to drive HIF1-depedent tumorigenesis under hypoxic conditions, but also has HIF-independent activity in normoxic and hypoxic cells. Identifying the role of STAT3 in the hypoxia response provides further data supporting the effectiveness of STAT3 inhibitors in solid tumor treatment owing to their usefulness in inhibiting both the STAT3 and HIF1 pro-tumorigenic signaling pathways in some cancer types.
Anisotropic bursts of gravitational radiation produced by events such as supermassive black hole mergers leave permanent imprints on space. Such gravitational wave 'memory' (GWM) signals are, in ...principle, detectable through pulsar timing as sudden changes in the apparent pulse frequency of a pulsar. If an array of pulsars is monitored as a GWM signal passes over the Earth, the pulsars would simultaneously appear to change pulse frequency by an amount that varies with their sky position in a quadrupolar fashion. Here, we describe a search algorithm for such events and apply the algorithm to approximately six years of data from the Parkes Pulsar Timing Array. We find no GWM events and set an upper bound on the rate for events which could have been detected. We show, using simple models of black hole coalescence rates, that this non-detection is not unexpected.
Developing low-cost and biodegradable piezoelectric nanogenerators is of great importance for a variety of applications, from harvesting low-grade mechanical energy to wearable sensors. Many of the ...most widely used piezoelectric materials, including lead zirconate titanate (PZT), suffer from serious drawbacks such as complicated synthesis, poor mechanical properties (e.g., brittleness), and toxic composition, limiting their development for biomedical applications and posing environmental problems for their disposal. Here, we report a low-cost, biodegradable, biocompatible, and highly compressible piezoelectric nanogenerator based on a wood sponge obtained with a simple delignification process. Thanks to the enhanced compressibility of the wood sponge, our wood nanogenerator (15 × 15 × 14 mm3, longitudinal × radial × tangential) can generate an output voltage of up to 0.69 V, 85 times higher than that generated by native (untreated) wood, and it shows stable performance under repeated cyclic compression (≥600 cycles). Our approach suggests the importance of increased compressibility of bulk materials for improving their piezoelectric output. We demonstrate the versatility of our nanogenerator by showing its application both as a wearable movement monitoring system (made with a single wood sponge) and as a large-scale prototype with increased output (made with 30 wood sponges) able to power simple electronic devices (a LED light, a LCD screen). Moreover, we demonstrate the biodegradability of our wood sponge piezoelectric nanogenerator by studying its decomposition with cellulose-degrading fungi. Our results showcase the potential application of a wood sponge as a sustainable energy source, as a wearable device for monitoring human motions, and its contribution to environmental sustainability by electronic waste reduction.
In this trial, women between the ages of 60 and 90 with low bone mineral density received twice-yearly subcutaneous injections of denosumab, a fully human monoclonal antibody against the receptor ...activator of nuclear factor-κB ligand, which inhibits the development and activity of osteoclasts, or placebo. Denosumab was associated with a reduced risk of vertebral, nonvertebral, and hip fractures.
Women between the ages of 60 and 90 with low bone mineral density received twice-yearly subcutaneous injections of denosumab, which inhibits the development and activity of osteoclasts, or placebo. Denosumab was associated with a reduced risk of vertebral, nonvertebral, and hip fractures.
Fractures are a major cause of disability and health care costs.
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The use of denosumab is a novel approach to fracture prevention. It is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), a cytokine that is essential for the formation, function, and survival of osteoclasts.
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By binding RANKL, denosumab prevents the interaction of RANKL with its receptor, RANK, on osteoclasts and osteoclast precursors and reversibly inhibits osteoclast-mediated bone resorption.
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In previous trials, the subcutaneous administration of 60 mg of denosumab every 6 months reduced bone turnover and increased bone mineral density.
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We . . .
Electron inflow and outflow velocities during magnetic reconnection at and near the dayside magnetopause are measured using satellites from NASA's Magnetospheric Multiscale (MMS) mission. A case ...study is examined in detail, and three other events with similar behavior are shown, with one of them being a recently published electron‐only reconnection event in the magnetosheath. The measured inflow speeds of 200–400 km/s imply dimensionless reconnection rates of 0.05–0.25 when normalized to the relevant electron Alfvén speed, which are within the range of expectations. The outflow speeds are about 1.5–3 times the inflow speeds, which is consistent with theoretical predictions of the aspect ratio of the inner electron diffusion region. A reconnection rate of 0.04 ± 25% was obtained for the case study event using the reconnection electric field as compared to the 0.12 ± 20% rate determined from the inflow velocity.
Key Points
Electron inflow velocities are determined for reconnection at the magnetopause and in the magnetosheath
For four events inflow velocities of 200–400 km/s imply normalized reconnection rates of 0.05–0.25
Reconnection rates using electron inflow velocities (0.12) and the reconnection electric field (0.04) are compared for one event
Plain Language Summary
When the solar wind impacts the Earth's magnetosphere, an explosive energy conversion process called magnetic reconnection opens the door for solar wind energy to enter the magnetosphere by interconnection of the magnetic fields of the solar wind and of Earth. In this process, magnetic energy is converted to charged‐particle energy. Magnetic reconnection is fairly well understood at large scales and even down to the ion scale. However, the breaking and linking of field lines and the acceleration of electrons occur at much smaller scales, which are only recently being accessed by the NASA Magnetospheric Multiscale mission. This paper analyzes the speed at which electrons flow into and out of reconnection sites. The inflow speeds are crucial because they provide a measurement of the rate at which reconnection proceeds.
Production and maintenance of virus‐free planting materials is pivotal for the control of viral diseases. The present study attempted to test exogenous application of melatonin for eradication of ...apple stem grooving virus (ASGV) from virus‐infected in vitro shoots of apple cultivar Gala. Exogenous application of 15 μm melatonin to the shoot proliferation medium significantly increased the number of shoots and shoot length. The level of endogenous indole‐3‐acetic acid (IAA) was the highest in the shoots proliferating on the shoot proliferation medium containing 15 μm melatonin. Shoot regrowth levels were significantly higher in shoot tips of the virus‐infected shoots cultured for 4 weeks on this medium than the control. In addition, culture of shoot tips of the virus‐infected in vitro shoots proliferated for 4 weeks on this medium resulted in 95% of shoots being virus‐free, while no virus‐free shoots were obtained in shoot tips of the virus‐infected shoots cultured without melatonin. Analyses by microtissue direct RT‐PCR and RT‐qPCR showed that ASGV concentration decreased in shoot tips of the virus‐infected shoots proliferating on the medium containing 15 μm melatonin for 4 weeks. Virus localization showed that exogenous application of melatonin enlarged the virus‐free area in the virus‐infected shoot tips. These data provide explanations as to why exogenous application of melatonin can efficiently eradicate ASGV. Exogenous application of melatonin provides an alternative means for plant virus eradication and has the potential to produce virus‐free plants.
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•We created a dataset of chemicals in consumer products (CP) using public data.•Nearly 1800 unique substances in 350 generic CP use categories were identified.•Generic CP formulations ...inform individual product compositions.•We identified clusters of trace, intermediate and ubiquitous chemical exposures.•Overlap with 70% of NHANES classes points to CP as a major chemical exposures source.
Consumer products are a primary source of chemical exposures, yet little structured information is available on the chemical ingredients of these products and the concentrations at which ingredients are present. To address this data gap, we created a database of chemicals in consumer products using product Material Safety Data Sheets (MSDSs) publicly provided by a large retailer. The resulting database represents 1797 unique chemicals mapped to 8921 consumer products and a hierarchy of 353 consumer product “use categories” within a total of 15 top-level categories. We examine the utility of this database and discuss ways in which it will support (i) exposure screening and prioritization, (ii) generic or framework formulations for several indoor/consumer product exposure modeling initiatives, (iii) candidate chemical selection for monitoring near field exposure from proximal sources, and (iv) as activity tracers or ubiquitous exposure sources using “chemical space” map analyses. Chemicals present at high concentrations and across multiple consumer products and use categories that hold high exposure potential are identified. Our database is publicly available to serve regulators, retailers, manufacturers, and the public for predictive screening of chemicals in new and existing consumer products on the basis of exposure and risk.
Submicron aerosol was analyzed during the MILAGRO field campaign in March 2006 at the T0 urban supersite in Mexico City with a High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-ToF-AMS) ...and complementary instrumentation. Mass concentrations, diurnal cycles, and size distributions of inorganic and organic species are similar to results from the CENICA supersite in April 2003 with organic aerosol (OA) comprising about half of the fine PM mass. Positive Matrix Factorization (PMF) analysis of the high resolution OA spectra identified three major components: chemically-reduced urban primary emissions (hydrocarbon-like OA, HOA), oxygenated OA (OOA, mostly secondary OA or SOA), and biomass burning OA (BBOA) that correlates with levoglucosan and acetonitrile. BBOA includes several very large plumes from regional fires and likely also some refuse burning. A fourth OA component is a small local nitrogen-containing reduced OA component (LOA) which accounts for 9% of the OA mass but one third of the organic nitrogen, likely as amines. OOA accounts for almost half of the OA on average, consistent with previous observations. OA apportionment results from PMF-AMS are compared to the PM2.5 chemical mass balance of organic molecular markers (CMB-OMM, from GC/MS analysis of filters). Results from both methods are overall consistent. Both assign the major components of OA to primary urban, biomass burning/woodsmoke, and secondary sources at similar magnitudes. The 2006 Mexico City emissions inventory underestimates the urban primary PM2.5 emissions by a factor of ~4, and it is ~16 times lower than afternoon concentrations when secondary species are included. Additionally, the forest fire contribution is at least an order-of-magnitude larger than in the inventory.
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