Aims/hypothesis
Kisspeptin is a novel peptide identified as an endogenous ligand of the G-protein-coupled receptor 54 (GPR-54), which plays a crucial role in puberty and reproductive function. High ...levels of GPR-54 and kisspeptin have been reported in the pancreas and we have previously shown that kisspeptin potentiates glucose-induced insulin release from isolated islets, although the mechanisms underlying this effect were unclear.
Methods
Insulin secretion from isolated mouse islets was measured to characterise the effects of kisspeptin. The effects of kisspeptin on both p42/44 mitogen-activated protein kinase (MAPK) phosphorylation and intracellular Ca
2+
(Ca
2+
i
) in mouse islets were also investigated. Furthermore, kisspeptin was administered to rats in vivo and effects on plasma insulin levels measured.
Results
In the current study, kisspeptin induced a concentration-dependent potentiation of glucose-induced (20 mmol/l) insulin secretion from mouse islets, with maximal effects at 1 µmol/l, but had no effect on insulin secretion at a substimulatory concentration of glucose (2 mmol/l). Activation of GPR-54 by kisspeptin also caused reversible increases in Ca
2+
i
in Fura-2 loaded dispersed islet cells. The kisspeptin-induced potentiation of glucose-induced insulin secretion was completely abolished by inhibitors of phospholipase C and p42/44 MAPK, but not by inhibitors of protein kinase C or p38 MAPK. Intravenous administration of kisspeptin into conscious, unrestrained rats caused an increase in circulating insulin levels, whilst central administration of kisspeptin had no effect, indicating a peripheral site of action.
Conclusions/interpretation
These observations suggest that neither typical protein kinase C isoforms nor p38 MAPK are involved in the potentiation of glucose-induced insulin release by kisspeptin, but intracellular signalling pathways involving phospholipase C, p42/44 MAPK and increased Ca
2+
i
are required for the stimulatory effects on insulin secretion. The observation that kisspeptin is also capable of stimulating insulin release in vivo supports the conclusion that kisspeptin is a regulator of beta cell function.
•Managed forests are 50years younger and have 50% lower C stocks than unmanaged.•Management factors shift allocation from fine roots and symbionts to woody biomass.•Many forest soils have a negative ...annual carbon balance, more so in managed forests.•Harvest disturbance has long-lasting effects on soil carbon decomposition.•Managing forests for productivity or C sequestration requires different approaches.
With an increasing fraction of the world’s forests being intensively managed for meeting humanity’s need for wood, fiber and ecosystem services, quantitative understanding of the functional changes in these ecosystems in comparison with natural forests is needed. In particular, the role of managed forests as long-term carbon (C) sinks and for mitigating climate change require a detailed assessment of their carbon cycle on different temporal scales. In the current review we assess available data on the structure and function of the world’s forests, explore the main differences in the C exchange between managed and unmanaged stands, and explore potential physiological mechanisms behind both observed and expected changes. Two global databases that include classification for management indicate that managed forests are about 50years younger, include 25% more coniferous stands, and have about 50% lower C stocks than unmanaged forests. The gross primary productivity (GPP) and total net primary productivity (NPP) are the similar, but relatively more of the assimilated carbon is allocated to aboveground pools in managed than in unmanaged forests, whereas allocation to fine roots and rhizosymbionts is lower. This shift in allocation patterns is promoted by increasing plant size, and by increased nutrient availability. Long-term carbon sequestration potential in soils is assessed through the ratio of heterotrophic respiration to total detritus production, which indicates that (i) the forest soils may be losing more carbon on an annual basis than they regain in detritus, and (ii) the deficit appears to be greater in managed forests. While climate change and management factors (esp. fertilization) both contribute to greater carbon accumulation potential in the soil, the harvest-related increase in decomposition affects the C budget over the entire harvest cycle. Although the findings do not preclude the use of forests for climate mitigation, maximizing merchantable productivity may have significant carbon costs for the soil pool. We conclude that optimal management strategies for maximizing multiple benefits from ecosystem services require better understanding of the dynamics of belowground allocation, carbohydrate availability, heterotrophic respiration, and carbon stabilization in the soil.
Multiplexed bead-based assays that use Luminex® xMAP® technology have become popular for measuring antibodies against proteins of interest in many fields, including malaria and more recently ...SARS-CoV-2/COVID-19. There are currently two formats that are widely used: non-magnetic beads or magnetic beads. Data are lacking regarding the comparability of results obtained using these two types of beads, and for assays run on different instruments. Whilst non-magnetic beads can only be run on flow-based instruments (such as the Luminex® 100/200™ or Bio-Plex® 200), magnetic beads can be run on both these and the newer MAGPIX® instruments. In this study we utilized a panel of purified recombinant Plasmodium vivax proteins and samples from malaria-endemic areas to measure P. vivax-specific IgG responses using different combinations of beads and instruments. We directly compared: i) non-magnetic versus magnetic beads run on a Bio-Plex® 200, ii) magnetic beads run on the Bio-Plex® 200 versus MAGPIX® and iii) non-magnetic beads run on a Bio-Plex® 200 versus magnetic beads run on the MAGPIX®. We also performed an external comparison of our optimized assay. We observed that IgG antibody responses, measured against our panel of P. vivax proteins, were moderately-strongly correlated in all three of our comparisons (pearson r>0.5 for 18/19 proteins), however higher amounts of protein were required for coupling to magnetic beads. Our external comparison indicated that results generated in different laboratories using the same coupled beads are also highly comparable (pearson r>0.7), particularly if a reference standard curve is used.
B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease.
To elucidate the involvement of B cells in Crohn's disease, ...we here performed an 'in depth' analysis of intestinal and blood B-cells in this chronic inflammatory disease.
Patients with Crohn's disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.
Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.
B cells in patients with Crohn's disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFα-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn's disease, which could be targeted with new therapeutics that specifically regulate B-cell function.
Multiple myeloma is a plasma cell disorder that is characterised by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal paraprotein in the blood or urine and associated ...organ dysfunction. It accounts for approximately 1% of cancers and 13% of haematological cancers. Myeloma arises from an asymptomatic proliferation of monoclonal plasma cells termed monoclonal gammopathy of undetermined significance (MGUS).
MicroRNA expression profiling of serum samples was performed on three patient groups as well as normal controls. Validation of the nine microRNAs detected as promising biomarkers was carried out using TaqMan quantitative reverse transcription PCR. MicroRNA levels in serum were normalised using standard curves to determine the numbers of microRNAs per μl of serum.
Three serum microRNAs, miR-720, miR-1308 and miR-1246, were found to have potential as diagnostic biomarkers in myeloma. Use of miR-720 and miR-1308 together provides a powerful diagnostic tool for distinguishing normal healthy controls, as well as patients with unrelated illnesses, from pre-cancerous myeloma and myeloma patients. In addition, the combination of miR-1246 and miR-1308 can distinguish MGUS from myeloma patients.
We have developed a biomarker signature using microRNAs extracted from serum, which has potential as a diagnostic and prognostic tool for multiple myeloma.
Freshwater mussels are frequently found in rivers receiving effluent from wastewater treatment plants (WWTP), and there is strong evidence that poor water quality is deleterious to freshwater mussel ...populations. WWTPs are among the main sources of pharmaceuticals and personal care products (PPCPs) in surface waters. We monitored 145 PPCPs in wild and caged mussels both upstream and downstream of the Kitchener WWTP in the Grand River, Ontario, as well as 118 PPCPs in water samples. Our objectives were to characterize the seasonal changes in PPCP concentrations in water, to calculate bioaccumulation factors (BAFs) of PPCPs in mussels, and to determine the chemical and physical properties of PPCPs driving the bioaccumulation. Seventy PPCPs were detected in water, and concentrations were highest in the summer or early fall, which corresponded to low river flow. Forty-three PPCPs from many pharmaceutical classes were detected in mussel tissues, including stimulants, a contrasting agent, anti-inflammatory drugs, anti-bacterial agents, antibiotics, antidepressants, antihistamines, progestins, and illicit drugs such as cocaine and amphetamines. The BAFs ranged from 0.66 for metformin to 32 022 for sertraline. Using partial least squares to predict BAFs based upon chemical properties, log KOC, Log KOW, and fugacity ratio (sediment) all had similar and positive loadings with BAFs (R2X = 0.70; caged mussels). BAFs of PPCPs in mussels were predictable from fugacity models that estimate bioconcentration factors using log KOW. Our study demonstrated that mussels readily bioaccumulate PPCPs, in a manner consistent with expectations based upon BCF models and the chemical characteristics of each compound.
•Bioaccumulation of 145 PPCPs were measured in mussels upstream and downstream of WWTPs.•43 PPCPs from many classes were detected in mussel tissue.•Seasonality in PPCP in water meant exposures were highest in late summer during low river flow.•The BAFs ranged from 0.66 for metformin to 32 022 for sertraline.•BAFs were predictable from log KOC, Log KOW, and fugacity ratio (R2X = 0.70).
Interstitial lung disease is a common manifestation of rheumatoid arthritis; however, little is known about factors that influence its prognosis. The aim of the present study was to determine whether ...or not the usual interstitial pneumonia pattern found on high-resolution computed tomography (HRCT) is of prognostic significance in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Patients with RA-ILD were identified retrospectively (n = 82). The relationship of a definite usual interstitial pneumonia pattern on HRCT to survival was determined and compared to that in a cohort of patients with radiologically diagnosed idiopathic pulmonary fibrosis (n = 51). A definite usual interstitial pneumonia pattern was seen in 20 (24%) out of 82 patients with RA-ILD. These patients showed worse survival than those without this pattern (median survival 3.2 versus 6.6 yrs), and a similar survival to those with idiopathic pulmonary fibrosis. On multivariate analysis, a definite usual interstitial pneumonia pattern on HRCT was associated with worse survival (hazard ratio of 2.3). Analysis of specific HRCT features demonstrated that traction bronchiectasis and honeycomb fibrosis were associated with worse survival (hazard ratio of 2.6 and 2.1, respectively). Female sex (hazard ratio of 0.30) and a higher baseline diffusing capacity of the lung for carbon monoxide (hazard ratio of 0.96) were associated with better survival. A definite usual interstitial pneumonia pattern on HRCT has important prognostic implications in RA-ILD.
High‐quality inverse‐opal photonic crystals (see Figure) are formed by TiO2 infiltration and subsequent removal of SiO2 opal templates. Low‐temperature atomic layer deposition followed by annealing ...yields highly conformal infiltrations with extremely smooth surfaces (less than 1 nm root‐mean‐square roughness) and filling fractions of ∼ 88 %. Photonic‐bandgap properties were determined using UV‐vis reflectivity and transmission measurements.
Healthcare-acquired COVID-19 has been an additional burden on hospitals managing increasing numbers of patients with SARS-CoV-2. One acute hospital (W) among three in a Scottish healthboard ...experienced an unexpected surge of COVID-19 clusters.
To investigate possible causes of COVID-19 clusters at Hospital W.
Daily surveillance provided total numbers of patients and staff involved in clusters in three acute hospitals (H, M and W) and care homes across the healthboard. All clusters were investigated and documented, along with patient boarding, community infection rates and outdoor temperatures from October 2020 to March 2021. Selected SARS-CoV-2 strains were genotyped.
There were 19 COVID-19 clusters on 14 wards at Hospital W during the six-month study period, lasting from two to 42 days (average, five days; median, 14 days) and involving an average of nine patients (range 1–24) and seven staff (range 0–17). COVID-19 clusters in Hospitals H and M reflected community infection rates. An outbreak management team implemented a control package including daily surveillance; ward closures; universal masking; screening; restricting staff and patient movement; enhanced cleaning; and improved ventilation. Forty clusters occurred across all three hospitals before a January window-opening policy, after which there were three during the remainder of the study.
The winter surge of COVID-19 clusters was multi-factorial, but clearly exacerbated by moving trauma patients around the hospital. An extended infection prevention and control package including enhanced natural ventilation helped reduce COVID-19 clusters in acute hospitals.
•High order (up to 10th) difference schemes on unstructured disordered node sets.•Spatially varying resolution, stencil optimisation and filtering.•High order boundary conditions for complex ...geometries.•Simulations of isothermal Navier-Stokes equations.•Moderate to high Reynolds number flows through porous media.
Mesh-free methods have significant potential for simulations of flows in complex geometries, with the difficulties of domain discretisation greatly reduced. However, many mesh-free methods are limited to low order accuracy. In order to compete with conventional mesh-based methods, high order accuracy is essential. The Local Anisotropic Basis Function Method (LABFM) is a mesh-free method introduced in King et al. (2020) 20, which enables the construction of highly accurate difference operators on disordered node discretisations. Here, we introduce a number of developments to LABFM, in the areas of basis function construction, stencil optimisation, stabilisation, variable resolution, and high order boundary conditions. With these developments, direct numerical simulations of the Navier Stokes equations are possible at extremely high order (up to 10th order in characteristic node spacing internally). We numerically solve the isothermal compressible Navier Stokes equations for a range of geometries: periodic and channel flows, flows past a cylinder, and porous media. Excellent agreement is seen with analytical solutions, published numerical results (using a spectral element method), and experiments. The potential of the method for direct numerical simulations in complex geometries is demonstrated with simulations of subsonic and transonic flows through an inhomogeneous porous media at pore Reynolds numbers up to Rep=968.
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