Genetic Diversity of PCR-Positive, Culture-Negative and Culture-Positive Mycobacterium ulcerans Isolated from Buruli Ulcer Patients in Ghana.

Culture of Mycobacterium ulcerans from Buruli ulcer patients has very low sensitivity. Thus confirmation of M. ulcerans infection is primarily based on PCR directed against IS2404. In this study we compare the genotypes obtained by variable number of tandem repeat analysis of DNA from IS2404-PCR positive cultures with that obtained from IS2404 positive, culture-negative tissue. A significantly greater genetic heterogeneity was found among culture-negative samples compared with that found in cultured strains but a single genotype is over-represented in both sample sets. This study provides evidence that both the focal location of bacteria in a lesion as well as differences in the ability to culture a particular genotype may underlie the low sensitivity of culture. Though preliminary, data from this work also suggests that mycobacteria previously associated with fish disease (M. pseudoshottsii) may be pathogenic for humans

CD169+ Monocyte and Regulatory T Cell Subsets Are Associated with Disease Activity in Rheumatoid Arthritis

Disease activity in rheumatoid arthritis (RA) is influenced by activation of circulating and synovial immune cells. Regulatory T cells (Tregs) and monocytes are key cells that drive inflammation in RA. This study investigated if a relationship exists between disease activity in RA and circulating Treg and monocyte numbers and phenotypes. A potential sialic acid (Sia) mediated link between Tregs and monocytes was also probed in vitro. Peripheral blood mononuclear cells (PBMCs) were isolated from RA patient (n = 62) and healthy control (n = 21) blood using density gradient separation. Flow cytometry was used to count and phenotype Treg and monocyte subsets, and to sort healthy control Tregs for Sia cell culture experiments. The effects of Sia on activated Treg FoxP3 and NFκB expression was assessed by flow cytometry and concentrations of secreted TNFα, IL-10 and IFNγ determined by ELISA. High disease activity RA patients who were unresponsive to disease modifying anti-rheumatic drugs (n = 31), have significantly lower relative numbers (percentages) of CD4(+)CD25(+)CD127(−) Tregs (p < 0.01) and memory CD45RA(−)FoxP3(+) Tregs (p < 0.01), compared to low disease activity responders (n = 24). Relative numbers of non-classical CD169(+) monocytes are associated with disease activity in RA (p = 0.012). Sia reduced Treg expression of FoxP3, NFκB and cytokines in vitro. A strong association has been identified between non-classical CD169(+) monocytes and post-treatment disease activity in RA. This study also indicates that Sia can reduce Treg activation and cytokine release. We postulate that such a reduction could be mediated by interaction with sialyted proteins captured by CD169(+) monocytes

Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.

Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli

Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents

AbstractThe adipose tissue hormone, leptin, and the neuropeptide glucagon-like peptide-1 (7–36) amide (GLP-1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB-Rb) was localized to GLP-1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP-1 receptor antagonist, exendin(9–39), at the onset of dark phase, did not affect feeding in saline pre-treated controls, but blocked the reduction in food intake and body weight of leptin pre-treated rats. These findings suggest that GLP-1 neurons are a potential target for leptin in its control of feeding

Effects of grid spacing on high-frequency precipitation variance in coupled high-resolution global ocean–atmosphere models

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Light, C., Arbic, B., Martin, P., Brodeau, L., Farrar, J., Griffies, S., Kirtman, B., Laurindo, L., Menemenlis, D., Molod, A., Nelson, A., Nyadjro, E., O’Rourke, A., Shriver, J., Siqueira, L., Small, R., & Strobach, E. Effects of grid spacing on high-frequency precipitation variance in coupled high-resolution global ocean–atmosphere models. Climate Dynamics, (2022): 1–27, https://doi.org/10.1007/s00382-022-06257-6.High-frequency precipitation variance is calculated in 12 different free-running (non-data-assimilative) coupled high resolution atmosphere–ocean model simulations, an assimilative coupled atmosphere–ocean weather forecast model, and an assimilative reanalysis. The results are compared with results from satellite estimates of precipitation and rain gauge observations. An analysis of irregular sub-daily fluctuations, which was applied by Covey et al. (Geophys Res Lett 45:12514–12522, 2018. https://doi.org/10.1029/2018GL078926) to satellite products and low-resolution climate models, is applied here to rain gauges and higher-resolution models. In contrast to lower-resolution climate simulations, which Covey et al. (2018) found to be lacking with respect to variance in irregular sub-daily fluctuations, the highest-resolution simulations examined here display an irregular sub-daily fluctuation variance that lies closer to that found in satellite products. Most of the simulations used here cannot be analyzed via the Covey et al. (2018) technique, because they do not output precipitation at sub-daily intervals. Thus the remainder of the paper focuses on frequency power spectral density of precipitation and on cumulative distribution functions over time scales (2–100 days) that are still relatively “high-frequency” in the context of climate modeling. Refined atmospheric or oceanic model grid spacing is generally found to increase high-frequency precipitation variance in simulations, approaching the values derived from observations. Mesoscale-eddy-rich ocean simulations significantly increase precipitation variance only when the atmosphere grid spacing is sufficiently fine (< 0.5°). Despite the improvements noted above, all of the simulations examined here suffer from the “drizzle effect”, in which precipitation is not temporally intermittent to the extent found in observations.Support for CXL’s effort on this project was provided by a Research Experiences for Undergraduates (REU) supplement for National Science Foundation (NSF) grant OCE-1851164 to BKA, which also provided partial support for PEM. In addition, BKA acknowledges NSF grant OCE-1351837, which provided partial support for AKO, Office of Naval Research grant N00014-19-1-2712 and NASA grants NNX17AH55G, which also provided partial support for ADN, and 80NSSC20K1135. JTF’s participation, and the SPURS-II buoy data, were funded by NASA grants 80NSSC18K1494 and NNX15AG20G

Transplantation in Remission Improves the Disease-Free Survival of Patients with Advanced Myelodysplastic Syndromes Treated with Myeloablative T Cell-Depleted Stem Cell Transplants from HLA-Identical Siblings

AbstractFrom 1985 to 2004, 49 patients with advanced myelodysplastic syndromes (MDS) (≥5% blasts) or acute myeloid leukemia (AML) transformed from MDS underwent T cell depleted bone marrow or peripheral blood hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings following conditioning with a myeloablative regimen that included total body irradiation (44 patients) or busulfan (5 patients). Thirty-six patients received chemotherapy (3 low dose and 33 induction doses) before conditioning, and 13 patients did not receive any chemotherapy. Prior to transplantation, 22 of the 36 treated patients were in hematologic remission; 4 were in a second refractory cytopenia phase (26 responders); 8 had failed to achieve remission; and 2 of the responders had progression or relapse of their MDS (10 failures). No post-transplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD) was given. The median age was 48 yrs (range 13-61). Forty-five of the 49 patients engrafted; 2 had primary graft failure; and 2 died before engraftment. Only 3 patients developed acute GVHD (aGVHD) (grades I and III) and 1 chronic GVHD (cGVHD). At 3 yrs post-transplantation, the overall survival (OS) was 54% in the responders; 31% in the untreated group; and 0% in the failure group (P=.0004). The disease free survival (DFS) was 50%, 15% and 0% in each group respectively (P=.0008). In multivariate analysis, disease status before cytoreduction remained highly correlated with DFS (P<.001). The cumulative incidence (CI) of relapse at 2-yrs post-transplantation for the responders was 23%; for the untreated group was 38%; and for the failures was 50%. The CI of non-relapse mortality at 2-yrs post-transplantation, for the responders was 23%; for the untreated group was 38%; and for the failures was 40%. All survivors achieved a Karnofsky Performance Status (KPS) of ≥90. These results indicate that patients with advanced MDS who achieve and remain in remission or a second refractory cytopenia phase with chemotherapy before conditioning can achieve successful long-term remissions following a myeloablative T cell depleted allogeneic HSCT

Multiple interactions between the alpha2C- and beta1-adrenergic receptors influence heart failure survival

<p>Abstract</p> <p>Background</p> <p>Persistent stimulation of cardiac β₁-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α_2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (<it>ADRB1 </it>and <it>ADRA2C</it>, respectively) on the risk of death/transplant in heart failure patients.</p> <p>Methods</p> <p>Sixteen sequence variations in <it>ADRA2C </it>and 17 sequence variations in <it>ADRB1 </it>were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation.</p> <p>Results</p> <p>Three polymorphisms in <it>ADRA2C </it>and five polymorphisms in <it>ADRB1 </it>were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18) relative to all other genotype classes.</p> <p>Conclusion</p> <p>Multiple polymorphisms act synergistically between the <it>ADRA2C </it>and <it>ADRB1 </it>genes to increase risk of death or cardiac transplant in heart failure patients.</p

Magnetic Resonance Guided Radiation Therapy for Pancreatic Adenocarcinoma, Advantages, Challenges, Current Approaches, and Future Directions

Introduction: Pancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC. Methods: A literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications. Results: Over 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed. Conclusions: The potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial

Garden and landscape-scale correlates of moths of differing conservation status: significant effects of urbanization and habitat diversity

Moths are abundant and ubiquitous in vegetated terrestrial environments and are pollinators, important herbivores of wild plants, and food for birds, bats and rodents. In recent years, many once abundant and widespread species have shown sharp declines that have been cited by some as indicative of a widespread insect biodiversity crisis. Likely causes of these declines include agricultural intensification, light pollution, climate change, and urbanization; however, the real underlying cause(s) is still open to conjecture. We used data collected from the citizen science Garden Moth Scheme (GMS) to explore the spatial association between the abundance of 195 widespread British species of moth, and garden habitat and landscape features, to see if spatial habitat and landscape associations varied for species of differing conservation status. We found that associations with habitat and landscape composition were species-specific, but that there were consistent trends in species richness and total moth abundance. Gardens with more diverse and extensive microhabitats were associated with higher species richness and moth abundance; gardens near to the coast were associated with higher richness and moth abundance; and gardens in more urbanized locations were associated with lower species richness and moth abundance. The same trends were also found for species classified as increasing, declining and vulnerable under IUCN (World Conservation Union) criteria

Growth and retreat of the last British–Irish Ice Sheet, 31 000 to 15 000 years ago: the BRITICE-CHRONO reconstruction

The BRITICE-CHRONO consortium of researchers undertook a dating programme to constrain the timing of advance, maximum extent and retreat of the British–Irish Ice Sheet between 31 000 and 15 000 years before present. The dating campaign across Ireland and Britain and their continental shelves, and across the North Sea included 1500 days of field investigation yielding 18 000 km of marine geophysical data, 377 cores of sea floor sediments, and geomorphological and stratigraphical information at 121 sites on land; generating 690 new geochronometric ages. These findings are reported in 28 publications including synthesis into eight transect reconstructions. Here we build ice sheet-wide reconstructions consistent with these findings and using retreat patterns and dates for the inter-transect areas. Two reconstructions are presented, a wholly empirical version and a version that combines modelling with the new empirical evidence. Palaeoglaciological maps of ice extent, thickness, velocity, and flow geometry at thousand-year timesteps are presented. The maximum ice volume of 1.8 m sea level equivalent occurred at 23 ka. A larger extent than previously defined is found and widespread advance of ice to the continental shelf break is confirmed during the last glacial. Asynchrony occurred in the timing of maximum extent and onset of retreat, ranging from 30 to 22 ka. The tipping point of deglaciation at 22 ka was triggered by ice stream retreat and saddle collapses. Analysis of retreat rates leads us to accept our hypothesis that the marine-influenced sectors collapsed rapidly. First order controls on ice-sheet demise were glacio-isostatic loading triggering retreat of marine sectors, aided by glaciological instabilities and then climate warming finished off the smaller, terrestrial ice sheet. Overprinted on this signal were second order controls arising from variations in trough topographies and with sector-scale ice geometric readjustments arising from dispositions in the geography of the landscape. These second order controls produced a stepped deglaciation. The retreat of the British–Irish Ice Sheet is now the world’s most well-constrained and a valuable data-rich environment for improving ice-sheet modelling.publishedVersio