bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct gene expression pathways in islets from individuals with short‐ and long‐duration type 1 diabetes
Authors: Mastracci Teresa L. , Turatsinze Jean‐Valery , Book Benita K. , Restrepo Ivan A. , Pugia Michael J. , Wiebke Eric A. , Pescovitz Mark D. , Eizirik Decio L. , Mirmira Raghavendra G. 
Published: March 2018

AimsOur current understanding of the pathogenesis of type 1 diabetes (T1D) arose, in large part, from studies using the non‐obese diabetic (NOD) mouse model. In the present study, we chose a human‐focused method to investigate T1D disease mechanisms and potential targets for therapeutic intervention by directly analysing human donor pancreatic islets from individuals with T1D.Materials and MethodsWe obtained islets from a young individual with T1D for 3 years and from an older individual with T1D for 27 years and performed unbiased functional genomic analysis by high‐depth RNA sequencing; the T1D islets were compared with islets isolated from 3 non‐diabetic donors.ResultsThe islets procured from these T1D donors represent a unique opportunity to identify gene expression changes in islets after significantly different disease duration. Data analysis identified several inflammatory pathways up‐regulated in short‐duration disease, which notably included many components of innate immunity. As proof of concept for translation, one of the pathways, governed by IL‐23(p19), was selected for further study in NOD mice because of ongoing human trials of biologics against this target for different indications. A mouse monoclonal antibody directed against IL‐23(p19) when administered to NOD mice resulted in a significant reduction in incidence of diabetes.ConclusionWhile the sample size for this study is small, our data demonstrate that the direct analysis of human islets provides a greater understanding of human disease. These data, together with the analysis of an expanded cohort to be obtained by future collaborative efforts, might result in the identification of promising novel targets for translation into effective therapeutic interventions for human T1D, with the added benefit of repurposing known biologicals for use in different indications.
Traumatic dental injuries—Prevalence and severity among 16‐year‐old pupils in western Norway
Authors: Bratteberg Magnus , Thelen Dorina S. , Klock Kristin S. , Bårdsen Asgeir 
Published: March 2018

AbstractBackground/AimsPublished data on prevalence and severity of traumatic dental injuries (TDI) in Norway are limited. The aims of this study were to assess prevalence, distribution and severity of TDI in the permanent dentition of 16‐year‐old pupils in western Norway.Material and methodsA retrospective longitudinal study, including historical clinical data, was conducted among 16‐year‐old high school pupils in the County of Hordaland, western Norway. First‐grade pupils attending high school, born in 1997, were invited to participate (n = 5184). Consent was given to access their dental records in the Public Dental Health Service in Hordaland, where information regarding TDI (diagnosis and treatment) and radiographs was interpreted. Only TDIs to anterior teeth were recorded (canine to canine in the maxilla and mandible) and classified using a modified version of the WHO’s classification.ResultsA total of 2055 participants were included (response rate 40%). TDI prevalence was 16.4% (338 pupils), with the maxillary central incisors most affected (64.7%). A total of 637 teeth were involved. Boys were more prone to injury than girls (P < 0.05). Severity of TDI was divided into 3 groups (mild, moderate and severe), with the following distribution: 563 mild (88.4%), 39 moderate (6.1%) and 35 severe (5.5%). Peak age for TDI was 8‐10 years (50.9%).ConclusionsPrevalence of TDI among Norwegian adolescents was moderate. Milder injuries were more frequent than moderate and severe injuries. Age and gender were risk factors with regard to TDI. Seasonal influence on the occurrence of TDI was not statistically significant.
Variability in the performance of juvenile Chinook salmon is explained primarily by when and where they resided in estuarine habitats
Authors: Chittaro Paul , Johnson Lyndal , Teel David , Moran Paul , Sol Sean , Macneale Kate , Zabel Richard 
Published: March 2018

AbstractEstuarine habitats provide rearing opportunities for the juvenile life stage of anadromous fishes. Because survival is positively correlated with juvenile performance, these estuarine habitats play an important role in population abundance and productivity. To provide information for the recovery of several depressed stocks of Chinook salmon in the Columbia River Basin, we sought to identify the factors that explain variability in performance. Using otolith‐derived estimates of juvenile somatic growth rate as an index of recent performance, we observed a negative nonlinear relationship between growth rate and day of year, and a decreasing and increasing trend of growth rate over the 8 years of this study and distance from the river mouth respectively. Using a generalised linear modelling approach, we found that variability in juvenile somatic growth rate was best explained by where and when individuals were collected, their body size, contaminant loads, stock of origin, and whether a fish was hatchery produced or unmarked. Lastly, we argue that a considerable improvement to the growth rate of juveniles in estuarine habitats is physiologically possible. The results of this 8‐year study provide a baseline of the performance of juvenile Chinook salmon to evaluate habitat restoration programs and to compare against future anthropogenic conditions.
Lenalidomide as immune adjuvant to a dendritic cell vaccine in chronic lymphocytic leukemia patients
Authors: Palma Marzia , Hansson Lotta , Mulder Tom A. , Adamson Lars , Näsman‐Glaser Barbro , Eriksson Ingrid , Heimersson Kia , Ryblom Harriet , Mozaffari Fariba , Svensson Ann , Gentilcore Giusy , Österborg Anders , Mellstedt Håkan 
Published: March 2018

AbstractObjectivesWe previously showed that immunization with ex vivo‐ generated autologous dendritic cells loaded with apoptotic tumor cells (Apo‐DC) potentiated tumor‐specific immunity in chronic lymphocytic leukemia (CLL) patients. Here, we evaluated safety and immunogenicity of Apo‐DC in combination with lenalidomide, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and low‐dose cyclophosphamide (CTX).MethodsTen previously untreated patients with slowly progressing CLL received 5 Apo‐DC vaccinations and lenalidomide orally for 24 weeks either alone (cohort I, n = 5) or together with subcutaneous GM‐CSF and intravenous CTX (cohort II, n = 5). Tumor‐specific T‐cell responses were measured by proliferation and IFN‐γ ELISPOT assays. Immune monitoring was performed by flow cytometry.ResultsDose‐limiting toxicity was observed in 3/10 patients, 2 in cohort I and one in cohort II. One patient developed autoimmune hemolytic anemia and another grade 4 thrombocytopenia. Vaccine‐induced immune responses were seen in 5/5 and 4/5 patients in cohort I and II, respectively. The expression of immune checkpoints on T cells did not change significantly.ConclusionsLenalidomide alone or in combination with GM‐CSF and low‐dose CTX as immune adjuvant to the Apo‐DC vaccine elicited tumor‐specific T‐cell responses in CLL patients. However, unexpected toxicity was observed and caution is suggested in further exploring this drug as immune adjuvant in CLL.
Adenosine A2A receptors modulate the dopamine D2 receptor‐mediated inhibition of synaptic transmission in the mouse prefrontal cortex
Authors: Real Joana I. , Simões Ana Patrícia , Cunha Rodrigo A. , Ferreira Samira G. , Rial Daniel 
Published: March 2018

AbstractPrefrontal cortex (PFC) circuits are modulated by dopamine acting on D1‐ and D2‐like receptors, which are pharmacologically exploited to manage neuropsychiatric conditions. Adenosine A2A receptors (A2AR) also control PFC‐related responses and A2AR antagonists are potential anti‐psychotic drugs. As tight antagonistic A2AR–D2R and synergistic A2AR–D1R interactions occur in other brain regions, we now investigated the crosstalk between A2AR and D1/D2R controlling synaptic transmission between layers II/III and V in mouse PFC coronal slices. Dopamine decreased synaptic transmission, a presynaptic effect based on the parallel increase in paired‐pulse responses. Dopamine inhibition was prevented by the D2R‐like antagonist sulpiride but not by the D1R antagonist SCH23390 and was mimicked by the D2R agonist sumanirole, but not by the agonists of either D4R (A‐412997) or D3R (PD128907). Dopamine inhibition was prevented by the A2AR antagonist, SCH58261, and attenuated in A2AR knockout mice. Accordingly, triple‐labelling immunocytochemistry experiments revealed the co‐localization of A2AR and D2R immunoreactivity in glutamatergic (vGluT1‐positive) nerve terminals of the PFC. This reported positive A2AR–D2R interaction controlling PFC synaptic transmission provides a mechanistic justification for the anti‐psychotic potential of A2AR antagonists.
Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus
Authors: Hassiotis Sofia , Manavis Jim , Blumbergs Peter C. , Hattersley Kathryn J. , Carosi Julian M. , Kamei Makoto , Sargeant Timothy J. 
Published: March 2018

AbstractLysosomal vesicles around neuritic plaques are thought to drive Alzheimer's disease by providing ideal microenvironments for generation of amyloid‐β. Although lysosomal vesicles are present at every amyloid plaque in mouse models of Alzheimer's disease, the number of amyloid plaques that contain lysosomal vesicles in the human brain remains unknown. This study aimed to quantify lysosomal vesicles at amyloid plaques in the human hippocampus. Lysosome‐associated membrane protein 1 (LAMP1)‐positive vesicles accumulated in both diffuse (Aβ42‐positive/AT8‐negative) and neuritic (Aβ42‐positive/AT8‐positive) plaques in all regions were analysed. In contrast to mouse models of Alzheimer's disease, however, not all amyloid plaques accumulated LAMP1‐positive lysosomal vesicles. Even at neuritic plaques, LAMP1 immunoreactivity was more abundant than phospho‐tau (AT8). Further, lysosomal vesicles colocalised weakly with phospho‐tau such that accumulation of lysosomal vesicles and phospho‐tau appeared to be spatially distinct events that occurred within dystrophic neurites. This quantitative study shows that diffuse plaques, as well as neuritic plaques, contain LAMP1 immunoreactivity in the human hippocampus.
Induction of IL‐10‐balanced immune profiles following exposure to LTA from Staphylococcus epidermidis
Authors: Volz Thomas , Kaesler Susanne , Draing Christian , Hartung Thomas , Röcken Martin , Skabytska Yuliya , Biedermann Tilo 
Published: March 2018

AbstractStaphylococcus epidermidis colonises human skin without apparent inflammation, but a dominance of S. epidermidis and S. aureus is characteristic of cutaneous microbial dysbiosis in atopic dermatitis (AD). While S. aureus can trigger AD, the role of S. epidermidis is less understood. We characterised consequences of innate immune sensing of lipoteichoic acid (LTA) preparations derived from S. epidermidis (epi‐LTA) or S. aureus (aureus‐LTA). Therefore, dendritic cell (DC) activation and consecutive priming of antigen‐specific T cells following exposure of DC to epi‐LTA or aureus‐LTA were investigated. Mimicking acute AD, exposure of DC to IL‐4 and LTAs was analysed. Exposure to epi‐LTA or aureus‐LTA activated human immune cells and murine dendritic cells (DCs) via TLR2/MyD88, however, resulting in divergent immune profiles. Differences between LTAs were significant for IL‐6, IL‐12p40 and IL‐12p70 but not for IL‐10, which was best reflected by the IL‐12p70‐to‐IL‐10 ratio being IL‐10‐balanced for epi‐LTA but pro‐inflammatory for aureus‐LTA. LTA‐exposed DCs activated CD4+ T cells; however, while T‐cell‐derived IL‐10 was equivalent between LTAs, IFN‐γ and IL‐17 were significantly higher for aureus‐LTA. Mimicking acute AD by exposing DCs to IL‐4 and LTAs revealed that IL‐4 significantly and uniformly suppressed epi‐LTA‐induced cytokine production, keeping the IL‐12p70‐to‐IL‐10 ratio balanced. In contrast, exposure of DCs to aureus‐LTA and IL‐4 enhanced IL‐12p70 but suppressed IL‐10 levels, further unbalancing the IL‐12p70‐to‐IL‐10 ratio. These data demonstrate opposing immune consequences following exposure to staphylococcal LTAs. Epi‐LTA induced IL‐10‐balanced, aureus‐LTA pro‐inflammatory immune profiles.
NDRG1 and FOXO1 regulate endothelial cell proliferation in infantile haemangioma
Authors: Byun Ji Won , An Hye Young , Yeom Seung Dohn , Lee Seok Jong , Chung Ho Yun 
Published: March 2018

AbstractThe etiopathogenesis of infantile haemangioma has not been well understood, and it is accepted that angiogenic mediator dysregulation is the main contributor to the abnormal haemangioma capillary formation. The role of NDRG1, a hypoxia‐inducible protein; FOXOs, which are tumor suppressor proteins; and the mTOR complex 2 pathway in infantile haemangioma have not been studied yet. The purpose of this study was to investigate NDRG1 and FOXO1 expression in the infantile haemangioma and the correlation of these proteins with proliferation and involution. Primary endothelial cells were obtained, with parental agreement, from 12 infantile haemangioma patients during surgery; 6 patients had proliferating infantile haemangiomas and 6 had involuting IHs. We compared the infantile haemangioma tissues and primary endothelial cells with human vein endothelial cells using microarrays, real‐time PCR, Western blotting and immunohistochemical staining. Our data indicated that FOXO1 expression was downregulated in proliferating infantile haemangioma tissue. We found that the expression of NDRG1, a molecule upstream of the FOXO1 pathway, increased during haemangioma proliferation. NDRG1 knockdown decreased haemangioma endothelial cell proliferation and downregulated c‐MYC oncoprotein levels. Our findings suggest that NDRG1 positively regulates haemangioma proliferation. FOXO1 dysregulation plays an important role in infantile haemangiomas pathogenesis.
A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death
Authors: Easton Jennifer A. , Albuloushi Ahmad K. , Kamps Miriam A. F. , Brouns Gladys H. M. R. , Broers Jos L. V. , Coull Barry J. , Oji Vincent , van Geel Michel , van Steensel Maurice A. M. , Martin Patricia E. 
Published: March 2018

AbstractErythrokeratodermia variabilis et progressiva (EKV‐P) is caused by mutations in either the GJB3 (Cx31) or GJB4 genes (Cx30.3). We identified a rare GJB3 missense mutation, c.134G>A (p.G45E), in two unrelated patients and investigated its cellular characteristics. Expression of Cx31G45E‐GFP caused previously undescribed changes within HeLa cells and HaCaT cells, a model human keratinocyte cell line. Cx31WT‐GFP localised to the plasma membrane, but expression of Cx31G45E‐GFP caused vacuolar expansion of the endoplasmic reticulum (ER), the mutant protein accumulated within the ER membrane and disassembly of the microtubular network occurred. No ER stress responses were evoked. Cx31WT‐myc‐myc‐6xHis and Cx31G45E‐GFP co‐immunoprecipitated, indicative of heteromeric interaction, but co‐expression with Cx31WT‐mCherry, Cx26 or Cx30.3 did not mitigate the phenotype. Cx31 and Cx31G45E both co‐immunoprecipitated with Cx43, indicating the ability to form heteromeric connexons. WT‐Cx31 and Cx43 assembled into large gap junction plaques at points of cell‐to‐cell contact; Cx31G45E restricted the ability of Cx43 to reach the plasma membrane in both HaCaT cells and HeLa cells stably expressing Cx43 where the proteins strongly co‐localised with the vacolourised ER. Cell viability assays identified an increase in cell death in cells expressing Cx31G45E‐GFP, which FACS analysis determined was necrotic. Blocking connexin channel function with 18α‐glycyrrhetinic acid did not completely rescue necrosis or prevent propidium iodide uptake, suggesting that expression of Cx31G45E‐GFP damages the cellular membrane independent of its channel function. Our data suggest that entrapment of Cx43 and necrotic cell death in the epidermis could underlie the EKV skin phenotype.
Explaining the doubling of N2O emissions under elevated CO2 in the Giessen FACE via in‐field 15N tracing
Authors: Moser Gerald , Gorenflo André , Brenzinger Kristof , Keidel Lisa , Braker Gesche , Marhan Sven , Clough Tim J. , Müller Christoph 
Published: March 2018

AbstractRising atmospheric CO2 concentrations are expected to increase nitrous oxide (N2O) emissions from soils via changes in microbial nitrogen (N) transformations. Several studies have shown that N2O emission increases under elevated atmospheric CO2 (eCO2), but the underlying processes are not yet fully understood. Here, we present results showing changes in soil N transformation dynamics from the Giessen Free Air CO2 Enrichment (GiFACE): a permanent grassland that has been exposed to eCO2, +20% relative to ambient concentrations (aCO2), for 15 years. We applied in the field an ammonium‐nitrate fertilizer solution, in which either ammonium () or nitrate () was labelled with 15N. The simultaneous gross N transformation rates were analysed with a 15N tracing model and a solver method. The results confirmed that after 15 years of eCO2 the N2O emissions under eCO2 were still more than twofold higher than under aCO2. The tracing model results indicated that plant uptake of did not differ between treatments, but uptake of was significantly reduced under eCO2. However, the and availability increased slightly under eCO2. The N2O isotopic signature indicated that under eCO2 the sources of the additional emissions, 8,407 μg N2O–N/m2 during the first 58 days after labelling, were associated with reduction (+2.0%), oxidation (+11.1%) and organic N oxidation (+86.9%). We presume that increased plant growth and root exudation under eCO2 provided an additional source of bioavailable supply of energy that triggered as a priming effect the stimulation of microbial soil organic matter (SOM) mineralization and fostered the activity of the bacterial nitrite reductase. The resulting increase in incomplete denitrification and therefore an increased N2O:N2 emission ratio, explains the doubling of N2O emissions. If this occurs over a wide area of grasslands in the future, this positive feedback reaction may significantly accelerate climate change.
Elevated CO2 did not affect the hydrological balance of a mature native Eucalyptus woodland
Authors: Gimeno Teresa E. , McVicar Tim R. , O'Grady Anthony P. , Tissue David T. , Ellsworth David S. 
Published: March 2018

AbstractElevated atmospheric CO2 concentration (eCa) might reduce forest water‐use, due to decreased transpiration, following partial stomatal closure, thus enhancing water‐use efficiency and productivity at low water availability. If evapotranspiration (Et) is reduced, it may subsequently increase soil water storage (ΔS) or surface runoff (R) and drainage (Dg), although these could be offset or even reversed by changes in vegetation structure, mainly increased leaf area index (L). To understand the effect of eCa in a water‐limited ecosystem, we tested whether 2 years of eCa (~40% increase) affected the hydrological partitioning in a mature water‐limited Eucalyptus woodland exposed to Free‐Air CO2 Enrichment (FACE). This timeframe allowed us to evaluate whether physiological effects of eCa reduced stand water‐use irrespective of L, which was unaffected by eCa in this timeframe. We hypothesized that eCa would reduce tree‐canopy transpiration (Etree), but excess water from reduced Etree would be lost via increased soil evaporation and understory transpiration (Efloor) with no increase in ΔS, R or Dg. We computed Et, ΔS, R and Dg from measurements of sapflow velocity, L, soil water content (θ), understory micrometeorology, throughfall and stemflow. We found that eCa did not affect Etree, Efloor, ΔS or θ at any depth (to 4.5 m) over the experimental period. We closed the water balance for dry seasons with no differences in the partitioning to R and Dg between Ca levels. Soil temperature and θ were the main drivers of Efloor while vapour pressure deficit‐controlled Etree, though eCa did not significantly affect any of these relationships. Our results suggest that in the short‐term, eCa does not significantly affect ecosystem water‐use at this site. We conclude that water‐savings under eCa mediated by either direct effects on plant transpiration or by indirect effects via changes in L or soil moisture availability are unlikely in water‐limited mature eucalypt woodlands.
Testate amoeba records indicate regional 20th‐century lowering of water tables in ombrotrophic peatlands in central‐northern Alberta, Canada
Authors: van Bellen Simon , Magnan Gabriel , Davies Lauren , Froese Duane , Mullan‐Boudreau Gillian , Zaccone Claudio , Garneau Michelle , Shotyk William 
Published: March 2018

AbstractTestate amoebae are abundant in the surface layers of northern peatlands. Analysis of their fossilized shell (test) assemblages allows for reconstructions of local water‐table depths (WTD). We have reconstructed WTD dynamics for five peat cores from peatlands ranging in distance from the Athabasca bituminous sands (ABS) region in western Canada. Amoeba assemblages were combined with plant macrofossil records, acid‐insoluble ash (AIA) fluxes and instrumental climate data to identify drivers for environmental change. Two functional traits of testate amoebae, mixotrophy and the tendency to integrate xenogenic mineral matter in test construction, were quantified to infer possible effects of AIA flux on testate amoeba presence. Age–depth models showed the cores each covered at least the last ~315 years, with some spanning the last millennium. Testate amoeba assemblages were likely affected by permafrost development in two of the peatlands, yet the most important shift in assemblages was detected after 1960 CE. This shift represents a significant apparent lowering of water tables in four out of five cores, with a mean drop of ~15 cm. Over the last 50 years, assemblages shifted towards more xerophilous taxa, a trend which was best explained by increasing Sphagnum s. Acutifolia and, to a lesser extent, mean summer temperature. This trend was most evident in the two cores from the sites located farthest away from the ABS region. AIA flux variations did not show a clear effect on mineral‐agglutinating taxa, nor on S. s. Acutifolia presence. We therefore suggest the drying trend was forced by the establishment of S. s. Acutifolia, driven by enhanced productivity following regional warming. Such recent apparent drying of peatlands, which may only be reconstructed by appropriate indicators combined with high chronological control, may affect vulnerability to future burning and promote emissions of CO2.