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Aims/Hypothesis: Post-bariatric hypoglycemia (PBH) is caused by postprandial hyperinsulinemia, due to anatomical alterations and changes in post-prandial metabolism after bariatric surgery. The mechanisms underlying the failing regulatory and compensatory systems are unclear. In this study, we investigated the differences in post-prandial hormones and metabolic profiles between patients with and without PBH. Methods: We performed a mixed meal test (MMT) in 63 subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery. Blood was withdrawn at 0, 10, 20, 30, 60, and 120 min after ingestion of a standardized meal. Glucose, insulin, GLP-1, FGF-19, and FGF-21 were measured and untargeted metabolomics analysis was performed on blood plasma to analyze which hormonal and metabolic systems were altered between patients with and without PBH. Results: Out of 63, a total of 21 subjects (33%) subjects developed PBH (glucose < 3.1 mmol/L) after surgery. Decreased glucose and increased insulin excursions during MMT were seen in PBH (p < 0.05). GLP-1, FGF-19, and FGF-21 were elevated after surgery (p < 0.001), but did not differ between PBH and non-PBH groups. We identified 20 metabolites possibly involved in carbohydrate metabolism which differed between the two groups, including increased carnitine and acylcholines in PBH. Conclusion: Overall, 33% of the subjects developed PBH 1 year after RYGB surgery. While GLP-1, FGF-19, and FGF-21 were similar in PBH and non-PBH patients, metabolomics analysis revealed changes in carnitine and acyclcholines that are possibly involved in energy metabolism, which may play a role in the occurrence of PBH. [ABSTRACT FROM AUTHOR]

Introduction and Hypothesis: This study investigated pessary self-management (PSM). The primary outcome was how often PSM was taught to patients with pelvic organ prolapse (POP). Secondary outcomes were associations of PSM with treatment continuation, side effects, changing to surgery, and number of doctor consultations in the first year after treatment initiation compared with clinical management (CM). Methods: A retrospective cohort study was conducted in 300 patients visiting three Dutch medical centres in 2019, and receiving a pessary for POP. The t test, Chi-squared test and logistic regression were performed to compare PSM with CM and to identify factors associated with treatment continuation. Results: A total of 35% of patients received PSM instructions, of which 92% were able to perform PSM successfully. Treatment was continued by 83% of patients practicing PSM and 75% of patients having CM (p = 0.16), side effects occurred in 26% and 39% respectively (p = 0.18). Pain or discomfort was associated with treatment discontinuation (p < 0.01). In a subgroup analysis of patients who had a pessary suitable for PSM, treatment continuation was significantly higher in the PSM group (97%) than in the CM group (74%; p < 0.01). Conclusions: Pessary self-management was only taught to 35% of patients who received a pessary, although the ability to perform PSM was high (92%). Treatment discontinuation was significantly lower in the PSM subgroup, when assessing the subgroup of patients using a pessary suitable for PSM. The large number of patients using a pessary suitable for PSM in the CM group implies that there is a lot to gain by promoting PSM. [ABSTRACT FROM AUTHOR]

Many animals return to their home areas (i.e., ‘homing’) after translocation to sites further away. Such translocations have traditionally been used in behavioral ecology to understand the orientation and migration behavior of animals. The movement itself can then be followed by marking and recapturing animals or by tracking, for example, using GPS systems. Most detailed studies investigating this behavior have been conducted in smaller vertebrates (e.g., birds, amphibians, and mice), whereas information on larger mammals, such as red deer, is sparse. We conducted GPS-assisted translocation experiments with red deer at two sites in the Czech Republic. Individuals were translocated over a distance of approximately 11 km and their home journey was tracked. Circular statistics were used to test for significant homeward orientation at distances of 100, 500, 1000, and 5000 m from the release site. In addition, we applied Lavielle trajectory segmentation to identify the different phases of homing behavior. Thirty-one out of 35 translocations resulted in successful homing, with a median time of 4.75 days (range 1.23–100 days). Animals were significantly oriented towards home immediately after release and again when they came closer to home; however, they did not show a significant orientation at the distances in between. We were able to identify three homing phases, an initial ‘exploratory phase’, followed by a ‘homing phase’ which sometimes was again followed by an ‘arrival phase’. The ‘homing phase’ was characterized by the straightest paths and fastest movements. However, the variation between translocation events was considerable. We showed good homing abilities of red deer after translocation. Our results demonstrate the feasibility of conducting experiments with environmental manipulations (e.g., to impede the use of sensory cues) close to the release site. The homing behavior of red deer is comparable to that of other species, and might represent general homing behavior patterns in animals. Follow-up studies should further dissect and investigate the drivers of the individual variations observed and try to identify the sensory cues used during homing. [ABSTRACT FROM AUTHOR]

A new photometric measurement method for the determination of temporally and spatially resolved light extinction coefficients in laboratory fire tests was recently presented. The approach relies on capturing the change in intensity of individual light sources (LEDs) due to fire smoke using a commercially available digital camera. Comparing the results for red light LEDs to measurements of the well-established MIREX system indicates the model is capable of capturing the investigated phenomena. However, a significant underestimation of this reference measurement taken in the infrared range is inconsistent with the expected increase of the extinction coefficients with lower wavelengths. In the context of new experimental investigations, this deficiency was remedied by evaluating multible colour channels of RAW image data instead of the previously used JPG files. Furthermore, extending the experimental setup by several LED strips as well as a second camera allows to verify the hypothesis of a homogeneous smoke layering. The study covers eight experiments including n-heptane fuel in style of the well documented EN 54 TF 5 testfire as well as two additional experiments with an n-heptane-toluene mixture. Considering spatial resolution as well as the high reproducibility of the results, the method appears to be a convenient tool for the validation of numerical visibility models. Nevertheless, a sensitivity analysis identified uncertainties that need to be addressed in upcoming investigations to further improve the accuracy. [ABSTRACT FROM AUTHOR]

In bioprocesses, the pH value is a critical process parameter that requires monitoring and control. For pH monitoring, potentiometric methods such as pH electrodes are state of the art. However, they are invasive and show measurement value drift. Spectroscopic pH monitoring is a non-invasive alternative to potentiometric methods avoiding this measurement value drift. In this study, we developed the Good pH probe, which is an approach for spectroscopic pH monitoring in bioprocesses with an effective working range between pH 6 and pH 8 that does not require the estimation of activity coefficients. The Good pH probe combines for the first time the Good buffer 3-(N-morpholino)propanesulfonic acid (MOPS) as pH indicator with Raman spectroscopy as spectroscopic technique, and Indirect Hard Modeling (IHM) for the spectral evaluation. During a detailed characterization, we proved that the Good pH probe is reversible, exhibits no temperature dependence between 15 and 40 °C, has low sensitivity to the ionic strength up to 1100 mM, and is applicable in more complex systems, in which other components significantly superimpose the spectral features of MOPS. Finally, the Good pH probe was successfully used for non-invasive pH in-line monitoring during an industrially relevant enzyme-catalyzed reaction with a root mean square error of prediction (RMSEP) of 0.04 pH levels. Thus, the Good pH probe extends the list of critical process parameters monitorable using Raman spectroscopy and IHM by the pH value. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is a rare, highly aggressive malignancy with a 5-year survival rate of 5–10% in advanced cases, highlighting the need for more effective therapies. The aim of this study was to identify potentially actionable therapeutic targets for GBC. Specimens and clinicopathological data of 642 GBC patients, diagnosed between 2000 and 2019 were collected using the Dutch Pathology Registry (PALGA) and the Netherlands Cancer Registry. All cases were histologically reviewed and a subset was subjected to a comprehensive next generation sequencing panel. We assessed mutations and gene amplifications in a panel of 54 actionable genes, tumor-mutational burden (TMB), and microsatellite instability (MSI). Additionally, the entire cohort was screened for HER2, PD-L1, pan-TRK, and p53 expression with immunohistochemistry. Histopathological subtypes comprised biliary-type adenocarcinoma (AC, 69.6%), intestinal-type AC (20.1%) and other subtypes (10.3%). The median total TMB was 5.5 mutations/Mb (range: 0–161.1) and 17.7% of evaluable cases had a TMB of >10 mutations/Mb. MSI was observed in two cases. Apart from mutations in TP53 (64%), tumors were molecularly highly heterogeneous. Half of the tumors (50%) carried at least one molecular alteration that is targetable in other tumor types, including alterations in CDKN2A (6.0% biallelically inactivated), ERBB2 (9.3%) and PIK3CA (10%). Immunohistochemistry results correlated well with NGS results for HER2 and p53: Pearson r = 0.82 and 0.83, respectively. As half of GBC patients carry at least one potentially actionable molecular alteration, molecular testing may open the way to explore targeted therapy options for GBC patients. [ABSTRACT FROM AUTHOR]

An incubation study was carried out to investigate the effects of litter quality, i.e. 15 N-labelled maize (C/N of 25.5) and Rhodes grass (C/N of 57.8) leaf litter on microbial carbon use efficiency (CUE) and priming effects in a moderate alkaline soil at two different temperatures (15 and 25 °C). CUE values were calculated from the isotopic composition of the particulate organic matter (POM) recovered as an index for the amount of non-decomposed litter. This approach allows the inclusion of microbial necromass growth components in the calculation of CUE values. Additionally, the soil was incubated for 10, 20, and 30 days to determine the optimum incubation period. Soil microbial CUE values of maize and Rhodes grass leaf litter, including microbial necromass C in the calculation of CUE, varied around 0.61, regardless of litter type, temperature, and incubation period. However, the optimum incubation time is between 20 and 30 days, depending on temperature. The strong priming effect on autochthonous soil organic carbon (SOC) mineralization was apparently not caused by N mining, as it was similar for both litter qualities. It most likely resulted from SOC being used by microbial co-metabolism. The litter-induced true priming effect was accompanied by a significant increase in autochthonous POM. The current approach, including microbial necromass as growth component, has been shown to be a strong tool for investigating CUE values and priming effects after application of litter and harvest residues to soil, probably under all environmental conditions. [ABSTRACT FROM AUTHOR]

Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) promote neurological recovery after middle cerebral artery occlusion (MCAO) in young rodents. Ischemic stroke mainly affects aged humans. MSC-sEV effects on stroke recovery in aged rodents had not been assessed. In a head-to-head comparison, we exposed young (4–5 months) and aged (19–20 months) male Sprague–Dawley rats to permanent distal MCAO. At 24 h, 3 and 7 days post-stroke, vehicle or MSC-sEVs (2 × 106 or 2 × 107 MSC equivalents/kg) were intravenously administered. Neurological deficits, ischemic injury, brain inflammatory responses, post-ischemic angiogenesis, and endogenous neurogenesis were evaluated over 28 days. Post-MCAO, aged vehicle-treated rats exhibited more severe motor-coordination deficits evaluated by rotating pole and cylinder tests and larger brain infarcts than young vehicle-treated rats. Although infarct volume was not influenced by MSC-sEVs, sEVs at both doses effectively reduced motor-coordination deficits in young and aged rats. Brain macrophage infiltrates in periinfarct tissue, which were evaluated as marker of a recovery-aversive inflammatory environment, were significantly stronger in aged than young vehicle-treated rats. sEVs reduced brain macrophage infiltrates in aged, but not young rats. The tolerogenic shift in immune balance paved the way for structural brain tissue remodeling. Hence, sEVs at both doses increased periinfarct angiogenesis evaluated by CD31/BrdU immunohistochemistry in young and aged rats, and low-dose sEVs increased neurogenesis in the subventricular zone examined by DCX/BrdU immunohistochemistry. Our study provides robust evidence that MSC-sEVs promote functional neurological recovery and brain tissue remodeling in aged rats post-stroke. This study encourages further proof-of-concept studies in clinic-relevant stroke settings. [ABSTRACT FROM AUTHOR]

Antidepressants have been reported to enhance stroke recovery independent of the presence of depressive symptoms. They have recently been proposed to exert their mood-stabilizing actions by inhibition of acid sphingomyelinase (ASM), which catalyzes the hydrolysis of sphingomyelin to ceramide. Their restorative action post-ischemia/reperfusion (I/R) still had to be defined. Mice subjected to middle cerebral artery occlusion or cerebral microvascular endothelial cells exposed to oxygen–glucose deprivation were treated with vehicle or with the chemically and pharmacologically distinct antidepressants amitriptyline, fluoxetine or desipramine. Brain ASM activity significantly increased post-I/R, in line with elevated ceramide levels in microvessels. ASM inhibition by amitriptyline reduced ceramide levels, and increased microvascular length and branching point density in wildtype, but not sphingomyelinase phosphodiesterase-1 ([Smpd1]−/−) (i.e., ASM-deficient) mice, as assessed by 3D light sheet microscopy. In cell culture, amitriptyline, fluoxetine, and desipramine increased endothelial tube formation, migration, VEGFR2 abundance and VEGF release. This effect was abolished by Smpd1 knockdown. Mechanistically, the promotion of angiogenesis by ASM inhibitors was mediated by small extracellular vesicles (sEVs) released from endothelial cells, which exhibited enhanced uptake in target cells. Proteomic analysis of sEVs revealed that ASM deactivation differentially regulated proteins implicated in protein export, focal adhesion, and extracellular matrix interaction. In vivo, the increased angiogenesis was accompanied by a profound brain remodeling response with increased blood–brain barrier integrity, reduced leukocyte infiltrates and increased neuronal survival. Antidepressive drugs potently boost angiogenesis in an ASM-dependent way. The release of sEVs by ASM inhibitors disclosed an elegant target, via which brain remodeling post-I/R can be amplified. [ABSTRACT FROM AUTHOR]

Few biodiversity indicators are available that reflect the state of broad-sense biodiversity—rather than of particular taxa—at fine spatial and temporal resolution. One such indicator, the Biodiversity Intactness Index (BII), estimates how the average abundance of the native terrestrial species in a region compares with their abundances in the absence of pronounced human impacts. We produced annual maps of modelled BII at 30-arc-second resolution (roughly 1 km at the equator) across tropical and subtropical forested biomes, by combining annual data on land use, human population density and road networks, and statistical models of how these variables affect overall abundance and compositional similarity of plants, fungi, invertebrates and vertebrates. Across tropical and subtropical biomes, BII fell by an average of 1.9 percentage points between 2001 and 2012, with 81 countries seeing an average reduction and 43 an average increase; the extent of primary forest fell by 3.9% over the same period. We did not find strong relationships between changes in BII and countries' rates of economic growth over the same period; however, limitations in mapping BII in plantation forests may hinder our ability to identify these relationships. This is the first time temporal change in BII has been estimated across such a large region. [ABSTRACT FROM AUTHOR]

Invasive bivalves can cause widespread ecological damage, but eradication has proved difficult. Identifying the pathways of dispersal is crucial to implementing more effective biocontainment measures. We examined the distribution of the highly invasive zebra mussel (Dreissena polymorpha) in Great Britain through Species Distribution Modelling to determine the drivers of distribution and generated suitability maps to predict future dispersal. Distance to boat ramps was the most important predictor of zebra mussel establishment, accounting for 27% of variation in occurrence. Probability of occurrence was highest within 3 km upstream of boat ramps, probably due to boating activity and the impounded waters typically associated with boat ramps. Our results highlight the need for implementing stringent control measures around boat ramps, and demonstrate the value of spatially modelling species distribution to create risk maps for targeting monitoring efforts at those locations most vulnerable to invasion. [ABSTRACT FROM AUTHOR]

With more than 1000 species, East African cichlid fishes represent the fastest and most species-rich vertebrate radiation known, providing an ideal model to tackle molecular mechanisms underlying recurrent adaptive diversification. We add high-quality genome reconstructions for two phylogenetic key species of a lineage that diverged about ~ 3–9 million years ago (mya), representing the earliest split of the so-called modern haplochromines that seeded additional radiations such as those in Lake Malawi and Victoria. Along with the annotated genomes we analysed discriminating genomic features of the study species, each representing an extreme trophic morphology, one being an algae browser and the other an algae grazer. The genomes of Tropheus moorii (TM) and Petrochromis trewavasae (PT) comprise 911 and 918 Mbp with 40,300 and 39,600 predicted genes, respectively. Our DNA sequence data are based on 5 and 6 individuals of TM and PT, and the transcriptomic sequences of one individual per species and sex, respectively. Concerning variation, on average we observed 1 variant per 220 bp (interspecific), and 1 variant per 2540 bp (PT vs PT)/1561 bp (TM vs TM) (intraspecific). GO enrichment analysis of gene regions affected by variants revealed several candidates which may influence phenotype modifications related to facial and jaw morphology, such as genes belonging to the Hedgehog pathway (SHH, SMO, WNT9A) and the BMP and GLI families. [ABSTRACT FROM AUTHOR]

Obtained from the right cell-type, mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs) promote stroke recovery. Within this process, microvascular remodeling plays a central role. Herein, we evaluated the effects of MSC-sEVs on the proliferation, migration, and tube formation of human cerebral microvascular endothelial cells (hCMEC/D3) in vitro and on post-ischemic angiogenesis, brain remodeling and neurological recovery after middle cerebral artery occlusion (MCAO) in mice. In vitro, sEVs obtained from hypoxic (1% O2), but not ‘normoxic’ (21% O2) MSCs dose-dependently promoted endothelial proliferation, migration, and tube formation and increased post-ischemic endothelial survival. sEVs from hypoxic MSCs regulated a distinct set of miRNAs in hCMEC/D3 cells previously linked to angiogenesis, three being upregulated (miR-126-3p, miR-140-5p, let-7c-5p) and three downregulated (miR-186-5p, miR-370-3p, miR-409-3p). LC/MS–MS revealed 52 proteins differentially abundant in sEVs from hypoxic and ‘normoxic’ MSCs. 19 proteins were enriched (among them proteins involved in extracellular matrix–receptor interaction, focal adhesion, leukocyte transendothelial migration, protein digestion, and absorption), and 33 proteins reduced (among them proteins associated with metabolic pathways, extracellular matrix–receptor interaction, focal adhesion, and actin cytoskeleton) in hypoxic MSC-sEVs. Post-MCAO, sEVs from hypoxic MSCs increased microvascular length and branching point density in previously ischemic tissue assessed by 3D light sheet microscopy over up to 56 days, reduced delayed neuronal degeneration and brain atrophy, and enhanced neurological recovery. sEV-induced angiogenesis in vivo depended on the presence of polymorphonuclear neutrophils. In neutrophil-depleted mice, MSC-sEVs did not influence microvascular remodeling. sEVs from hypoxic MSCs have distinct angiogenic properties. Hypoxic preconditioning enhances the restorative effects of MSC-sEVs. [ABSTRACT FROM AUTHOR]

Rivers support some of Earth's richest biodiversity1 and provide essential ecosystem services to society2, but they are often fragmented by barriers to free flow3. In Europe, attempts to quantify river connectivity have been hampered by the absence of a harmonized barrier database. Here we show that there are at least 1.2 million instream barriers in 36 European countries (with a mean density of 0.74 barriers per kilometre), 68 per cent of which are structures less than two metres in height that are often overlooked. Standardized walkover surveys along 2,715 kilometres of stream length for 147 rivers indicate that existing records underestimate barrier numbers by about 61 per cent. The highest barrier densities occur in the heavily modified rivers of central Europe and the lowest barrier densities occur in the most remote, sparsely populated alpine areas. Across Europe, the main predictors of barrier density are agricultural pressure, density of river-road crossings, extent of surface water and elevation. Relatively unfragmented rivers are still found in the Balkans, the Baltic states and parts of Scandinavia and southern Europe, but these require urgent protection from proposed dam developments. Our findings could inform the implementation of the EU Biodiversity Strategy, which aims to reconnect 25,000 kilometres of Europe's rivers by 2030, but achieving this will require a paradigm shift in river restoration that recognizes the widespread impacts caused by small barriers. Validated barrier inventories and modelling indicate that Europe's rivers are fragmented by more than one million barriers, such as dams, weirs and fords, causing major impacts on biodiversity. [ABSTRACT FROM AUTHOR]

Error monitoring during task execution is reflected in post-error slowing (PES), which refers to the tendency to slow down performance after making an error in order to prevent future mistakes. The key question of the present study is whether poor error monitoring (reduced magnitude of PES) has negative consequences for daily life executive function skills, as well as functioning in different life settings such as work, family, social, and academic settings. Eighty-five university students performed a lexical decision task and completed The Executive Function Index Scale (EFI), and the Weiss Functional Impairments Rating Scale (WFIRS). Individual academic achievement was measured using the Grade Point Average. Statistical analysis revealed that a decreased magnitude of PES was weakly associated with less efficient planning (one of the executive functions). Results suggest that error monitoring, as measured by PES, was not associated with functioning in a naturalistic environment, but could be interpreted to some extent as an experimental marker of planning in daily life executive functioning. [ABSTRACT FROM AUTHOR]

In the absence of dispersal barriers, species with great dispersal ability are expected to show little, if at all, phylogeographic structure. The East African Great Lakes and their diverse fish faunas provide opportunities to test this hypothesis in pelagic fishes, which are presumed to be highly mobile and unrestricted in their movement by physical barriers. Here, we address the link between panmixis and pelagic habitat use by comparing the phylogeographic structure among four deepwater cichlid species of the tribe Bathybatini from Lake Tanganyika. We show that the mitochondrial genealogies (based on the most variable part or the control region) of the four species are very shallow (0.8-4% intraspecific divergence across entire distribution ranges) and that all species experienced recent population growth. A lack of phylogeographic structure in the two eupelagic species, Bathybates fasciatus and B. leo, was consistent with expectations and with findings in other pelagic cichlid species. Contrary to expectations, a clear phylogeographic structure was detected in the two benthopelagic species, B. graueri and Hemibates stenosoma. Differences in genetic diversity between eupelagic and benthopelagic species may be due to differences in their dispersal propensity, mediated by their respective predatory niches, rather than precipitated by external barriers to dispersal. [ABSTRACT FROM AUTHOR]

A variety of literature addresses the question of how the age distribution of deaths changes over time as life expectancy increases. However, corresponding terms such as extension, compression, or rectangularization are sometimes defined only vaguely, and statistics used to detect certain scenarios can be misleading. The matter is further complicated because mixed scenarios can prevail, and the considered age range can have an impact on observed mortality patterns. In this article, we establish a unique classification framework for realized mortality scenarios that allows for the detection of both pure and mixed scenarios. Our framework determines whether changes of the deaths curve over time show elements of extension or contraction; compression or decompression; left- or right-shifting mortality; and concentration or diffusion. The framework not only can test the presence of a particular scenario but also can assign a unique scenario to any observed mortality evolution. Furthermore, it can detect different mortality scenarios for different age ranges in the same population. We also present a methodology for the implementation of our classification framework and apply it to mortality data for U.S. females. [ABSTRACT FROM AUTHOR]

The advent of Fastloc-GPS is helping to transform marine animal tracking by allowing the collection of high-quality location data for species that surface only briefly. We show how the improved location accuracy of Fastloc-GPS compared to Argos tracking is expected to lead to far more accurate home range estimates, particularly for animals moving over the scale of a few km. We reach this conclusion using simulated data and home range estimates derived from empirical tracking data for green sea turtles ( Chelonia mydas) equipped with Argos linked Fastloc-GPS tags at three different foraging areas (western Indian Ocean, Western Australia, and Caribbean). Poor-quality Argos locations (e.g., location classes A, B) produced home range estimates ranging from 10 to 100 times larger than those derived from Fastloc-GPS data, whereas high-quality Argos locations (location classes 1-3) produced home range estimates that were generally comparable to those derived from Fastloc-GPS data. However, the limited number of Argos class 1-3 locations obtained for all three turtles-an average of 14.6 times more Fastloc-GPS locations were obtained compared to Argos class 1-3 locations-resulted in blurred patterns of space use. In contrast, the high volume of Fastloc-GPS locations revealed fine-scale movements in striking detail (i.e., use of discrete patches separated by just a few 100 m). We recommend careful consideration of the effects of location accuracy and data volume when developing sampling regimes for marine tracking studies and make recommendations regarding how sampling can be standardized to facilitate meaningful spatial and temporal comparisons of space use. [ABSTRACT FROM AUTHOR]

In Lake Tanganyika, lake level fluctuations were shown to have had a major impact on the evolution of littoral species. Many species are subdivided into arrays of populations, geographical races and sister species, each colonizing a particular section of the shore. Their often limited dispersal abilities promoted geographic isolation and, on the long run, allopatric speciation. With more than 120 distinct populations, the genus Tropheus represents the most spectacular and best-studied example of this phenomenon. The present study aims at the fine-scale reconstruction of the spread of two mitochondrial Tropheus-lineages in the very north of the lake, where two species, T. sp. 'black' and T. brichardi, occur. Using mtDNA sequences and AFLP-data, we analyzed samples from 21 localities and found a highly complex conglomerate of introgressed populations formed by the repeated contact of two lineages. Our data suggest repeated cross-lake dispersal of T. sp. 'black' haplotypes along the ridge between the West and East Ubwari Fault, supporting an additional persisting lowstand-lake in the Bujumbura subbasin at the very north of the lake and highlighting once more the impact of lake level fluctuations on the genetic structure and evolution of stenotopic rock-dwelling cichlid species. [ABSTRACT FROM AUTHOR]

Spontaneous eye blink rate is modulated by task demands and internal state, and is demonstrated to reflect central dopamine activity. Also, spontaneous eye blinks are strategically timed around salient stimuli. This study investigates whether children with attention deficit hyperactivity disorder (ADHD) show reduced blink rates, blink modulation and blink timing, and whether this is influenced by stimulant medication. The electrooculogram was measured in 18 typically developing children, 16 children with ADHD off methylphenidate (Mph), and 16 children with ADHD on Mph during a rest period and during performance of a 60-min visual selective attention task. Blink rate and timing was extracted from the electrooculogram. No evidence was found for aberrant blink rate or blink modulation in children with ADHD off Mph. All groups increased blink rates from rest to task, and no group differences were found in blink rate during rest and task, or in the modulation of blink rate from rest to task. Time-on task resulted in a similar increase in blink rates in all three groups. Stimulant medication appeared not to influence blink rate and blink modulation, except that in the ADHD off Mph group the blink rate was enhanced only under conditions with performance feedback. All groups inhibited blinks before stimulus presentation and strategically timed their blinks after the stimulus. Children with ADHD off Mph showed reduced blink inhibition before the stimulus; however, given the low incidence (<1 % of the trials) and long latency this is not likely to impair their visual intake. [ABSTRACT FROM AUTHOR]

Background: T-cell responses contribute to the anti-tumoural effect of photodynamic therapy (PDT). For such responses to occur, dendritic cells (DCs) have to migrate to the tumour, take up tumour antigens and respond to danger signals with maturation, before they engage in T-cell activation. Here, we have studied the effect of 5-aminolevulinic acid (ALA)-mediated PDT on DCs in vitro in a human spheroid model of glioblastoma (GB).Methods: Spheroids of the GB cell lines U87 and U251 were treated with ALA/PDT, and effects on attraction, uptake of tumour antigens and maturation of DCs were studied. To block heat-shock protein-70 (HSP-70) on the spheroids, neutralising antibodies were used.Results: 5-Aminolevulinic acid /PDT-treated GB spheroids attracted DCs that acquired tumour antigens from the spheroids effectively. Moreover, co-culture with ALA/PDT-treated spheroids induced DC maturation as indicated by the upregulation of CD83 and co-stimulatory molecules as well as increased T-cell stimulatory activity of the DCs. Heat-shock protein-70 was upregulated on the spheroids after ALA/PDT treatment. Uptake of tumour antigens and DC maturation induced by the ALA/PDT-treated spheroids were inhibited when HSP-70 was blocked.Conclusion: ALA/PDT treatment of glioma spheroids promotes the three initial steps of the afferent phase of adaptive immunity, which is at least partially mediated by HSP-70. [ABSTRACT FROM AUTHOR]

Background: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (CRC). KRAS mutation analysis is usually performed on primary tumour tissue because metastatic tissue is often not available. However, controversial data are available on the concordance of test results between primary tumours and corresponding metastases. We assessed the concordance of KRAS mutation status in a study of 305 primary colorectal tumours and their corresponding liver metastases.Methods: Patients with histologically confirmed CRC who underwent surgical resection of the primary tumour and biopsy or surgical resection of the corresponding liver metastasis were included. KRAS mutation analysis was performed for codons 12 and 13.Results: KRAS mutation was detected in 108 out of 305 primary tumours (35.4%). In 11 cases (3.6%), we found a discordance between primary tumour and metastasis: 5 primary tumours had a KRAS mutation with a wild-type metastasis, 1 primary tumour was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumour and the metastasis had a different KRAS mutation.Conclusion: We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6-98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0%; 95% CI 0.7-4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis. [ABSTRACT FROM AUTHOR]

Scepticism over stated preference surveys conducted online revolves around the concerns over 'professional respondents' who might rush through the questionnaire without sufficiently considering the information provided. To gain insight on the validity of this phenomenon and test the effect of response time on choice randomness, this study makes use of a recently conducted choice experiment survey on ecological and amenity effects of an offshore windfarm in the UK. The positive relationship between self-rated and inferred attribute attendance and response time is taken as evidence for a link between response time and cognitive effort. Subsequently, the generalised multinomial logit model is employed to test the effect of response time on scale, which indicates the weight of the deterministic relative to the error component in the random utility model. Results show that longer response time increases scale, i.e. decreases choice randomness. This positive scale effect of response time is further found to be non-linear and wear off at some point beyond which extreme response time decreases scale. While response time does not systematically affect welfare estimates, higher response time increases the precision of such estimates. These effects persist when self-reported choice certainty is controlled for. Implications of the results for online stated preference surveys and further research are discussed. [ABSTRACT FROM AUTHOR]

A concurrent Abstract State Machine (ASM) is a family of agents each equipped with a sequential ASM to execute. We define the semantics of concurrent ASMs by concurrent ASM runs which overcome the problems of Gurevich's distributed ASM runs and generalize Lamport's sequentially consistent runs. A postulate characterizing an intuitive understanding of concurrency is formulated. It allows us to state and prove an extension of the sequential ASM thesis to a concurrent ASM thesis. [ABSTRACT FROM AUTHOR]

Hyperpolarization activated and cyclic nucleotide-gated (HCN) ion channels as well as cyclic nucleotide-gated (CNG) ion channels are essential for the regulation of cardiac cells, neuronal excitability, and signaling in sensory cells. Both classes are composed of four subunits. Each subunit comprises a transmembrane region, intracellular N- and C-termini, and a C-terminal cyclic nucleotide-binding domain (CNBD). Binding of cyclic nucleotides to the CNBD promotes opening of both CNG and HCN channels. In case of CNG channels, binding of cyclic nucleotides to the CNBD is sufficient to open the channel. In contrast, HCN channels open upon membrane hyperpolarization and their activity is modulated by binding of cyclic nucleotides shifting the activation potential to more positive values. Although several high-resolution structures of CNBDs from HCN and CNG channels are available, the gating mechanism for murine HCN2 channel, which leads to the opening of the channel pore, is still poorly understood. As part of a structural investigation, here, we report the complete backbone and side chain resonance assignments of the murine HCN2 CNBD with part of the C-linker. [ABSTRACT FROM AUTHOR]

Tissue damage due to apoptotic or necrotic cell death typically initiates distinct cellular responses, leading either directly to tissue repair and regeneration or to immunological processes first, to clear the site, for example, of potentially damage-inducing agents. Mesenchymal stem cells (MSC) as well as immature dendritic cells (iDC) and monocytes migrate to injured tissues. MSC have regenerative capacity, whereas monocytes and iDC have a critical role in inflammation and induction of immune responses, including autoimmunity after tissue damage. Here, we investigated the influence of apoptotic and necrotic cell death on recruitment of MSC, monocytes and iDC, and identified hepatocyte growth factor (HGF) and the alarmin high mobility group box 1 (HMGB1) as key factors differentially regulating these migratory responses. MSC, but not monocytes or iDC, were attracted by apoptotic cardiomyocytic and neuronal cells, whereas necrosis induced migration of monocytes and iDC, but not of MSC. Only apoptotic cell death resulted in HGF production and HGF-mediated migration of MSC towards the apoptotic targets. In contrast, HMGB1 was predominantly released by the necrotic cells and mediated recruitment of monocytes and iDC via the receptor of advanced glycation end products. Moreover, necrotic cardiomyocytic and neuronal cells caused an HMGB1/toll-like receptor-4-dependent inhibition of MSC migration towards apoptosis or HGF, while recruitment of monocytes and iDC by necrosis or HMGB1 was not affected by apoptotic cells or HGF. Thus, the type of cell death differentially regulates recruitment of either MSC or monocytes and iDC through HGF and HMGB1, respectively, with a dominant, HMGB1-mediated role of necrosis in determining tropism after tissue injury. [ABSTRACT FROM AUTHOR]

Human activities, especially conversion and degradation of habitats, are causing global biodiversity declines. How local ecological assemblages are responding is less clear-a concern given their importance for many ecosystem functions and services. We analysed a terrestrial assemblage database of unprecedented geographic and taxonomic coverage to quantify local biodiversity responses to land use and related changes. Here we show that in the worst-affected habitats, these pressures reduce within-sample species richness by an average of 76.5%, total abundance by 39.5% and rarefaction-based richness by 40.3%. We estimate that, globally, these pressures have already slightly reduced average within-sample richness (by 13.6%), total abundance (10.7%) and rarefaction-based richness (8.1%), with changes showing marked spatial variation. Rapid further losses are predicted under a business-as-usual land-use scenario; within-sample richness is projected to fall by a further 3.4% globally by 2100, with losses concentrated in biodiverse but economically poor countries. Strong mitigation can deliver much more positive biodiversity changes (up to a 1.9% average increase) that are less strongly related to countries' socioeconomic status. [ABSTRACT FROM AUTHOR]

The cultivation of rubber trees in Xishuangbanna Prefecture in China's Yunnan Province has triggered an unprecedented economic development but it is also associated with severe environmental problems. Rubber plantations are encroaching the indigenous rain forests at a large scale and a high speed in Xishuangbanna. Many rare plant and animal species are endangered by this development, the natural water management is disturbed, and even the microclimate in this region has changed over the past years. The present study aims at an assessment of the environmental benefits accruing from a reforestation project partly reversing the deforestation that has taken place over the past years. To this end, a Contingent Valuation survey has been conducted in Xishuangbanna to elicit local residents' willingness to pay for this reforestation program that converts existing rubber plantations back into forest. It is shown that local people's awareness of the environmental problems caused by increasing rubber plantation is quite high and that in spite of the economic advantages of rubber plantation there is a positive willingness among the local population to contribute financially to a reduction of existing rubber plantations for the sake of a partial restoration of the local rain forest. These results could be used for the practical implementation of a Payments for Eco-System Services system for reforestation in Xishuangbanna. [ABSTRACT FROM AUTHOR]