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Large‐scale biodiversity databases have great potential for quantifying long‐term trends of species, but they also bring many methodological challenges. Spatial bias of species occurrence records is well recognized. Yet, the dynamic nature of this spatial bias – how spatial bias has changed over time – has been largely overlooked. We examined the spatial bias of species occurrence records within multiple biodiversity databases in Germany and tested whether spatial bias in relation to land cover or land use (urban and protected areas) has changed over time. We focused our analyses on urban and protected areas as these represent two well‐known correlates of sampling bias in biodiversity datasets. We found that the proportion of annual records from urban areas has increased over time while the proportion of annual records within protected areas has not consistently changed. Using simulations, we examined the implications of this changing sampling bias for estimation of long‐term trends of species' distributions. When assessing biodiversity change, our findings suggest that the effects of spatial bias depend on how it affects sampling of the underlying land‐use change drivers affecting species. Oversampling of regions undergoing the greatest degree of change, for instance near human settlements, might lead to overestimation of the trends of specialist species. For robust estimation of the long‐term trends in species' distributions, analyses using species occurrence records may need to consider not only spatial bias, but also changes in the spatial bias through time.

Over the last decades, the worldwide decline of amphibian populations has become a major concern of researchers and conservationists. Studies have reported a diversity of trends, with some species strongly declining, others remaining stable and still others increasing. However, only a few species have been monitored annually for a long period of time by specific monitoring programmes. Instead, there are many heterogeneous datasets that contain observations of amphibians from professional surveys as well as diverse citizen science and other voluntary surveys. The use of these data brings a number of challenges, raising concerns about their validity and use in ecological research and conservation. We assessed to what extent such heterogeneous occurrence data can provide information on the status and trends of amphibians by contrasting different approaches to overcoming challenges with the data, using the German state of Saxony as an example. We assessed the effects of data processing decisions to infer absences, the use of survey method information and the statistical model (generalised linear mixed-effect occurrence model [GLMM] versus occupancy-detection model) and compared the trends with expert opinions (Red Lists). The different data processing decisions mainly led to similar annual occupancy estimates, newts being an exception. Annual occupancy estimates were typically less certain when attempting to account for the effects of survey methods, which could be explained by many missing values on methods. Separate models for drift fence data reduced the uncertainty in the annual occurrence probability estimates of the GLMM models, but uncertainty remained high for occupancy-detection models. For both methods, strong peaks and troughs in the annual occupancy estimates occurred for several species, which were not biologically plausible. Some peaks align with periods of lower sampling effort and were probably caused by shifts in the sampling locations or target species amongst years. Only for three species ( Bufotes viridis , Hyla arborea and Pelophylax esculentus ) were the trend results consistent amongst approaches and with expert opinions. For most other species, some inconsistencies appeared amongst models or approaches, indicating that trend assessments are sensitive to analytical choices. While heterogeneous data have proved useful for other taxa, our results highlight the complexity of using them for amphibians. We strongly recommend better harmonisation of data collection and metadata documentation, including explicit absence data and, if available, abundance data, to enable more robust trend assessments in the future.

Background The European spurge hawkmoth, Hyles euphorbiae (Lepidoptera, Sphingidae), has been intensively studied as a model organism for insect chemical ecology, cold hardiness and evolution of species delineation. To understand species isolation mechanisms at a molecular level, this study aims at determining genetic factors underlying two adaptive ecological trait candidates, phorbol ester (TPA) detoxification and seasonal cold acclimation. Method A draft transcriptome of H. euphorbiae was generated using Illumina sequencing, providing the first genomic resource for the hawkmoth subfamily Macroglossinae. RNA expression levels in tissues of experimental TPA feeding larvae and cooled pupae was compared to levels in control larvae and pupae using 26 bp RNA sequence tag libraries (DeepSuperSAGE). Differential gene expression was assessed by homology searches of the tags in the transcriptome. Results In total, 389 and 605 differentially expressed transcripts for detoxification and cold hardiness, respectively, could be identified and annotated with proteins. The majority (22 of 28) of differentially expressed detox transcripts of the four ‘drug metabolism’ enzyme groups (cytochrome P450 (CYP), carboxylesterases (CES), glutathione S-transferases (GST) and lipases) are up-regulated. Triacylglycerol lipase was significantly over proportionally annotated among up-regulated detox transcripts. We record several up-regulated lipases, GSTe2, two CESs, CYP9A21, CYP6BD6 and CYP9A17 as candidate genes for further H. euphorbiae TPA detoxification analyses. Differential gene expression of the cold acclimation treatment is marked by metabolic depression with enriched Gene Ontology terms among down-regulated transcripts almost exclusively comprising metabolism, aerobic respiration and dissimilative functions. Down-regulated transcripts include energy expensive respiratory proteins like NADH dehydrogenase, cytochrome oxidase and ATP synthase. Gene expression patterns show shifts in carbohydrate metabolism towards cryoprotectant production. The Glycolysis enzymes, G1Pase, A1e, Gpi and an Akr isoform are up-regulated. Glycerol, an osmolyte which lowers the body liquid supercooling point, appears to be the predominant polyol cryoprotectant in H. euphorbiae diapause pupae. Several protein candidates involved in glucose, glycerol, myo-inositol and potentially sorbitol and trehalose synthesis were identified. Conclusions A majority of differently expressed transcripts unique for either detoxification or cold hardiness indicates highly specialized functional adaptation which may have evolved from general cell metabolism and stress response.The transcriptome and extracted candidate biomarkers provide a basis for further gene expression studies of physiological processes and adaptive traits in H. euphorbiae .

The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two known isoforms of the adiponectin receptor. The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite—sphingosine-1-phosphate (S1P)—independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

Analysis of gene-expression patterns led to the development of a molecular definition of Burkitt's lymphoma that distinguishes it from other types of mature aggressive B-cell lymphoma. Almost all cases defined by the gene-expression signature as Burkitt's lymphoma had the typical Burkitt's IG-myc translocation. Patients whose tumors did not have the Burkitt's signature had a poor outcome if the tumor cells had complex chromosomal changes. Analysis of gene-expression patterns led to the development of a molecular definition of Burkitt's lymphoma that distinguishes it from other types of mature aggressive B-cell lymphoma. Patients whose tumors did not have the Burkitt's signature had a poor outcome if the tumor cells had complex chromosomal changes. Burkitt's lymphoma and diffuse large-B-cell lymphoma are mature aggressive B-cell lymphomas. If left untreated, they follow a rapid clinical course and are fatal within months. Burkitt's lymphoma is a distinct entity that includes endemic and sporadic types and cases associated with immunodeficiency or immunosuppression. 1 With the use of chemotherapy regimens that involve methotrexate and cytarabine, cure rates for sporadic Burkitt's lymphoma approach 90 percent in children and 70 percent in adults. 2 Diffuse large-B-cell lymphoma, by contrast, is biologically and clinically heterogeneous and comprises five morphologic variants and three subtypes. 3 Treatment with a combination of chemotherapy based on cyclophosphamide, doxorubicin, vincristine, . . .

Migalastat stabilizes mutant α-galactosidase in Fabry's disease, reducing globotriaosylceramide deposition. In this study, the percentage of patients with a decrease of 50% or more in kidney interstitial capillary deposition at 6 months was similar in the migalastat and placebo groups. Fabry’s disease is a rare, progressive, and devastating X-linked disorder caused by the functional deficiency of lysosomal α-galactosidase. 1 The resultant accumulation of glycosphingolipids, predominantly globotriaosylceramide (GL-3), can lead to multisystem disease and early death. 2 Binding of the pharmacologic chaperone migalastat to the active site of α-galactosidase stabilizes certain mutant enzymes, thus facilitating proper trafficking to lysosomes, where dissociation of migalastat allows α-galactosidase to catabolize accumulated substrates. 3 – 7 In patients with mutant enzymes that are identified with the validated assay, orally administered migalastat may be an alternative treatment option for addressing certain unmet medical needs associated with enzyme-replacement therapy — for . . .

Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Data were evaluated in two subgroups of patients with migalastat-amenable GLA variants: “classic phenotype” (n=14; males with residual peripheral blood mononuclear cell α-galactosidase A <3% normal and multiorgan system involvement) and “other patients” (n=36; males not meeting classic phenotype criteria and all females). Endpoints included estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMi), Gastrointestinal Symptoms Rating Scale diarrhea subscale (GSRS-D), renal peritubular capillary (PTC) globotriaosylceramide (GL-3) inclusions, and plasma globotriaosylsphingosine (lyso-Gb3). Baseline measures in the classic phenotype patients suggested a more severe phenotype. At month 24, mean (SD) annualized change in eGFRCKD-EPI with migalastat was −0.3 (3.76) mL/min/1.73m2 in the classic phenotype subgroup; changes in LVMi, GSRS-D, and lyso-Gb3 were −16.7 (18.64) g/m2, −0.9 (1.66), and −36.8 (35.78) nmol/L, respectively. At month 6, mean PTC GL-3 inclusions decreased with migalastat (−0.8) and increased with placebo (0.3); switching from placebo to migalastat, PTC inclusions decreased by −0.7. Numerically smaller changes in these endpoints were observed in the other patients. Migalastat provided clinical benefit to patients with Fabry disease and amenable variants, regardless of disease severity.

The Deep Convective Clouds and Chemistry (DC3) field experiment produced an exceptional dataset on thunderstorms, including their dynamical, physical, and electrical structures and their impact on the chemical composition of the troposphere. The field experiment gathered detailed information on the chemical composition of the inflow and outflow regions of midlatitude thunderstorms in northeast Colorado, west Texas to central Oklahoma, and northern Alabama. A unique aspect of the DC3 strategy was to locate and sample the convective outflow a day after active convection in order to measure the chemical transformations within the upper-tropospheric convective plume. These data are being analyzed to investigate transport and dynamics of the storms, scavenging of soluble trace gases and aerosols, production of nitrogen oxides by lightning, relationships between lightning flash rates and storm parameters, chemistry in the upper troposphere that is affected by the convection, and related source characterization of the three sampling regions. DC3 also documented biomass-burning plumes and the interactions of these plumes with deep convection.

Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of α-Gal to facilitate normal lysosomal trafficking.MethodsThe main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.ResultsFifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5:1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of α-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (−6.6 g/m2 (−11.0 to −2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.ConclusionsMigalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.Trial registration number:NCT00925301; Pre-results.