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981.
Yurong Cheng Yong Li Nora Scherer Franziska Grundner-Culemann Terho Lehtimki Binisha H. Mishra Olli T. Raitakari Matthias Nauck Kai-Uwe Eckardt Peggy Sekula Ulla T. Schultheiss 《PLoS genetics》2022,18(4)
Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology. 相似文献
982.
Studies on the aerobic utilization of synthesis gas (syngas) by wild type and recombinant strains of Ralstonia eutropha H16 下载免费PDF全文
The biotechnical platform strain Ralstonia eutropha H16 was genetically engineered to express a cox subcluster of the carboxydotrophic Oligotropha carboxidovoransOM5, including (i) the structural genes coxM, ‐S and ‐L, coding for an aerobic carbon monoxide dehydrogenase (CODH) and (ii) the genes coxD, ‐E, ‐F and ‐G, essential for the maturation of CODH. The coxOc genes expressed under control of the CO2‐inducible promoter PL enabled R. eutropha to oxidize CO to CO2 for the use as carbon source, as demonstrated by 13CO experiments, but the recombinant strains remained dependent on H2 as external energy supply. Therefore, a synthetic metabolism, which could be described as ‘carboxyhydrogenotrophic’, was established in R. eutropha. With this extension of the bacterium's substrate range, growth in CO‐, H2‐ and CO2‐containing artificial synthesis gas atmosphere was enhanced, and poly(3‐hydroxybutyrate) synthesis was increased by more than 20%. 相似文献
983.
Siem Jakob Veenstra Heinrich Rueeger Markus Voegtle Rainer Lueoend Philipp Holzer Konstanze Hurth Marina Tintelnot-Blomley Mathias Frederiksen Jean-Michel Rondeau Laura Jacobson Matthias Staufenbiel Ulf Neumann Rainer Machauer 《Bioorganic & medicinal chemistry letters》2018,28(12):2195-2200
New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen. 相似文献
984.
Anette Christ Patrick Günther Mario A.R. Lauterbach Peter Duewell Debjani Biswas Karin Pelka Claus J. Scholz Marije Oosting Kristian Haendler Kevin Baßler Kathrin Klee Jonas Schulte-Schrepping Thomas Ulas Simone J.C.F.M. Moorlag Vinod Kumar Min Hi Park Leo A.B. Joosten Laszlo A. Groh Eicke Latz 《Cell》2018,172(1-2):162-175.e14
985.
Nielsen AB Székely K Gath J Ernst M Nielsen NC Meier BH 《Journal of biomolecular NMR》2012,52(4):283-288
We present a scheme that allows the simultaneous detection of PAR and PAIN correlation spectra in a single two-dimensional
experiment. For both spectra, we obtain almost the same signal-to-noise ratio as if a PAR or PAIN spectrum is recorded separately,
which in turn implies that one of the spectra may be considered additional information for free. The experiment is based on
the observation that in a PAIN experiment, the PAR condition is always also fulfilled. The performance is demonstrated experimentally
using uniformly 13C,15N-labeled samples of N–f–MLF–OH and ubiquitin. 相似文献
986.
Breitbach N Tillmann S Schleuning M Grünewald C Laube I Steffan-Dewenter I Böhning-Gaese K 《Oecologia》2012,168(2):425-437
Land-use intensification is a major cause for the decline in species diversity in human-modified landscapes. The loss of functionally
important species can reduce a variety of ecosystem functions, such as pollination and seed dispersal, but the intricate relationships
between land-use intensity, biodiversity and ecosystem functioning are still contentious. Along a gradient from forest to
intensively used farmland, we quantified bee species richness, visitation rates of bees and pollination success of wild cherry
trees (Prunus avium). We analysed the effects of structural habitat diversity at a local scale and of the proportion of suitable habitat around
each tree at a landscape scale. We compared these findings with those from previous studies of seed-dispersing birds and mammals
in the same model system and along the same land-use gradient. Bee species richness and visitation rates were found to be
highest in structurally simple habitats, whereas bird species richness—but not their visitation rates—were highest in structurally
complex habitats. Mammal visitation rates were only influenced at the landscape scale. These results show that different functional
groups of animals respond idiosyncratically to gradients in habitat and landscape structure. Despite strong effects on bees
and birds, pollination success and bird seed removal did not differ along the land-use gradient at both spatial scales. These
results suggest that mobile organisms, such as bees and birds, move over long distances in intensively used landscapes and
thereby buffer pollination and seed-dispersal interactions. We conclude that measures of species richness and interaction
frequencies are not sufficient on their own to understand the ultimate consequences of land-use intensification on ecosystem
functioning. 相似文献
987.
Kapil Kishor Khadka Joshua Shek Justine Hoffman Ryan Vulin Matthias Foellmer 《Journal of Insect Behavior》2012,25(1):96-103
Animals use a variety of chemosensory functions to coordinate behavioral actions, such as sexual recognition and courtship. In particular, many insects use antennae as a vital chemosensory organ to transmit and receive sexual signals that are believed to be crucial in mate recognition and mating in various species of insects. Crickets provide a usable model to test the significance of antennae in insects. The general importance of antennae in male crickets to initiate courtship, ensure copulation, and post-copulatory mate guarding has been documented in studies that performed full antennectomy. Our study is the first to perform partial antennectomy to test the hypothesis that even partial loss due to injury has negative effects on sexual behaviors. We found that partially antennectomized males are not slower than control males in mate recognition and courtship initiation. However, we found that partially antennectomized males take longer to achieve copulation than control males with normal uncut antennae. Our results suggest that male crickets require long, undamaged antennae to efficiently engage in mating behavior and may already incur fitness costs when they lose half of their antennae. 相似文献
988.
Johanna Schöner Andreas Heinz Matthias Endres Karen Gertz Golo Kronenberg 《Journal of cellular and molecular medicine》2017,21(10):2248-2256
Post‐traumatic stress disorder (PTSD) is a psychiatric disorder of high prevalence and major socioeconomic impact. Patients suffering from PTSD typically present intrusion and avoidance symptoms and alterations in arousal, mood and cognition that last for more than 1 month. Animal models are an indispensable tool to investigate underlying pathophysiological pathways and, in particular, the complex interplay of neuroendocrine, genetic and environmental factors that may be responsible for PTSD induction. Since the 1960s, numerous stress paradigms in rodents have been developed, based largely on Seligman's seminal formulation of ‘learned helplessness’ in canines. Rodent stress models make use of physiological or psychological stressors such as foot shock, underwater trauma, social defeat, early life stress or predator‐based stress. Apart from the brief exposure to an acute stressor, chronic stress models combining a succession of different stressors for a period of several weeks have also been developed. Chronic stress models in rats and mice may elicit characteristic PTSD‐like symptoms alongside, more broadly, depressive‐like behaviours. In this review, the major existing rodent models of PTSD are reviewed in terms of validity, advantages and limitations; moreover, significant results and implications for future research—such as the role of FKBP5, a mediator of the glucocorticoid stress response and promising target for therapeutic interventions—are discussed. 相似文献
989.
A P4‐ATPase subunit of the Cdc50 family plays a role in iron acquisition and virulence in Cryptococcus neoformans 下载免费PDF全文
Guanggan Hu Mélissa Caza Erik Bakkeren Matthias Kretschmer Gaurav Bairwa Ethan Reiner James Kronstad 《Cellular microbiology》2017,19(6)
The pathogenic fungus Cryptococcus neoformans delivers virulence factors such as capsule polysaccharide to the cell surface to cause disease in vertebrate hosts. In this study, we screened for mutants sensitive to the secretion inhibitor brefeldin A to identify secretory pathway components that contribute to virulence. We identified an ortholog of the cell division control protein 50 (Cdc50) family of the noncatalytic subunit of type IV P‐type ATPases (flippases) that establish phospholipid asymmetry in membranes and function in vesicle‐mediated trafficking. We found that a cdc50 mutant in C. neoformans was defective for survival in macrophages, attenuated for virulence in mice and impaired in iron acquisition. The mutant also showed increased sensitivity to drugs associated with phospholipid metabolism (cinnamycin and miltefosine), the antifungal drug fluconazole and curcumin, an iron chelator that accumulates in the endoplasmic reticulum. Cdc50 is expected to function with catalytic subunits of flippases, and we previously documented the involvement of the flippase aminophospholipid translocases (Apt1) in virulence factor delivery. A comparison of phenotypes with mutants defective in genes encoding candidate flippases (designated APT1, APT2, APT3, and APT4) revealed similarities primarily between cdc50 and apt1 suggesting a potential functional interaction. Overall, these results highlight the importance of membrane composition and homeostasis for the ability of C. neoformans to cause disease. 相似文献
990.