Abstract We confirm TOI-4201 b as a transiting Jovian-mass planet orbiting an early M dwarf discovered by the Transiting Exoplanet Survey Satellite. Using ground-based photometry and precise radial ...velocities from NEID and the Planet Finder Spectrograph, we measure a planet mass of 2.59 − 0.06 + 0.07 M J , making this one of the most massive planets transiting an M dwarf. The planet is ∼0.4% of the mass of its 0.63 M ⊙ host and may have a heavy-element mass comparable to the total dust mass contained in a typical class II disk. TOI-4201 b stretches our understanding of core accretion during the protoplanetary phase and the disk mass budget, necessitating giant planet formation to take place either much earlier in the disk lifetime or perhaps through alternative mechanisms like gravitational instability.
MEX3A belongs to the MEX3 (Muscle EXcess) protein family consisting of four members (MEX3A-D) in humans. Characteristic for MEX3 proteins is their domain structure with 2 HNRNPK homology (KH) domains ...mediating RNA binding and a C-terminal really interesting new gene (RING) domain that harbors E3 ligase function. In agreement with their domain composition, MEX3 proteins were reported to modulate both RNA fate and protein ubiquitination. MEX3 paralogs exhibit an oncofetal expression pattern, they are severely downregulated postnatally, and re-expression is observed in various malignancies. Enforced expression of MEX3 proteins in various cancers correlates with poor prognosis, emphasizing their oncogenic potential. The latter is supported by MEX3A's impact on proliferation, self-renewal as well as migration of tumor cells in vitro and tumor growth in xenograft studies.
More and more households are installing residential electricity storage systems to increase the self-consumption of electricity they produced. Some governments have accelerated this development ...through specific financial support schemes to offset the costs, which still remain high. Compared to the use of single-household systems, the sharing of mid-scale electricity storage systems in neighborhoods could reduce the Levelized Costs of Storage (LCOS). However, a model for the shared usage of storage by multiple households has yet to emerge. We investigated eight demonstration projects in Germany and Western Australia with capacities between 100 and 1100 kW h with respect to potential business models and barriers in a cross-case study based on document analyses and expert interviews. We found that models relying on the transmission of electricity from individual rooftop photovoltaics to a shared storage system through the public grid are facing significant regulatory barriers. Removing these policy barriers would enable a more efficient use of electricity storage systems. By contrast, projects relying on a less regulated microgrid managed by the administration or strata entities of multi-household developments already seem promising under the current regulatory framework.
•Sharing electricity storage at the community level would decrease costs.•A case study of eight demonstration projects in Germany and Australia is conducted.•Analysis w.r.t. potential business models and barriers.•Fees and taxes make sharing through the public grid economically unattractive.•Models using a customer-owned microgrid face fewer barriers and are promising.
The IGF2 mRNA-binding protein 1 (IGF2BP1) is a non-catalytic post-transcriptional enhancer of tumor growth upregulated and associated with adverse prognosis in solid cancers. However, conserved ...effector pathway(s) and the feasibility of targeting IGF2BP1 in cancer remained elusive. We reveal that IGF2BP1 is a post-transcriptional enhancer of the E2F-driven hallmark in solid cancers. IGF2BP1 promotes G1/S cell cycle transition by stabilizing mRNAs encoding positive regulators of this checkpoint like E2F1. This IGF2BP1-driven shortening of the G1 cell cycle phase relies on 3'UTR-, miRNA- and m6A-dependent regulation and suggests enhancement of cell cycle progression by m6A-modifications across cancers. In addition to E2F transcription factors, IGF2BP1 also stabilizes E2F-driven transcripts directly indicating post-transcriptional 'super'-enhancer role of the protein in E2F-driven gene expression in cancer. The small molecule BTYNB disrupts this enhancer function by impairing IGF2BP1-RNA association. Consistently, BTYNB interferes with E2F-driven gene expression and tumor growth in experimental mouse tumor models.
The solute carrier family SLC10 consists of seven members, including the bile acid transporters Na
/taurocholate co-transporting polypeptide (NTCP) and apical sodium-dependent bile acid transporter ...(ASBT), the steroid sulfate transporter SOAT as well as four orphan carriers (SLC10A3, SLC10A4, SLC10A5 and SLC10A7). Previously, homodimerization of NTCP, ASBT and SOAT was described and there is increasing evidence that carrier oligomerization is an important regulatory factor for protein sorting and transport function. In the present study, homo- and heterodimerization were systematically analyzed among all SLC10 carriers (except for SLC10A3) using the yeast-two-hybrid membrane protein system. Strong homodimerization occurred for NTCP/NTCP, ASBT/ASBT and SLC10A7/SLC10A7. Heterodimerization was observed for most of the SLC10 carrier combinations. Heterodimerization of NTCP was additionally investigated by co-localization of NTCP-GFP and NTCP-mScarlet with respective SLC10 carrier constructs. NTCP co-localized with SLC10A4, SLC10A5, SOAT and SLC10A7. This co-localization was most pronounced for SLC10A4 and was additionally confirmed by co-immunoprecipitation. Interestingly, SLC10 carrier co-expression decreased the taurocholate transport function of NTCP for most of the analyzed constructs, indicating that SLC10 carrier heterodimerization is of functional relevance. In conclusion, homo- and heterodimerization is a common feature of the SLC10 carriers. The relevance of this finding for regulation and transport function of the SLC10 carriers
needs further investigation.
Current treatment options against hepatitis B and D virus (HBV/HDV) infections have only limited curative effects. Identification of Na
/taurocholate co-transporting polypeptide (NTCP) as the ...high-affinity hepatic receptor for both viruses in 2012 enables target-based development of HBV/HDV cell-entry inhibitors. Many studies already identified appropriate NTCP inhibitors. However, most of them interfere with NTCP's physiological function as a hepatic bile acid transporter. To overcome this drawback, the present study aimed to find compounds that specifically block HBV/HDV binding to NTCP without affecting its transporter function. A novel assay was conceptualized to screen for both in parallel; virus binding to NTCP (measured via binding of a preS1-derived peptide of the large HBV/HDV envelope protein) and bile acid transport via NTCP. Hits were subsequently validated by in vitro HDV infection studies using NTCP-HepG2 cells. Derivatives of the birch-derived pentacyclic lupane-type triterpenoid betulin revealed clear NTCP inhibitory potency and selectivity for the virus receptor function of NTCP. Best performing compounds in both aspects were 2, 6, 19, and 25. In conclusion, betulin derivatives show clear structure-activity relationships for potent and selective inhibition of the HBV/HDV virus receptor function of NTCP without tackling its physiological bile acid transport function and therefore are promising drug candidates.
The multidrug resistance gene MDR1 (syn. ABCB1) encodes for the multidrug efflux transporter P-glycoprotein (P-gp), which is highly expressed at the blood-brain barrier and protects the brain from ...potentially neurotoxic compounds, such as ivermectin. MDR1 mutation in dogs is known to be linked to dramatically increased brain accumulation of ivermectin and life-threatening neurological toxicity. The present report describes two suspected ivermectin-sensitive Maine Coon cats, which exhibited neurological toxicity following subcutaneous application of therapeutic doses of ivermectin. Both cats showed a homozygous 2-bp deletion in the MDR1/ABCB1 coding sequence (
ABCB1
1930_1931del TC, syn. MDR1 nt1930(del2)) that had previously been associated with a drug-sensitive phenotype in cats. For cat MDR1 genotyping, a novel TaqMan allelic discrimination assay was established and validated. This assay was used for
ABCB1
1930_1931del TC genotyping of the drug-sensitive cats as well as of more than 50 relatives. About half of them had the heterozygous MDR1(+/-) genotype, while none of these related cats with former ivermectin treatment had a history of drug-sensitivity. In conclusion: The present study supports previous findings on drug-sensitivity in cats with homozygous
ABCB1
1930_1931del TC mutation. The newly established TaqMan allelic discrimination assay provides a useful and reliable method for routine MDR1 genotyping in cats in order to identify drug-sensitive cats prior to treatment with established P-gp substrates such as ivermectin and other macrocyclic lactones and thus to improve therapeutic safety.
This study focuses on seafloor methane seep sites and their distribution in the northwestern part of the German North Sea. Methane seepage is a common phenomenon along marine shelves and known to ...occur in the North Sea, but proof of their existence was lacking in the study area. Using a ship-based multibeam echosounder we detected a minimum of 166 flares that are indicative for free gas releases from the seafloor in the German “Entenschnabel” area, which are not related to morphologic expressions at the seafloor. However, a group of small depressions was detected lacking water column anomalies but with indications of dissolved fluid release. Spatial analysis revealed that flares were not randomly distributed but show a relation to locations of subsurface salt diapirs. More than 60% of all flares were found in the vicinity of the salt diapir “Berta”. Dissolved methane concentrations of ∼100 nM in bottom waters were ten times the background value in the “Entenschnabel” area (CH
4
< 10 nM), supporting the finding of enhanced seepage activity in this part of our study area. Furthermore, locations of flares were often related to acoustic blanking and high amplitude reflections in sediment profiler echograms, most prominently observed at location Berta. These hydroacoustic signatures are interpreted to result from increased free gas concentrations in the sediments. Electromagnetic seabed mapping depicts local sediment conductivity anomalies below a flare cluster at Berta, which can be explained by small amounts of free gas in the sediment. In our area of interest, ten abandoned well sites were included in our mapping campaign, but flare observations were spatially not related to these wells. Naturally seeping methane is presumably transported to the seafloor along sub-vertical faults, which have formed concurrently to the updoming salt. Due to the shallow water depths of 30 to 50 m in the study area, flares were observed to reach close to the sea surface and a slight oversaturation of surface waters with methane in the flare-rich northeastern part of the working area indicates that part of the released methane through seepage may contribute to the atmospheric inventory.
Fibroblast growth factor (FGF)-23 is a phosphaturic hormone. An association between increasing FGF-23 levels and progression of chronic kidney disease (CKD) was documented in cats, dogs, and humans. ...The information regarding reference intervals (RIs) of FGF-23 in cats is limited. We aimed to establish RIs in a large cohort of clinically healthy cats and to investigate correlations with sex and age. A total of 118 cats with unremarkable complete blood count and serum chemistry profile were included. Clinically sick cats, cats with concurrent diseases, suspicion of CKD, or receiving renal diets were excluded. FGF-23 concentrations were measured with the FGF-23 ELISA Kit. RIs were calculated using the reference interval advisor software 2.1 (Microsoft Excel). FGF-23 concentrations were correlated with sex and age. The RI for FGF-23 concentrations spanned 85.8 to 387.0 pg/mL (90% confidence interval: lower limit 40.5 to 103.9 pg/mL, upper limit: 354.6 to 425.0 pg/mL). No significant relationships (r2 = 0.044) were detected with age (p = 0.081) or sex (p = 0.191). Other studies of the same diagnostic assay calculated RIs of 56 to 700 pg/mL in 79 cats and <336 pg/mL in 108 cats, and in concordance with the present study, did not detect any correlation with sex or age.
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