Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), owing to upstream signals from the B cell receptor (BCR) and MyD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase γ, a necessary event in some pathways that engage NF-κB. Two germ line polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11/MALT1/BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RFN31-RBCK1 binding, decreased NF-κB and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.
We have designed and implemented a practical nanoelectronic interface to G-protein coupled receptors (GPCRs), a large family of membrane proteins whose roles in the detection of molecules outside eukaryotic cells make them important pharmaceutical targets. Specifically, we have coupled olfactory receptor proteins (ORs) with carbon nanotube transistors. The resulting devices transduce signals associated with odorant binding to ORs in the gas phase under ambient conditions and show responses that are in excellent agreement with results from established assays for OR–ligand binding. The work represents significant progress on a path toward a bioelectronic nose that can be directly compared to biological olfactory systems as well as a general method for the study of GPCR function in multiple domains using electronic readout.
We implemented a nanoelectronic interface between graphene field effect transistors (FETs) and soluble proteins. This enables production of bioelectronic devices that combine functionalities of the biomolecular and inorganic components. The method serves to link polyhistidinetagged proteins to graphene FETs using the tag itself. Atomic Force Microscopy and Raman spectroscopy provide structural understanding of the bio/nano hybrid; current-gate voltage measurements are used to elucidate the electronic properties. As an example application, we functionalize graphene FETs with fluorescent proteins to yield hybrids that respond to light at wavelengths defined by the optical absorption spectrum of the protein.
Although microdialysis measurements suggest that extracellular dopamine concentrations in the rat striatum are in the low nanomolar range, some recent voltammetry studies suggest that the concentration may be considerably higher, perhaps in the micromolar range. The presence of such high dopamine levels in the extracellular space has to be rationalized with the rapid, linear clearance of extracellular dopamine observed after electrical stimulation of the medial forebrain bundle. Kinetic analysis of dopamine clearance after evoked release suggests that the basal extracellular dopamine concentration is below the K M of dopamine uptake, which is near 0.2 lM. However, dopamine clearance after pressure ejection of dopamine into the rat striatum is slow and non-linear, which may alternatively be a sign that basal dopamine release is only slightly slower than the maximal velocity of dopamine uptake, V max . A high basal extracellular dopamine concentration would exist if basal dopamine release were only slightly slower than the V max of uptake. This report introduces a new kinetic analysis of dopamine uptake that sheds light on the possible source of the different clearance rates observed following evoked dopamine release and dopamine pressure ejection. Furthermore, the analysis rationalizes the rapid dopamine clearance after evoked release with the possibility that basal extracellular dopamine levels are above the K M of the transporter.
Aspirin was administered by oral gavage to 25 gravid Sprague-Dawley rats on gestation day 10, as a single dose of 500 mg/kg, in a concentration of 50 mg/ml. The aspirin was suspended in a mixture of 0.5% w/v hydroxypropylmethylcellulose (Methocel E-4M) and 0.1% w/v polysorbate 80 (Tween 80). A control group of 25 gravid rats was given 10 ml/kg/day of the suspending vehicle alone, by oral gavage, on gestation days 6 through 15. C-sections were performed on gestation day 20. Approximately two-thirds of the fetuses were processed for skeletal examination with Alizarin Red S; the remaining fetuses were placed in Bouin's solution. Examination of the fetal skeletal specimens from the aspirin-treated group revealed a 20% fetal (43% litter) incidence of an accessory skull bone, located between the nasal and frontal bones. This structure ranged in size from a small, barely discernible, circular ossification site (less than 0.5 mm) to a relatively large, bilobate bone (approximately 2 mm). This anomaly has not been previously reported in fetal rats.
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