Bacterial riboswitches are structured RNAs that bind small metabolites to control downstream gene expression. Two riboswitch classes have been reported to sense nicotinamide adenine dinucleotide (NAD⁺), which plays a key redox role in cellular metabolism. The NAD⁺-I (class I) riboswitch stands out because it comprises two homologous, tandemly arranged domains. However, previous studies examined the isolated domains rather than the full-length riboswitch. Crystallography and ligand binding analyses led to the hypothesis that each domain senses NAD⁺ but with disparate equilibrium binding constants (K_D) of 127 μM (domain I) and 3.4 mM (domain II). Here, we analyzed individual domains and the full-length riboswitch by isothermal titration calorimetry to quantify the cofactor affinity and specificity. Domain I senses NAD⁺ with a K_D of 24.6 ± 8.4 μM but with a reduced ligand-to-receptor stoichiometry, consistent with nonproductive domain self-association observed by gel-filtration chromatography; domain II revealed no detectable binding. By contrast, the full-length riboswitch binds a single NAD⁺ with a K_D of 31.5 ± 1.5 μM; dinucleotides NADH and AP₂-ribavirin also bind with one-to-one stoichiometry. Unexpectedly, the full-length riboswitch also binds a single ATP equivalent (K_D = 11.0 ± 3.5 μM). The affinity trend of the full-length riboswitch is ADP = ATP > NAD⁺ = AP₂-ribavirin > NADH. Although our results support riboswitch sensing of a single NAD⁺ at concentrations significantly below the intracellular levels of this cofactor, our findings do not support the level of specificity expected for a riboswitch that exclusively senses NAD⁺. Gene regulatory implications and future challenges are discussed.

01 Sep 2023·Clinical imaging

The efficacy of abbreviated breast MRI protocols using 1.5 T MRI in the preoperative staging of newly diagnosed breast cancers.

Article

Author: Metin, Nurgül Orhan ; Tasci, Filiz ; Kupeli, Ali ; Ozdemir, Oguzhan ; Metin, Yavuz ; Kadioglu, Maksude Esra

PURPOSETo determine the efficacy of abbreviated breast magnetic resonance imaging (MRI) protocols using 1.5 T MRI in the preoperative staging of newly diagnosed breast cancers.METHODSEighty patients who underwent 1.5 T MRI between August 2014 and January 2018 for the preoperative staging of breast cancer were evaluated retrospectively. Three separate abbreviated breast MRI protocols (AP) were created from a full protocol, and the images were evaluated independently by two radiologists. AP1 included axial fat-saturated T2 weighted and diffusion-weighted (DW) images, while subtracted axial fat-saturated T1 weighted images were obtained 2 min after contrast administration in AP2. Finally, AP2 and DW images were evaluated in AP3. Lesion location, number, and size, and presence of axillary lymphadenopathy were evaluated in each protocol. Pathological data (lesion quadrant, lesion size, and presence of axillary metastases) from the 80 patients were compared with the abbreviated protocols and full diagnostic protocol.RESULTSThe best correlation with the full protocol for detecting the lesion quadrant, number of lesions, and presence of axillary lymphadenopathy was achieved with AP3 for both readers (κ = 0.954, 0.954 for the lesion quadrant, κ = 0.971, 0.910 for the number of lesions, and κ = 0.973, 0.865 for the axillary lymphadenopathy). The evaluation time in all abbreviated protocols was shorter than for the full protocol (p < 0.05). Comparing the abbreviated protocols with pathological data for both readers, the best correlation for detecting the lesion quadrant, number of lesions, and presence of axillary lymphadenopathy was achieved with AP3 (κ = 0.939, 0.954 for the lesion quadrant, κ = 0.941, 0.879 for the number of lesions, and κ = 0.842, 0.740 for axillary lymphadenopathy, respectively).CONCLUSIONAbbreviated breast MRI protocols can provide sufficient diagnostic accuracy in the preoperative staging of breast cancer, with shorter imaging and evaluation times.

23 Aug 2022·ACS Nano

Signature Effects of Vector-Guided Systemic Nano Bioconjugate Delivery Across Blood-Brain Barrier of Normal, Alzheimer’s, and Tumor Mouse Models

Article

Author: Black, Keith L. ; Koronyo-Hamaoui, Maya ; Patil, Rameshwar ; Israel, Liron L. ; Ljubimova, Julia Y. ; Grodzinski, Zachary ; Galstyan, Anna ; Rashid, Mohammad-Harun ; Sun, Tao ; Cox, Alysia ; Chiechi, Antonella ; Holler, Eggehard ; Fuchs, Dieu-Trang ; Shatalova, Ekaterina S.

The ability to cross the blood-brain barrier (BBB) is critical for targeted therapy of the central nerve system (CNS). Six peptide vectors were covalently attached to a 50 kDa poly(β-l-malic acid)-trileucine polymer forming P/LLL(40%)/vector conjugates. The vectors were Angiopep-2 (AP2), B6, Miniap-4 (M4), and d-configurated peptides D1, D3, and ACI-89, with specificity for transcytosis receptors low-density lipoprotein receptor-related protein-1 (LRP-1), transferrin receptor (TfR), bee venom-derived ion channel, and Aβ/LRP-1 related transcytosis complex, respectively. The BBB-permeation efficacies were substantially increased ("boosted") in vector conjugates of P/LLL(40%). We have found that the copolymer group binds at the endothelial membrane and, by an allosterically membrane rearrangement, exposes the sites for vector-receptor complex formation. The specificity of vectors is indicated by competition experiments with nonconjugated vectors. P/LLL(40%) does not function as an inhibitor, suggesting that the copolymer binding site is eliminated after binding of the vector-nanoconjugate. The two-step mechanism, binding to endothelial membrane and allosteric exposure of transcytosis receptors, is supposed to be an integral feature of nanoconjugate-transcytosis pathways. In vivo brain delivery signatures of the nanoconjugates were recapitulated in mouse brains of normal, tumor (glioblastoma), and Alzheimer's disease (AD) models. BBB permeation of the tumor was most efficient, followed by normal and then AD-like brain. In tumor-bearing and normal brains, AP2 was the top performing vector; however, in AD models, D3 and D1 peptides were superior ones. The TfR vector B6 was equally efficient in normal and AD-model brains. Cross-permeation efficacies are manifested through modulated vector coligation and dosage escalation such as supra-linear dose dependence and crossover transcytosis activities.

100 Deals associated with Simetride/Anhydrous Caffeine

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Indication	Country/Location	Organization	Date
Dysmenorrhea	JP	KYORIN Pharmaceutical Co., Ltd.	14 Aug 1980
Cancer Pain	JP	KYORIN Pharmaceutical Co., Ltd.	05 Nov 1966
Earache	JP	KYORIN Pharmaceutical Co., Ltd.	05 Nov 1966
Headache	JP	KYORIN Pharmaceutical Co., Ltd.	05 Nov 1966
Low Back Pain	JP	KYORIN Pharmaceutical Co., Ltd.	05 Nov 1966
Neuralgia	JP	KYORIN Pharmaceutical Co., Ltd.	05 Nov 1966
Pain, Postoperative	JP	KYORIN Pharmaceutical Co., Ltd.	05 Nov 1966
Toothache	JP	KYORIN Pharmaceutical Co., Ltd.	05 Nov 1966

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