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To date, little is known about applicability and/or generality of molecular features and how they impact small molecule permeation into Gram-negative bacteria. Identifying motifs or structural trends that correlate with broad and/or species-specific permeation would enable the rational design of new antibacterials. The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered todoi:10.1101/2022.06.27.497815 fatcat:eikv5rywvreklp6b4a5ext7ey4
more »... umulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. E. coli, A. baumannii, and P. aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer-membrane and/or enhance efflux susceptibility broadly and specifically between species. The results of this study illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogs (3e, 12f, and 14) were identified from this study that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.
Dementia with Lewy bodies (DLB) and Corticobasal Syndrome (CBS) are atypical parkinsonian disorders with fronto-subcortical and posterior cognitive dysfunction as common features. While visual hallucinations are a good predictor of Lewy body pathology and are rare in CBS, they are not exhibited in all cases of DLB. Given the clinical overlap between these disorders, neuropsychological and imaging markers may aid in distinguishing these entities. Methods: Prospectively recruited case-controldoi:10.1186/s13195-014-0071-4 pmid:25484929 pmcid:PMC4256921 fatcat:l7o3ztswkvc6zgwryymzel3iui
more »... rts of CBS (n =31) and visual hallucination-free DLB (n =30), completed neuropsychological and neuropsychiatric measures as well as brain perfusion single-photon emission computed tomography and structural magnetic resonance imaging (MRI). Perfusion data were available for forty-two controls. Behavioural, perfusion, and cortical volume and thickness measures were compared between the groups to identify features that serve to differentiate them.
The Ras/MAPK (RAF/MEK/ERK) pathway plays a central role in regulating mammalian cell growth, differentiation, and survival by relaying extracellular signals from ligand bound cell surface tyrosine kinase receptors, making it an excellent target for treatment for cancers with activation of this pathway. This poster presents the identification of the initial hit from ALIS (Automated Ligand Identification System) and the optimization of the hit towards MK 8353. The modifications were required todoi:10.1107/s0108767318098021 fatcat:7jlv2ac2rzccbegif4rc4qgqly
more »... prove activity, pharmacokinetics, and off target activity (HERG and CYP), while maintaining the novel movements of the glycine rich loop which opens up a new cavity for interaction with the inhibitor and ERK, allowing for better selectivity against other Kinases. MK 8353 was found to have an overall response rate of 20% (evaluable patients) during its Phase 1a/2b MK 8353 001 clinical trial.
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound 5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 7. Lead optimizationdoi:10.1021/acsmedchemlett.8b00220 pmid:30034615 pmcid:PMC6047169 fatcat:gx23f22vtbcqvmyfoywbndnds4
more »... ough focused structure−activity relationship led to the discovery of a clinical candidate MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.
CHAKESPEARE AND BRADLEY.—Who was the author of the lines referred to in “The Library "’ (ante p. 269) about Shake- speare and Bradley? ... The English paper for the year : Had several questions on ‘‘ King Lear,” Which Shakespeare answered very badly, Because he hadn't read his Bradley ! Ww. ACES. ...doi:10.1093/nq/184.12.345a fatcat:ma7wcpwvdjdgndfepa3phjrcmq
Journal of Paleontology
P., and SYLVESTER-BRADLEY, P. C., 1953, The ostracod genus Trachyleberis: Bull. British Mus. (Nat. Hist.), Zoology, vol. 2, pp. 1-16, pls. 1, 2. ... israelskyi Howe & Pyeatt, 1935 I. fissicostis Triebel, 1940 Cythereis excavata Chapman & Sherborn, 1893 Pseudocythereis reticulata Jennings, 1936 Cythereis fullonica Jones & Sherborn, 1888 O. delumbata ...
CHAKESPEARE AND BRADLEY.—Who was the author of the lines referred to in “The Library "’ (ante p. 269) about Shake- speare and Bradley? ... The English paper for the year : Had several questions on ‘‘ King Lear,” Which Shakespeare answered very badly, Because he hadn't read his Bradley ! Ww. ACES. ...doi:10.1093/nq/184.12.345c fatcat:tbd6ndhqtva6rjaw6fg36qertu
CHAKESPEARE AND BRADLEY.—Who was the author of the lines referred to in “The Library "’ (ante p. 269) about Shake- speare and Bradley? ... The English paper for the year : Had several questions on ‘‘ King Lear,” Which Shakespeare answered very badly, Because he hadn't read his Bradley ! Ww. ACES. ...doi:10.1093/nq/184.12.345d fatcat:wblgmrihpredfcxwerlsx7ts7y
<i>Lophocythere fulgurata</i> (Jones &amp; Sherborn, 1888) is demonstrated to be an instar of <i>F. juglandica major. ... Of these, <i>F. juglandica juglandica, F. juglandica major</i> (Jones &amp; Sherborn, 1888) and <i>F. juglandica postrotunda</i> subsp. nov., described as new herein, are all confined to the Upper ... var. major by Jones & Sherborn (1888) , as plesiotype of Progonocythere juglandica (Jones & Sherborn) by Sylvester-Bradley (1948) , and re-figured as Fastigatocythere juglandica by Bate (1969 ), ...doi:10.1144/jm.21.2.155 fatcat:srii3zvvv5g4razco6bfu5fmum
Journal of Paleontology
OLIGOCYTHEREIS FULLONICA (Jones and Sherborn) Plate 122, figures 1-6 Cythereis fullonica, Jones and Sherborn, 1888. Cythereis fullonica, S-Bradley, 1948, (part). Description —Carapace subrectangular. ... SYLVESTER-BRADLEY author’s Bed No. 47 FW 9, at the top of the economic Fuller’s Earth (Bathonian), mined near Combe Hay, Bath, England. OLIGOCYTHEREIS WOODWARDI Sylvester- Bradley, n. sp. ...
Correlation of the Middle-Upper Bathonian (Middle Jurassic) succession between Bath and Sherborne. Geoscience in south-west England, 9, 236-239. ... Correlation of the Middle-Upper Bathonian succession between Bath and Sherborne is reviewed in the light of a recently-published lithostratigraphical revision of this sequence. ... Wattonensis Beds with the Rugitela Beds of the Frome area, following Sylvester-Bradley and Hodson (1957) . ...doi:10.1016/s0016-7878(96)80017-4 fatcat:frx6xsfwzfdppagugiihsbetmm
CHESTER BRADLEY, Berkeley, California. (After July 15th, Cornell University, Ithaca, N. Y.) Paectes oculatrix, June 16-July 7. Exyra rolandiana, July 10, one. Melanomma auricinctaria, Aug. ...doi:10.1155/1907/64394 fatcat:4ub7fbiv2nd45osxyzylyfymsm
Massachusetts Law Review
SHERBORN REFORMATORY. We have been requested by Dr. Stearns to call the attention of the Judges to a change in policy in the matter of commitments to Sherborn Reformatory. During Mrs. ... The Board of Probation recently announced the appointment of Albert Bradley Carter as Commissioner of Probation to suc- ceed Herbert C. Parsons, resigned. Mr. ...
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