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Keith Smith

Publications and source records attributed to Keith Smith.

17 recordsLinked to original sources
PubMed2026

A combined stimulus of acute fasting and exercise modulates hippocampal mitochondrial quality control in healthy mice.

BACKGROUND AND AIMS: Exercise and fasting are recognized for their ability to improve brain health and mitigate neurodegeneration. However, little is known about how these interventions acutely impact mitochondrial quality control mechanisms including mitophagy. METHODS: We examined the effects of a single bout of fasting and exercise (FEx) on hippocampal mitochondrial function and proteomic remodeling in male and female mice. To assess in vivo autophagy dynamics, we combined proteomics with chloroquine (CQ) inhibition of autophagic flux. Mice were assigned to sedentary (Sed), fasting (F), exercise (Ex), or combined FEx groups and received unilateral intrahippocampal injections of CQ or PBS following treatments. Four hours later, hippocampi were collected for analysis. RESULTS: LC3-II levels significantly increased in the FEx group only following CQ treatment, indicating enhanced autophagic flux. Proteomic profiling showed sedentary males failed to mount a robust response to FEx however females exhibited upregulation of proteins involved in the TCA cycle, glutathione metabolism, and oxidative phosphorylation, suggesting greater mitochondrial adaptability. Functional assays supported these findings, females showed increased complex IV activity post-FEx. The mitochondrial DNA / nuclear DNA ratio increased after FEx regardless of sex, and upstream regulator analysis predicted activation of mitochondrial biogenesis. CONCLUSIONS: Together, these data reveal sex-specific mitochondrial remodeling in response to acute fasting and exercise. Defining these normative responses is critical for understanding how mitochondrial adaptability shapes resilience or vulnerability to neurological challenges.

Animals↗
PubMed2006

A novel supported Katsuki-type (salen)Mn complex for asymmetric epoxidation.

We have successfully prepared an unsymmetrical analogue of a Katsuki-type salen ligand having a hydroxyalkyl group at the 6-position of just one of the binaphthyl units in the ligand, and also several Mn(III) complexes; these complexes have been attached to a polymer by an ester link and such polymer catalysts have been shown to be highly enantioselective and recoverable catalysts for the epoxidation of 1,2-dihydronaphthalene.

Journal Article↗
PubMed2005

Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase.

Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.

Administration, Oral↗
PubMed2005

An extensive study of bromination of cis,trans,trans-1,5,9-cyclododecatriene: product structures and conformations.

Bromine has been added to cis,trans,trans-1,5,9-cyclododecatriene under various reaction conditions. All expected direct addition products have been isolated, and their structures have been determined by microanalysis, NMR and X-ray crystallography. Advanced NMR techniques were used to determine solution conformations of several of the compounds, enabling comparison with the solid-state conformations obtained by crystallography.

Journal Article↗
PubMed2004

Study of regioselective methanesulfonylation of simple aromatics with methanesulfonic anhydride in the presence of zeolite catalysts.

Regioselective methanesulfonylation of simple aromatics using methanesulfonic anhydride can be achieved over zeolite catalysts. For example, methanesulfonylation of toluene over various cation-exchanged zeolite beta catalysts affords higher para-selectivity in the synthesis of methyl tolyl sulfone than standard Friedel-Crafts methanesulfonylation utilising aluminium chloride.

Journal Article↗
PubMed2003

Mapping the kinase domain of Janus Kinase 3.

The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.

Adjuvants, Immunologic↗
PubMed2003

Potent small molecule inhibitors of spleen tyrosine kinase (Syk).

A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).

Animals↗
PubMed2003

Acylation of aromatic ethers over solid acid catalysts: scope of the reaction with more complex acylating agents.

Acylation of anisole with 2-phenylbutanoic acid derivatives, over zeolite catalysts, gives the corresponding 4-acyl derivatives with high regioselectivity. In an analogous way, 2,3-dihydrobenzofuran reacts with acid anhydrides or chlorides in the presence of catalytic quantities of zeolites to give the corresponding 5-acyl-2,3-dihydrobenzofurans. The zeolite can be recovered, regenerated and used again to give almost the same yield as with fresh zeolite. The reaction has been applied to the synthesis of ethyl (2,3-dihydrobenzofuran-5-yl)glyoxylate.

Journal Article↗
PubMed2003

Study of regioselective dialkylation of naphthalene in the presence of reusable zeolite catalysts.

Highly regioselective dialkylation of naphthalene using various alkylating agents can be achieved over zeolite catalysts. For example, the tert-butylation of naphthalene (1) using tert-butanol in cyclohexane over a dealuminated H-Mordenite (HM) zeolite has been optimised to give a 60% yield of 2.6-di-tert-butylnaphthalene (3) with a 2.6/2.7 ratio of over 50. This has been achieved by varying the reaction time, temperature, solvent, pressure, amount of tert-butanol, solvent and catalyst, Si/Al ratio of the catalyst, and the mode of addition. The zeolites can be easily regenerated by heating and reused.

Journal Article↗
PubMed2003

Locomotion, incidental learning, and the selection of spatial reference systems.

In three experiments, we examined the effects of locomotion and incidental learning on the formation of spatial memories. Participants learned the locations of objects in a room and then made judgments of relative direction, using their memories (e.g., "Imagine you are standing at the clock, facing the jar. Point to the book"). The experiments manipulated the number of headings experienced, the amount of interaction with the objects, and whether the participants were informed that their memories of the layout would be tested. When participants were required to maintain a constant body orientation during learning (Experiment 1), they represented the layout in terms of a single reference direction parallel to that orientation. When they were allowed to move freely in the room (Experiment 2), they seemed to use two orthogonal reference axes aligned with the walls of the enclosing room. Extensive movement under incidental learning conditions (Experiment 3) yielded a mixture of these two encoding strategies across participants. There was no evidence that locomotion, interaction with objects, or incidental learning led to the formation of spatial memories that differed from those formed from static viewing.

Adult↗
PubMed2002

High-grade osteosarcoma of the extremity: differences between localized and metastatic tumors at presentation.

BACKGROUND: In osteosarcoma, as in other tumors, the presence of metastases at presentation is generally considered a consequence of late diagnosis. To verify this, the authors investigated whether there was a relationship between the stage of the disease at presentation and several clinical and pathologic characteristics, including the interval between the onset of first symptoms or signs and the final diagnosis. PATIENTS AND METHODS: One thousand seventy-one patients with high-grade osteosarcoma of the extremity were observed between 1980 and 1999. Of these, 891 had a localized tumor and 180 had metastases at the time of diagnosis. RESULTS: Compared with patients with localized disease, patients with detectable metastases at the time of diagnosis had higher serum levels of alkaline phosphatase, larger primary lesions, and tumors often located in the femur and humerus. In terms of time to diagnosis, the interval between the onset of first symptoms and the final diagnosis was significantly shorter in patients with metastases than in patients with localized tumor. This surprising finding probably reflects a more rapid growth of the tumor. CONCLUSIONS: These results suggest a different biologic phenotype and aggressiveness of the tumor in a subgroup of patients and that the stage of the disease at presentation depends more on the properties of these tumors than on late diagnosis.

Adolescent↗
PubMed1996

Lithiation of 3-(Acylamino)-2-unsubstituted-, 3-(Acylamino)-2-ethyl-, and 3-(Acylamino)-2-propyl-4(3H)-quinazolinones: Convenient Syntheses of More Complex Quinazolinones(1).

3-(Pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones react with alkyllithium reagents to give 1,2-addition products in very good yields. Lithiation takes place with LDA and is regioselective at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the corresponding substituted derivatives in very good yields. Reactions of the lithium reagents with iodine give oxidatively dimerized cyclic structures. 3-(Pivaloylamino)- and 3-(acetylamino)-2-ethyl-4(3H)-quinazolinones and 3-(pivaloylamino)- and 3-(acetylamino)-2-propyl-4(3H)-quinazolinones are lithiated at the benzylic position with LDA. The lithium reagents so produced also react with a variety of electrophiles to give the corresponding 2-substituted-4(3H)-quinazolinone derivatives in very good yields. However, lithiation of 3-(acylamino)-2-(1-methylethyl)-4(3H)-quinazolinones was unsuccessful, as were lithiations of compounds having a diacetylamino group at position 3. The amide groups have been cleaved in good yield under basic or acidic conditions from some of the products to provide access to the free amino compounds.

Journal Article↗
PubMed1996

Lithiation of 2-Alkyl-3-amino- and 2-Alkyl-3-(methylamino)-4(3H)-quinazolinones(1).

3-Amino-2-methyl-4(3H)-quinazolinone has been doubly lithiated, on nitrogen and in the 2-methyl group, with n-butyllithium. The lithium reagent thus obtained reacts with a variety of electrophiles (D(2)O, benzophenone, cyclohexanone, cyclopentanone, acetophenone, benzaldehyde, tetraisopropylthiuram disulfide (TITD)) to give the corresponding 2-substituted derivatives in very good yields. Reactions of the dilithio reagent with 2 molar equiv of methyl iodide or phenyl isocyanate give disubstituted derivatives. Double lithiation of the 2-ethyl and 2-propyl analogues have been achieved using LDA, and subsequent reactions with most electophiles are then similar. In the reaction of the dianion of the 2-ethyl compound with TITD, deamination from position 3 takes place with the formation of the 2-substituted derivative. In reactions with prochiral ketones, the dianion of the 2-ethyl compound gives very high diastereoselectivity. Lithiation and subsequent reactions of 3-(methylamino) analogues take place in a similar manner, thus providing access to a range of substituted 3-(methylamino)-2-alkyl-4(3H)-quinazolinones by a general procedure. Lithiation of 3-(dimethylamino)-2-ethyl-4(3H)-quinazolinone did not take place under similar conditions. Lithiation of 3-amino-2-unsubstituted-4(3H)-quinazolinone was also unsuccessful.

Journal Article↗
PubMed1996

First Synthesis of 3-Mercapto-2(1H)-pyridinone, a Simple Disubstituted Pyridine Useful for Synthesis of the 4-Azaphenoxathiine Ring System and Its Novel Diazaphenoxathiine Analogs: 1,6-Diazaphenoxathiine and 2,6-Diazaphenoxathiine(1).

3-Mercapto-2(1H)-pyridinone (1) can be synthesized in three simple high-yielding steps from readily available 2-tert-butylthiazolo[4,5-b]pyridine (2). Its disodium salt condenses with o-chloronitrobenzene, 2-chloro-3-nitropyridine, and 3-chloro-4-nitropyridine 1-oxide to give respectively 4-azaphenoxathiine (10), 1,6-diazaphenoxathiine (12), and 2,6-diazaphenoxathiine 2-oxide (14) which reduces to 2,6-diazaphenoxathiine (15). The structures of these previously unreported azaphenoxathiine systems were confirmed by assignment of their respective (13)C NMR spectra.

Journal Article↗