Biomedical subjects

Joseph Cherian

Publications and source records attributed to Joseph Cherian.

5 recordsLinked to original sources

PubMed2006

Probing cell-division phenotype space and Polo-like kinase function using small molecules.

Cell-permeable small molecules that inhibit their targets on fast timescales are powerful probes of cell-division mechanisms. Such inhibitors have been identified using phenotype-based screens with chemical libraries. However, the characteristics of compound libraries needed to effectively span cell-division phenotype space, to find probes that target different mechanisms, are not known. Here we show that a small collection of 100 diaminopyrimidines (DAPs) yields a range of cell-division phenotypes, including changes in spindle geometry, chromosome positioning and mitotic index. Monopolar mitotic spindles are induced by four inhibitors, including one that targets Polo-like kinases (Plks), evolutionarily conserved serine/threonine kinases. Using chemical inhibitors and high-resolution live-cell microscopy, we found that Plk activity is needed for the assembly and maintenance of bipolar mitotic spindles. Plk inhibition destabilizes kinetochore microtubules while stabilizing other spindle microtubules, leading to monopolar spindles. Further testing of compounds based on 'privileged scaffolds', such as the DAP scaffold, could lead to new cell-division probes and antimitotic agents.

Animals↗

PubMed2006

Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence.

Growth of bacteria and fungi on fatty acid substrates requires the catabolic beta-oxidation cycle and the anaplerotic glyoxylate cycle. Propionyl-CoA generated by beta-oxidation of odd-chain fatty acids is metabolized via the methylcitrate cycle. Mycobacterium tuberculosis possesses homologues of methylcitrate synthase (MCS) and methylcitrate dehydratase (MCD) but not 2-methylisocitrate lyase (MCL). Although MCLs share limited homology with isocitrate lyases (ICLs) of the glyoxylate cycle, these enzymes are thought to be functionally non-overlapping. Previously we reported that the M. tuberculosis ICL isoforms 1 and 2 are jointly required for growth on fatty acids, in macrophages, and in mice. ICL-deficient bacteria could not grow on propionate, suggesting that in M. tuberculosis ICL1 and ICL2 might function as ICLs in the glyoxylate cycle and as MCLs in the methylcitrate cycle. Here we provide biochemical and genetic evidence supporting this interpretation. The role of the methylcitrate cycle in M. tuberculosis metabolism was further evaluated by constructing a mutant strain in which prpC (encoding MCS) and prpD (encoding MCD) were deleted. The DeltaprpDC strain could not grow on propionate media in vitro or in murine bone marrow-derived macrophages infected ex vivo; growth under these conditions was restored by complementation with a plasmid containing prpDC. Paradoxically, bacterial growth and persistence, and tissue pathology, were indistinguishable in mice infected with wild-type or DeltaprpDC bacteria.

Animals↗

PubMed2005

Recurrent pulmonary embolism despite inferior vena cava filter placement in patients with the antiphospholipid syndrome.

In patients at risk for pulmonary emboli, consideration is often given to placement of an inferior vena cava (IVC) filter to prevent propagation of a distal thrombus. However, long-term benefits remain controversial, and deep venous thrombosis and IVC thrombosis may result from the procedure itself. Whether a filter if beneficial or even detrimental in patients with the antiphospholipid syndrome (APS) is unclear. We reviewed clinical outcomes in 2 patients who had IVC filter placement years before the diagnosis of the APS and 1 who had a contraindication to anticoagulation. Recurrent pulmonary emboli were seen despite the presence of the filter. IVC pathology sometimes revealed thrombus both proximal and distal to the IVC filter. Pulmonary emboli in the APS may be secondary to deep venous thrombosis (DVT). They may also occur secondary to a cardiac source or in situ thrombosis in the pulmonary vessels. An IVC filter will not be of benefit if the heart or the lungs are the primary source for the emboli. It may also not protect against propagation of a more distal thrombus if collateral vessels develop around the filter or a thrombus is present on the proximal side of the filter. Recurrence of pulmonary emboli after a filter placement should alert the clinician to the possibility of a hypercoagulable state such as APS. Clinicians need to assess risks and benefits carefully before placing a permanent IVC filter in patients with APS. Whether a temporary or retrievable filter is safer in APS and more effective is unknown at the present time.

Adult↗

PubMed2004

Synthesis of the putative structure of eupomatilone-6.

[reaction: see text] The synthesis of eupomatilone-6 (1) has been achieved by using Suzuki coupling, Sharpless asymmetric dihydroxylation, and intramolecular Horner-Wadsworth-Emmons reactions. The spectroscopic studies carried out on synthetic eupomatilone-6 do not agree with those reported for the natural product, and therefore revision of the assigned structure is warranted.

Benzofurans↗

PubMed2003

Synthesis of spirocycles via ring closing metathesis of heterocycles carrying gem-diallyl substituents obtained via ring opening of (halomethyl)cyclopropanes with allyltributyltin.

In the presence of allyl tri-n-butyltin--AIBN, cyclopropylmethyl bromides/xanthates undergo ring-opening reaction with concomitant formation of geminal diallyl derivatives in good yields. The ring closing metathesis reactions on geminal diallyl derivatives with Grubbs' catalyst provided spirocyclopentenyl products. Combination of these two methodologies has been applied to the synthesis of mono-, bis-cyclopentyl-carbohydrates as well as spirocyclopentylproline derivatives.

Cyclopropanes↗