Letter to the Editor: 1H, 15N, and 13C chemical shift assignments of the resuscitation promoting factor domain of Rv1009 from Mycobacterium tuberculosis

International audienceNo abstract availabl

Brain barriers and brain fluid research in 2016: advances, challenges and controversies

Abstract This editorial highlights some of the advances that occurred in relation to brain barriers and brain fluid research in 2016. It also aims to raise some of the attendant controversies and challenges in such research.http://deepblue.lib.umich.edu/bitstream/2027.42/136059/1/12987_2017_Article_52.pd

The year in review: progress in brain barriers and brain fluid research in 2018

Abstract This editorial focuses on the progress made in brain barrier and brain fluid research in 2018. It highlights some recent advances in knowledge and techniques, as well as prevalent themes and controversies. Areas covered include: modeling, the brain endothelium, the neurovascular unit, the blood–CSF barrier and CSF, drug delivery, fluid movement within the brain, the impact of disease states, and heterogeneity.https://deepblue.lib.umich.edu/bitstream/2027.42/147737/1/12987_2019_Article_124.pd

Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65903/1/j.1471-4159.2007.04905.x.pd

Glutamine Uptake at the Blood-Brain Barrier Is Mediated by N-System Transport

The mechanism of unidirectional transport of glutamine from blood to brain in pentobarbital-anesthetized rats was examined using in situ perfusion. Amino acid uptake into brain across the blood-brain barrier (BBB) is classically thought to be via the Na-independent large neutral (L-system), acidic and basic amino acid transporters. In the presence of physiological concentrations of amino acids in the perfusate, which should saturate the known amino acid transporters at the BBB, the cortical transfer constant ( K i ) for l-[ 14 C]glutamine was 11.6 ± 1.1 µl/g/min. The addition of either 10 m M 2-amino-2-norbornanecarboxylic acid or 10 m M 2-amino-2-norbornanecarboxylic acid and 5 m M cysteine had no effect on the cortical K i for l-[ 14 C]glutamine, indicating that glutamine transport under these conditions does not occur by the L-, A-, or ASC-systems. Decreasing perfusate Na from 140 to 2.4 m M by Tris substitution reduced the cortical K i for l-[ 14 C]glutamine by 62% ( p ≤ 0.001). The Na-dependent uptake has the characteristics of N-system transport. It was inhibited by l-histidine and l-glutamine, both N-system substrates, and it was pH sensitive and moderately tolerant of Li substitution for Na. This putative N-system transporter at the luminal membrane of the BBB plays an important role in mediating brain glutamine uptake.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65581/1/j.1471-4159.1998.71062565.x.pd

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154657/1/fsb2fj201700699r-sup-0003.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154657/2/fsb2fj201700699r.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154657/3/fsb2fj201700699r-sup-0002.pd

How coenzyme B12 radicals are generated: the crystal structure of methylmalonyl-coenzyme A mutase at 2 å resolution

AbstractBackground: The enzyme methylmalonyl-coenzyme A (CoA) mutase, an αβ heterodimer of 150 kDa, is a member of a class of enzymes that uses coenzyme B12 (adenosylcobalamin) as a cofactor. The enzyme induces the formation of an adenosyl radical from the cofactor. This radical then initiates a free-radical rearrangement of its substrate, succinyl-CoA, to methylmalonyl-CoA.Results Reported here is the crystal structure at 2 å resolution of methylmalonyl-CoA mutase from Propionibacterium shermanii in complex with coenzyme B12 and with the partial substrate desulpho-CoA (lacking the succinyl group and the sulphur atom of the substrate). The coenzyme is bound by a domain which shares a similar fold to those of flavodoxin and the B12-binding domain of methylcobalamin-dependent methionine synthase. The cobalt atom is coordinated, via a long bond, to a histidine from the protein. The partial substrate is bound along the axis of a (β/α)8 TIM barrel domain.Conclusion The histidine–cobalt distance is very long (2.5 å compared with 1.95–2.2 å in free cobalamins), suggesting that the enzyme positions the histidine in order to weaken the metal–carbon bond of the cofactor and favour the formation of the initial radical species. The active site is deeply buried, and the only access to it is through a narrow tunnel along the axis of the TIM barrel domain

Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases

The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic routes have been reported, the substrate scope is limited to certain structural motifs. The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynthesis, has been shown to perform stereoselective Pictet–Spengler reactions between dopamine and several carbonyl substrates. Here, benzaldehydes are explored as substrates and found to be accepted by both wild-type and mutant constructs of NCS. In particular, the variant M97V gives a range of (1 S)-aryl-THIQs in high yields (48–99%) and e.e.s (79–95%). A co-crystallised structure of the M97V variant with an active site reaction intermediate analogue is also obtained with the ligand in a pre-cyclisation conformation, consistent with (1 S)-THIQs formation. Selected THIQs are then used with catechol O-methyltransferases with exceptional regioselectivity. This work demonstrates valuable biocatalytic approaches to a range of (1 S)-THIQs

Animals can assign novel odours to a known category

The ability to identify a novel stimulus as a member of a known category allows an organism torespond appropriately towards it. Categorisation is thus a fundamental component of cognition andan essential tool for processing and responding to unknown stimuli. Therefore, one might expectto observe it throughout the animal kingdom and across sensory domains. There is much evidenceof visual categorisation in non-human animals, but we currently know little about this process inother modalities. In this experiment, we investigated categorisation in the olfactory domain. Dogswere trained to discriminate between 40 odours; the presence or absence of accelerants formed thecategorical rule. Those in the experimental group were rewarded for responding to substrates withaccelerants (either burnt or un-burnt) and inhibit responses to the same substrates (either burnt or unburnt)without accelerants (S+ counterbalanced). The pseudocategory control group was trained onthe same stimuli without the categorical rule. The experimental group learned the discrimination andanimals were able to generalise to novel stimuli from the same category. None of the control animalswere able to learn the discrimination within the maximum number of trials. This study provides the firstevidence that non-human animals can learn to categorise non-biologically relevant odour information

The role of the coagulation cascade in brain edema formation after intracerebral hemorrhage

The coagulation cascade has a potential role in brain edema formation due to intracerebral hemorrhage. In this study blood and other solutions were injected stereotactically into the right basal ganglia in rats. Twenty-four hours following injection, brain water and ion contents were measured to determine the amount of brain edema. Intracerebral blood resulted in an increase in brain water content. The amount of brain edema surrounding the intracerebral hematoma was reduced by a thrombin inhibitor Na-(2-Naphthalenesulfonylglycyl)-4-amidino-DL-phenylalaninepiperidide, (α-NAPAP) infused into the hematoma after the clot had been allowed to solidify. The inhibitor did not alter the actual size of the clot mass. An artificial clot composed of fibrinogen, thrombin, and styrene microspheres also produced brain edema. A fibrin clot led to edema formation even in the absence of mass effect provided by the microspheres. The single component responsible for production of brain edema in all these models was thrombin. The edema was formed in response to a fibrinogen-independent pathway. These results indicate that the coagulation cascade is involved in brain edema that develops adjacent to an intracerebral hematoma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41647/1/701_2005_Article_BF01420301.pd