Conformational restriction approach to BACE1 inhibitors II: SAR study of the isocytosine derivatives fixed with a cis-cyclopropane ring

To improve the efficacy of the conformationally restricted BACE1 inhibitors, structural modifications were investigated using two strategies: (a) modification of the terminal aromatic ring and (b) insertion of a spacer between the aromatic rings. In the latter approach, another type of inhibitor 17 bearing an ethylene spacer between two aromatic rings was found to exhibit good BACE1 inhibitory activity, while the corresponding conformationally unrestricted compound 25 showed no activity. This result revealed an interesting effect of a conformational restriction with a cyclopropane ring.     

<Emphasis Type="Italic">Oncorhynchus kawamurae</Emphasis> “Kunimasu,” a deepwater trout,discovered in Lake Saiko, 70 years after extinction in the original habitat,Lake Tazawa,Japan

Oncorhynchus kawamurae (Osteichthyes: Salmonidae) (common name “Kunimasu”), a species endemic to Lake Tazawa, Akita Prefecture, Japan, was believed to have been extinct since 1940. However, nine specimens were discovered in March and April 2010 in Lake Saiko, Yamanashi Prefecture, one of the lakes to which eyed eggs of the species were introduced in 1935. These were identified as O. kawamurae because of having 47–62 pyloric caeca, 37–43 gill-rakers, a black-colored body, and spawning at 30–40 m depth in early spring, which are unique characteristics within Oncorhynchus. Furthermore, the distinctiveness of Kunimasu from sympatric kokanee (O. nerka) was supported by microsatellite DNA data.     

A Novel Transporter of SLC22 Family Specifically Transports Prostaglandins and Co-localizes with 15-Hydroxyprostaglandin Dehydrogenase in Renal Proximal Tubules

We identified a novel prostaglandin (PG)-specific organic anion transporter (OAT) in the OAT group of the SLC22 family. The transporter designated OAT-PG from mouse kidney exhibited Na⁺-independent and saturable transport of PGE₂ when expressed in a proximal tubule cell line (S₂). Unusual for OAT members, OAT-PG showed narrow substrate selectivity and high affinity for a specific subset of PGs, including PGE₂, PGF_2α, and PGD₂. Similar to PGE₂ receptor and PGT, a structurally distinct PG transporter, OAT-PG requires for its substrates an α-carboxyl group, with a double bond between C13 and C14 as well as a (S)-hydroxyl group at C15. Unlike the PGE₂ receptor, however, the hydroxyl group at C11 in a cyclopentane ring is not essential for OAT-PG substrates. Addition of a hydroxyl group at C19 or C20 impairs the interaction with OAT-PG, whereas an ethyl group at C20 enhances the interaction, suggesting the importance of hydrophobicity around the ω-tail tip forming a “hydrophobic core” accompanied by a negative charge, which is essential for substrates of OAT members. OAT-PG-mediated transport is concentrative in nature, although OAT-PG mediates both facilitative and exchange transport. OAT-PG is kidney-specific and localized on the basolateral membrane of proximal tubules where a PG-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase, is expressed. Because of the fact that 15-keto-PGE₂, the metabolite of PGE₂ produced by 15-hydroxyprostaglandin dehydrogenase, is not a substrate of OAT-PG, the transport-metabolism coupling would make unidirectional PGE₂ transport more efficient. By removing extracellular PGE₂, OAT-PG is proposed to be involved in the local PGE₂ clearance and metabolism for the inactivation of PG signals in the kidney cortex.     

The nucleus together with the cytosol generates patterns of specific cellular calcium signatures in tobacco suspension culture cells

Plant cell suspension cultures respond to osmotic changes by alterations in levels of free cellular calcium. Using the aequorin recombinant method, we have measured the spatial and temporal characteristics of calcium signatures in the nucleus and the cytosol of BY-2 tobacco suspension cells challenged with hypo- or hyper-osmotic shock. We show here that the nuclear compartment contributes together with the cytosol to produce calcium signal patterns that discriminate hypo- from hyper-osmotic treatments, i.e. turgor from tension. We also demonstrate that calcium responses in the nucleus and the cytosol are differentially modulated by the strength and the nature of hyper-osmotic treatments. We conclude that qualitative and quantitative changes in the parameters of an external stimulus such as osmotic changes are converted into calcium signatures, distinctive in their temporal and subcellular characteristics, involving both the nucleus and the cytosol. Our results illustrate the versatility of calcium signaling in plant cells. In addition to the physiological 'address' of the cell, the compartmentation of the calcium signal is probably an important parameter in encoding response specificity.     

Porocottus leptosomus sp. nov., from the west coast of Korea, Yellow Sea (Scorpaeniformes: Cottidae)

 A new cottid species, Porocottus leptosomus, is described on the basis of 12 specimens collected from Taean, west coast of Korea, Yellow Sea. The species is distinguished from other species of Porocottus by the following combination of characters: a strongly compressed body, two pairs of branched cirri on the dorsal surface of the head, bases of head cirri smooth, a single cirrus on the dorsal tip of each spine of the first dorsal fin, a single opening of the sixth canaliculus of the infraorbital sensory canal, a long posterior medial canaliculus of the occipital canal with the terminal pore and a few supplementary pores, and melanophores on the isthmus hidden beneath the branchiostegal membrane. Received: January 11, 2001 / Revised: February 7, 2002 / Accepted: March 4, 2002     

Hospital Topics: Examination of the Whole Colon with the Fibreoptic Colonoscope

During examination of the intact colon with the Olympus CF LB 185-cm colonoscope it has proved possible to reach the caecum or terminal ileum in 47 out of 50 cases (94%). Careful bowel preparation, moderately heavy sedation, and some x-ray screening are necessary for the procedure, but it was well tolerated by all patients and there was no morbidity. The average time taken to the caecum was 40 minutes and the average time to completion of examination 90 minutes. The long colonoscope was as convenient to use as the fibresigmoidoscope in examinations confined to the sigmoid colon or in patients with a colostomy, ileostomy, or ileorectal anastomosis. Of the two, the long colonoscope is the instrument of choice for clinical use.Because of the expense, time, and equipment involved colonoscopy appears to be best offered as a specialist service after x-ray studies. There is alo a limited place for colonoscopy during abdominal surgery, when it is technically an easier procedure. In this series 10 patients were saved exploratory laparotomy by examination with the colonocope, and we also diagnosed four resectable carcinomas not seen on double-contrast barium-enema studies. The colonoscope provides an effective new means of diagnosis of lesions throughout the colon.     

CHANGE OF UBIQUITINATED PROTEINS DURING THE CELL CYCLE IN CHLAMYDOMONAS (CHLOROPHYTA)1

Changes in the amount of heat shock-related ubiquitinated proteins in Chlamydomonas were investigated during the cell cycle and gamete induction. In a division-synchronized culture induced by periodic illumination, the amount of the 28-kDa ubiquitinated protein increased during the dark phase. This increase correlated with the increase of total DNA. Such an increase was repressed when nuclear DNA replication was inhibited with aphidicolin. These results suggest that ubiquitination to form the 28-kDa protein is involved in nuclear DNA replication or during the cell cycle. The amount of 31-kDa ubiquitinated protein gradually increased throughout the light phase and decreased in the dark phase. The amount of 28-kDa ubiquitinated protein also increased during gamete induction caused by nitrogen starvation, while that of the 31-kDa did not. These results suggest that the change of ubiquitination of 28-kDa protein mat play a fundamental role in the cell cycle and gamete induction in Chlamydomonas.     

Three dimensional organization of mammalian adrenal cortex

Summary The adrenal cortex of different mammals was studied by SEM in order to demonstrate its actual three-dimensional organization. In the rat, as well as in the cat and pig, the adrenal cortex appeared as a tunnelled continuum of polyhedral cells arranged in plate-like structures (laminae). This laminar arrangement was more evident in the inner fasciculate and reticular zones where the cortex revealed a striking similarity to liver tissue. The polyhedral cells of all cortical zones possessed regular facets populated by small pits, larger invaginations and numerous microvilli with the exception of very short and smooth areas probably corresponding to attachment zones and/or gap junctions. This cellular architecture produced a labyrinthic system of intercellular channels or lacunae in which the capillaries were suspended.The pericapillary areas of this labyrinth contained microvilli, amorphous material, a delicate net of fibrils and occasional cells. The intercellular compartment of this lacunar system was mainly bordered by numerous microvilli arising from endocrine cells.The luminal surface of the capillary wall showed not only irregularly protruding margins (interpretable as endothelial junctions) but also clearly overlapping and flattened endothelial extensions.In all the animals and areas of the adrenal cortex examined, the endothelial wall was provided with abundant clusters of small fenestrations (about 50 nm in diameter) generally arranged in sieve plates. Larger fenestrations were noted mainly in the fasciculate and reticular zones of the cat and pig and occasionally in the rat.A final point related to the nature and significance of sinusoidal fenestrations was the occurrence of irregularly shaped and intracapillary located cells mainly noted in the deeper zones of the fasciculate and reticular zones of the gland. These elements — possessing the surface characteristics of macrophages — were observed, with their irregular and slender evaginations, in close proximity to the large fenestrations in a manner reminiscent of Kupffer cells within the lumen of liver sinusoids.     

Altered White Matter Architecture in BDNF Met Carriers

Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin''s activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects'' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture.