Novel and selective spiroindoline-based inhibitors of Sky kinase

We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.     

Regeneration and micrografting of lentil shoots

Summary A protocol for regeneration and micrografting of shoots of lentil (Lens culinaris Medik) was developed. Multiple shoots (4–5) were regenerated from cotyledonary node explants on Murashige and Skoog (MS) medium containing 8.8 μM 6-benzylaminopurine. In vitro regenerated shoots were micrografted on rootstocks with 96% efficiency. The successful grafts were transplanted to pots in Redi-earth^TM, hardened off and were grown to maturity with 100% success. The success of the micrografting was independent of the nature and concentration of growth regulator used in shoot initiation medium and the time period for induction of shoots. The protocol was successful with several cultivars of lentil. The advantages of micrografting over in vitro rooting are discussed.     

Differentially Expressed miRNAs Influence Metabolic Processes in Pituitary Oncocytoma

Neurochemical Research - Spindle cell oncocytomas (SCO) of the pituitary are rare tumors accounting for 0.1–0.4% of all sellar tumors. Due to their rarity, little information is available...     

Perinatal mortality and morbidity among babies delivered in water: surveillance study and postal survey

AimTo compare perinatal morbidity and mortality for babies delivered in water with rates for babies delivered conventionally (not in water).DesignSurveillance study (of all consultant paediatricians) and postal survey (of all NHS maternity units).SettingBritish Isles (surveillance study); England and Wales (postal survey).SubjectsBabies born in the British Isles between April 1994 and March 1996 who died perinatally or were admitted for special care within 48 hours of birth after delivery in water or after labour in water followed by conventional delivery (surveillance study); babies delivered in water in England and Wales in the same period (postal survey).Results4032 deliveries (0.6% of all deliveries) in England and Wales occurred in water. Perinatal mortality was 1.2/1000 (95% confidence interval 0.4 to 2.9) live births; 8.4/1000 (5.8 to 11.8) live births were admitted for special care. No deaths were directly attributable to delivery in water, but 2 admissions were for water aspiration. UK reports of mortality and special care admission rates for babies of women considered to be at low risk of complications during delivery who delivered conventionally ranged from 0.8/1000 (0.2 to 4.2) to 4.6/1000 (0.1 to 25) live births and from 9.2 (1.1 to 33) to 64/1000 (58 to 70) live births respectively. Compared with regional data for low risk, spontaneous, normal vaginal deliveries at term, the relative risk for perinatal mortality associated with delivery in water was 0.9 (99% confidence interval 0.2 to 3.6).ConclusionsPerinatal mortality is not substantially higher among babies delivered in water than among those born to low risk women who delivered conventionally. The data are compatible with a small increase or decrease in perinatal mortality for babies delivered in water.

Key messages

• Data on adverse effects of delivery in water have been limited
• Perinatal mortality and risk of admission for special care is similar for babies delivered in water and for low risk deliveries that do not take place in water
• The risk of perinatal mortality for babies delivered in water is similar to the risk for babies born by normal vaginal delivery to women at low risk of adverse outcome
• Delivery in water may have caused water aspiration in two babies and contributed to snapped umbilical cord in five

     

Evaluation of Bone Strength During Aflatoxicosis and Ochratoxicosis

Young chickens were fed graded levels of aflatoxin (0, 0.625, 1.25, 2.5, 5.0, and 10.0 μg/g of diet) or ochratoxin (0, 0.5, 1.0, 2.0, 4.0, and 8.0 μg/g of diet), and the breaking strength, displacement before failure, and diameter of their tibias were determined. Breaking strength was decreased at growth inhibitory levels of aflatoxin (2.5 μg/g) and ochratoxin (2 μg/g), whereas a reduction in diameter required higher levels (5.0 and 4.0 μg/g, respectively). Bones from birds with ochratoxicosis selected to have diameters equal to control bones had lower breaking strength. In an attempt to negate mathematically the effect of decreased diameter and bias in any selection process, stress at time of failure of the bones was calculated and found to be decreased by feeding aflatoxin but not ochratoxin. Total displacement of bones before breaking was increased significantly (P < 0.05) by both toxins at the highest levels administered, but this increase was primarily the result of an increase in displacement from the start of failure to complete failure. Increased displacement associated with both toxicoses was equal in bones selected to be of equal diameter or in bones from the same treatment but of different diameters. However, calculation of modulus of elasticity which is corrected for diameter revealed aflatoxin had no effect whereas ochratoxin tripled the effect. These data indicate that the material properties of bones can be altered during mycotoxicoses and suggest yet another way in which mycotoxins are detrimental to animal health.     

Discovery of N-benzyl-N'-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (II): modification of the acyl portion

Modification of the acyl moiety in the CCR5 lead molecule 2 led to identification of several new classes of CCR5 antagonists. Antiviral activity and pharmacokinetic properties of the synthesized compounds were evaluated. Structure-activity relationship (SAR) derived from these studies further guided the optimization efforts, ultimately leading to the discovery of 36 with an acceptable drug-like profile.     

Functional protofilament numbering of ciliary, flagellar, and centriolar microtubules

This article discusses the current state of knowledge about the evolutionarily conserved structure of ciliary, flagellar and centriolar microtubules, and formally proposes a functional numbering convention for their protofilaments.