Potent and broad-spectrum antibacterial activity of indole-based bisamidine antibiotics: Synthesis and SAR of novel analogs of MBX 1066 and MBX 1090

The prevalence of drug-resistant bacteria in the clinic has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We have previously described a set of bisamidine antibiotics that contains a core composed of two indoles and a central linker. The first compounds of the series, MBX 1066 and MBX 1090, have potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. We have conducted a systematic exploration of the amidine functionalities, the central linker, and substituents at the indole 3-position to determine the factors involved in potent antibacterial activity. Some of the newly synthesized compounds have even more potent and broad-spectrum activity than MBX 1066 and MBX 1090.     

Neuregulin3 alters cell fate in the epidermis and mammary gland

Background  

The Neuregulin family of ligands and their receptors, the Erbb tyrosine kinases, have important roles in epidermal and mammary gland development as well as during carcinogenesis. Previously, we demonstrated that Neuregulin3 (Nrg3) is a specification signal for mammary placode formation in mice. Nrg3 is a growth factor, which binds and activates Erbb4, a receptor tyrosine kinase that regulates cell proliferation and differentiation. To understand the role of Neuregulin3 in epidermal morphogenesis, we have developed a transgenic mouse model that expresses Nrg3 throughout the basal layer (progenitor/stem cell compartment) of mouse epidermis and the outer root sheath of developing hair follicles.     

Developmental and neurobehavioural toxicity study of arsenic on rats following gestational exposure

To characterize developmental and behavioral alterations induced by arsenic exposure, Albino rats were exposed to arsenic (0, 1.5, 3.0 and 4.5 mg/kg/day/po) from gestation day 8 to till parturition and the offspring were observed over the first 3 postnatal weeks, until they were weaned on post-natal day (PND) 21. Once the pups were delivered (PND0), the treatment was discontinued. All pups were assessed for physical development, reflex development, strength and motor coordination from standard neurobehavioural developmental test batteries beginning on PND1. Gestational administration of arsenic at tested dose levels, showed no significant changes in the day of appearance of eye opening, startle reflex, negative geotaxis and spontaneous alteration performance in comparison to the control group. The number of live fetuses, mean fetal body weight and percentages of resorptions or malformations per litter were not affected by arsenic exposure. No treatment-related malformations or developmental variations were noted at any exposure level, suggesting that arsenic exposure at this dose level did not adversely affect behavioural endpoints of developmental toxicity.     

Multiphase hemodynamic simulation of pulsatile flow in a coronary artery

A multiphase transient non-Newtonian three-dimensional (3-D) computational fluid dynamics (CFD) simulation has been performed for pulsatile hemodynamics in an idealized curved section of a human coronary artery. We present the first prediction, to the authors' knowledge, of particulate buildup on the inside curvature using the multiphase theory of dense suspension hemodynamics. In this study, the particulates are red blood cells (RBCs). The location of RBC buildup on the inside curvature correlates with lower wall shear stress (WSS) relative to the outside curvature. These predictions provide insight into how blood-borne particulates interact with artery walls and hence, have relevance for understanding atherogenesis since clinical observations show that atherosclerotic plaques generally form on the inside curvatures of arteries. The buildup of RBCs on the inside curvature is driven by the secondary flow and higher residence times. The higher viscosity in the central portion of the curved vessel tends to block their flow, causing them to migrate preferentially through the boundary layer. The reason for this is the nearly neutrally buoyant nature of the dense two-phase hemodynamic flow. The two-phase non-Newtonian viscosity model predicts greater shear thinning than the single-phase non-Newtonian model. Consequently, the secondary flow induced in the curvature is weaker. The waveforms for computed hemodynamic parameters, such as hematocrit, WSS, and viscosity, follow the prescribed inlet velocity waveforms. The lower oscillatory WSS produced on the inside curvature has implications for understanding thickening of the intimal layer.     

Evaluation of basic,heterocyclic ring systems as templates for use as potassium competitive acid blockers (pCABs)

A variety of basic, heterocyclic templates has been reported as potassium-competitive, acid pump antagonists. Herein, we report a comparison of potencies of these templates and others to establish which offers the best start point for further systematic optimisation. Modifications were carried out to improve the developability profile of the more potent 1H-pyrrolo[2,3-c]pyridine template, affording molecules with improved overall in vitro characteristics versus the reported clinical candidate AR-H047108, and comparable to the clinically efficacious AZD-0865.     

Management of craniosynostosis

Learning Objectives: After studying this article, the participant should be able to: 1. Review the etiopathogenesis of craniosynostosis and craniofacial anomalies. 2. Develop a basic understanding of the clinical manifestations and diagnosis of craniofacial anomalies. 3. Describe the surgical principles of managing craniosynostosis and craniofacial anomalies.Craniosynostosis, or the premature closure of calvarial sutures, results in deformed calvaria at birth. Although the etiology of craniosynostosis is currently unknown, animal experiments and a recent interest in molecular biology point toward interplay between the dura and the underlying brain. This interaction occurs by means of a local alteration in the expression of transforming growth factor, MSX2, fibroblast growth factor receptor, and TWIST. The fused suture restricts growth of the calvaria, thus leading to a characteristic deformation, each associated with a different type of craniosynostosis. Uncorrected craniosynostosis leads to a continuing progression of the deformity, and in some cases, an elevation of intracranial pressure. Clinical examination should include not only an examination of the skull but also a general examination to rule out the craniofacial syndromes that accompany craniosynostosis. Because deformational plagiocephaly, or plagiocephaly without synostosis, occurs secondary to sleeping in the supine position during the early perinatal period, the physician should be aware of this abnormality. Treatment for deformational plagiocephaly is conservative when compared with treatment for craniosynostosis, which requires surgery. Appropriate investigations should include genetic screening, radiologic examination with a computerized tomographic scan, and neurodevelopmental analysis. Surgical intervention should be performed during infancy, preferably in the first 6 months of postnatal life, to prevent the further progression of the deformity and possible complications associated with increased intracranial pressure. The principles of surgical intervention are not only to excise the fused suture but also to attempt to normalize the calvarial shape. Long-term follow-up is critical to determine the effect of the surgical outcome.     

Application of HN(C)N to rapid estimation of 1J(N-C(alpha)) coupling constants correlated to psi torsion angles in proteins: implication to structural genomics

We recently described a triple resonance experiment, HN(C)N, for sequential correlation of H(N) and 15N atoms in (15N, 13C) labeled proteins [J. Biomol. NMR. 20 (2001) 135]. Here, we describe an approach based on this experiment for estimation of one bond N-C(alpha) J-couplings in medium size labeled proteins, which seem to show good correlations with psi torsion angles along the protein backbone. The approach uses the ratio of the intensities of the sequential and diagonal peaks in the F(2)-F(3) planes of the HN(C)N spectrum. The reliability of the approach has been demonstrated using a short peptide wherein the coupling constants have been measured by the present method and also independently from peak splittings in HSQC spectra. The two results agree within 10%. The applicability of the procedure to proteins has been demonstrated using doubly labeled FK506 binding protein (FKBP, molecular mass approximately 12 kDa). Coupling constant estimates have been obtained for 62 out of 100 non-proline residues and they show a correlation with psi torsion angles, as has been reported before. This semi-quantitative application of HN(C)N extends the significance of the experiment especially, in the context of structural genomics, since the single experiment, not only provides a great enhancement in the speed of resonance assignment, but also provides quantitative structural information.     

Sagittal craniosynostosis outcome assessment for two methods and timings of intervention.

A retrospective quantitative analysis of 40 infants who underwent surgery for sagittal craniosynostosis was conducted to determine whether any difference in outcome, with respect to cranial index (cranial width/cranial length x 100), could be associated with either the age at surgery or the extent of the operation. Children < or = 13 months old at surgery and for whom there were archived computed tomography digital data preoperatively, perioperatively, and 1 year postoperatively were studied. For statistical analysis, the operation was classified as either extended strip craniectomy or subtotal calvarectomy, and the age at operation was either < or = 4 months or > 4 months. Twenty-eight patients underwent extended strip craniectomy at a mean age of 5.1 months. Their mean cranial index preoperatively was 67 versus 71 at 1 year postoperatively (p < 0.0001). Of extended strip craniectomy patients, 15 were operated on at age < or = 4 months (mean = 2.9 months) and 13 at age > 4 months (mean = 7.6 months). Mean cranial indices for age at operation groups did not achieve age-appropriate normal range values 1 year postoperatively for either group, and there was no significant difference between the mean percentages of improvement achieved (p = 0.143). Twelve patients underwent subtotal calvarectomy at a mean age of 5.2 months. Their mean cranial index preoperatively was 66 versus 74 at 1 year postoperatively (p < 0.0001). The mean cranial index in this group reached age-appropriate normal range values 1 year postoperatively. The percentage improvement in cranial index 1 year after subtotal calvarectomy was greater than after extended strip craniectomy (p = 0.003). Extended strip craniectomy for sagittal craniosynostosis does not achieve normal cranial width:length proportions, even when performed before 4 months of age. Subtotal calvarectomy for sagittal craniosynostosis does achieve normal cranial width:length proportions in the majority of the children, at least when performed within the first 13 months of life.