Evolving anisotropy and degree of elastolytic insult in abdominal aortic aneurysms: Potential clinical relevance?

Accurately estimating patient-specific rupture risk remains a primary challenge in timing interventions for abdominal aortic aneurysms (AAAs). By re-analyzing published biaxial mechanical testing data from surgically repaired human AAAs, material anisotropy emerged as a potentially important determinant of patient-specific lesion progression. That is, based on a new classification scheme, we discovered that anisotropic aneurysmal specimens correlated with increased patient age at surgery when compared with more isotropic specimens (79.7 vs. 70.9 years, p<0.002), despite no significant difference in maximum diameter. Furthermore, using an idealized axisymmetric, finite-element growth and remodeling model of AAA progression, we found that both the initial axial extent of elastin loss and ongoing damage to elastin in the shoulder region of the AAA directly affected the degree of anisotropy as the lesion evolved, with more extensive insults increasing the anisotropy. This effect appeared to be mediated by alterations in axial loading and subsequent differences in orientation of deposited collagen fibers. While the observed increased age before surgical intervention may suggest a potential benefit of anisotropic remodeling, future biaxial tests coupled with pre-surgical data on expansion rates and detailed theoretical analyses of the biostability of a lesion as a function of anisotropy will be required to verify its clinical relevance to patient-specific rupture risk.     

Recent encounters with atropisomerism in drug discovery

Atropisomerism is stereochemistry arising from restricted bond rotation that creates a chiral axis. Atropisomers are subject to time-dependent inversion of chirality via bond rotation, a property which in drug molecules introduces complexity and challenges for drug discovery and development processes. Greater recognition of the occurrence of atropisomerism and improved characterization techniques have helped medicinal chemists successfully advance atropisomeric drug molecules. This review provides recent examples of atropisomerism encountered in medicinal chemistry efforts and the strategies used to address the accompanying challenges.     

球结膜下注射不同浓度消旋山莨菪碱液对雏鸡形觉剥夺近视眼轴的影响

目的研究不同浓度消旋山莨菪碱液对雏鸡形觉剥夺近视眼轴的影响。方法 3日龄雏鸡60只右眼遮盖半透明塑料膜,随机分为6组:给药组4组,不同浓度消旋山莨菪碱液(0.05%组,0.1%组,1%组,2.5%组),隔天行右眼球结膜下注射,每次给药50μL,共4次;对照组为生理盐水组,注射方法同给药组;单纯形觉剥夺组,不做干预。8 d后观察药物对眼轴的影响。结果 2.5%浓度组右眼与左眼眼轴差异显著小于低浓度组及对照组(P<0.05),给药组未发现组织病理毒性。结论消旋山莨菪碱对雏鸡近视眼轴增长有一定抑制作用,无毒副作用,有一定浓度依赖性。     

Retinoic acid and Wnt/β-catenin have complementary roles in anterior/posterior patterning embryos of the basal chordate amphioxus

A role for Wnt/β-catenin signaling in axial patterning has been demonstrated in animals as basal as cnidarians, while roles in axial patterning for retinoic acid (RA) probably evolved in the deuterostomes and may be chordate-specific. In vertebrates, these two pathways interact both directly and indirectly. To investigate the evolutionary origins of interactions between these two pathways, we manipulated Wnt/β-catenin and RA signaling in the basal chordate amphioxus during the gastrula stage, which is the RA-sensitive period for anterior/posterior (A/P) patterning. The results show that Wnt/β-catenin and RA signaling have distinctly different roles in patterning the A/P axis of the amphioxus gastrula. Wnt/β-catenin specifies the identity of the ends of the embryo (high Wnt = posterior; low Wnt = anterior) but not intervening positions. Thus, upregulation of Wnt/β-catenin signaling induces ectopic expression of posterior markers at the anterior tip of the embryo. In contrast, RA specifies position along the A/P axis, but not the identity of the ends of the embryo—increased RA signaling strongly affects the domains of Hox expression along the A/P axis but has little or no effect on the expression of either anterior or posterior markers. Although the two pathways may both influence such things as specification of neuronal identity, interactions between them in A/P patterning appear to be minimal.     

Differential occupation of axial morphospace

The postcranial system is composed of the axial and appendicular skeletons. The axial skeleton, which consists of serially repeating segments commonly known as vertebrae, protects and provides leverage for movement of the body. Across the vertebral column, much numerical and morphological diversity can be observed, which is associated with axial regionalization. The present article discusses this basic diversity and the early developmental mechanisms that guide vertebral formation and regionalization. An examination of vertebral numbers across the major vertebrate clades finds that actinopterygian and chondrichthyan fishes tend to increase vertebral number in the caudal region whereas Sarcopterygii increase the number of vertebrae in the precaudal region, although exceptions to each trend exist. Given the different regions of axial morphospace that are occupied by these groups, differential developmental processes control the axial patterning of actinopterygian and sarcopterygian species. It is possible that, among a variety of factors, the differential selective regimes for aquatic versus terrestrial locomotion have led to the differential use of axial morphospace in vertebrates.     

Compartment-dependent activities of Wnt3a/β-catenin signaling during vertebrate axial extension

Extension of the vertebrate body results from the concerted activity of many signals in the posterior embryonic end. Among them, Wnt3a has been shown to play relevant roles in the regulation of axial progenitor activity, mesoderm formation and somitogenesis. However, its impact on axial growth remains to be fully understood. Using a transgenic approach in the mouse, we found that the effect of Wnt3a signaling varies depending on the target tissue. High levels of Wnt3a in the epiblast prevented formation of neural tissues, but did not impair axial progenitors from producing different mesodermal lineages. These mesodermal tissues maintained a remarkable degree of organization, even within a severely malformed embryo. However, from the cells that failed to take a neural fate, only those that left the epithelial layer of the epiblast activated a mesodermal program. The remaining tissue accumulated as a folded epithelium that kept some epiblast-like characteristics. Together with previously published observations, our results suggest a dose-dependent role for Wnt3a in regulating the balance between renewal and selection of differentiation fates of axial progenitors in the epiblast. In the paraxial mesoderm, appropriate regulation of Wnt/β-catenin signaling was required not only for somitogenesis, but also for providing proper anterior–posterior polarity to the somites. Both processes seem to rely on mechanisms with different requirements for feedback modulation of Wnt/β-catenin signaling, once segmentation occurred in the presence of high levels of Wnt3a in the presomitic mesoderm, but not after permanent expression of a constitutively active form of β-catenin. Together, our findings suggest that Wnt3a/β-catenin signaling plays sequential roles during posterior extension, which are strongly dependent on the target tissue. This provides an additional example of how much the functional output of signaling systems depends on the competence of the responding cells.     

Role of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) in assessing disease control in Asian patients with axial spondyloarthritis

Introduction: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) which are used for assessment of axial spondyloarthritis (AxSpA) related disease activity have poor specificity and sensitivity. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) have not been investigated as disease activity markers among Asian AxSpA patients.

Methodology: A retrospective, cross-sectional study was conducted in Singapore General Hospital from January 2013 to December 2015 to investigate the role of NLR, PLR and MPV as disease activity markers in AxSpA patients.

Results: The mean age of patients (n?=?122) was 37.0?±?12.5 years old and majority of them were male (n?=?93, 76.2%). No significant differences were found between patients with disease with regards to age, gender, ethnicity, HLAB-27 status, age at onset of diagnosis of AxSpA, duration of disease and comorbidities such as cardiac disease (p?>?0.05).

There were no significant differences in the ESR, NLR, PLR and MPV between the four disease activity groups (p?>?0.05). However, patients with very high disease activity had higher ESR and CRP compared to patients with inactive disease and moderate disease activity (p?Conclusion: NLR, PLR and MPV were not associated with disease activity in Asian AxSpA patients.     

Solution NMR views of dynamical ordering of biomacromolecules

Background

To understand the mechanisms related to the ‘dynamical ordering’ of macromolecules and biological systems, it is crucial to monitor, in detail, molecular interactions and their dynamics across multiple timescales. Solution nuclear magnetic resonance (NMR) spectroscopy is an ideal tool that can investigate biophysical events at the atomic level, in near-physiological buffer solutions, or even inside cells.

Fgf19 is required for zebrafish lens and retina development

Fgf signaling plays crucial roles in morphogenesis. Fgf19 is required for zebrafish forebrain development. Here, we examined the roles of Fgf19 in the formation of the lens and retina in zebrafish. Knockdown of Fgf19 caused a size reduction of the lens and the retina, failure of closure of the choroids fissure, and a progressive expansion of the retinal tissue to the midline of the forebrain. Fgf19 expressed in the nasal retina and lens was involved in cell survival but not cell proliferation during embryonic lens and retina development. Fgf19 was essential for the differentiation of lens fiber cells in the lens but not for the neuronal differentiation and lamination in the retina. Loss of nasal fate in the retina caused by the knockdown of Fgf19, expansion of nasal fate in the retina caused by the overexpression of Fgf19 and eye transplantation indicated that Fgf19 in the retina was crucial for the nasal-temporal patterning of the retina that is critical for the guidance of retinal ganglion cell axons. Knockdown of Fgf19 also caused incorrect axon pathfinding. The present findings indicate that Fgf19 positively regulates the patterning and growth of the retina, and the differentiation and growth of the lens in zebrafish.     

Two deltaC splice-variants have distinct signaling abilities during somitogenesis and midline patterning

Notch signaling is required for many developmental processes, yet differences in the signaling abilities of various Notch ligands are poorly understood. Here, we have isolated a splice variant of the zebrafish Notch ligand deltaC in which the inclusion of the last intron leads to a truncation of the C-terminal 39 amino acids (deltaC^tv2). We show that, unlike deltaC^tv1, deltaC^tv2 cannot function effectively in somitogenesis but has an enhanced ability to signal during midline development. Additionally, over-expression of deltaC^tv2 preferentially affects anterior midline development, while another Notch ligand, deltaD, shows a posterior bias. Using chimeric Deltas we show that the intracellular domain is responsible for the strength of signal in midline development, while the extracellular domain influences the anterior-posterior bias of the effect. Together our data show that different deltas can signal in biologically distinct ways in both midline formation and somitogenesis. Moreover, it illustrates the importance of cell-type-dependent modifiers of Notch signaling in providing ligand specificity.