Modeling craniofacial development reveals spatiotemporal constraints on robust patterning of the mandibular arch

How does pattern formation occur accurately when confronted with tissue growth and stochastic fluctuations (noise) in gene expression? Dorso-ventral (D-V) patterning of the mandibular arch specifies upper versus lower jaw skeletal elements through a combination of Bone morphogenetic protein (Bmp), Endothelin-1 (Edn1), and Notch signaling, and this system is highly robust. We combine NanoString experiments of early D-V gene expression with live imaging of arch development in zebrafish to construct a computational model of the D-V mandibular patterning network. The model recapitulates published genetic perturbations in arch development. Patterning is most sensitive to changes in Bmp signaling, and the temporal order of gene expression modulates the response of the patterning network to noise. Thus, our integrated systems biology approach reveals non-intuitive features of the complex signaling system crucial for craniofacial development, including novel insights into roles of gene expression timing and stochasticity in signaling and gene regulation

Can fingernail quality predict bone damage in Type 2 diabetes mellitus? a pilot study

Type 2 diabetes mellitus (T2DM) adversely affects the normal functioning, intrinsic material properties, and structural integrity of many tissues, including bone. It is well known that the clinical utility of areal bone mineral density (aBMD) is limited to assess bone strength in individuals with T2DM. Therefore, there is a need to explore new diagnostic techniques that can better assist and improve the accuracy of assessment of bone tissue quality. The present study investigated the link between bone and fingernail material/compositional properties in type 2 diabetes mellitus (T2DM). For that, femoral head and fingernail samples were obtained from twenty-five adult female patients (with/without T2DM) with fragility femoral neck fractures undergoing hemi/total hip arthroplasty. Cylindrical cores of trabecular bone were subjected to micro-CT, and lower bone volume fraction was observed in the diabetic group than the non-diabetic group due to fewer and thinner trabeculae in individuals with T2DM. The material and compositional properties of bone/fingernail were estimated using nanoindentation and Fourier Transform Infrared Spectroscopy, respectively. Both bone/fingernails in T2DM had lower reduced modulus (Er), hardness (H), lower Amide I and Amide II area ratio (protein content), higher sugar-to-matrix ratio, and relatively high carboxymethyl-lysine (CML) content compared with non-diabetic patients. Sugar-to-matrix ratio and relative CML content were strongly and positively correlated with HbA1c for both bone/fingernail. There was a positive correlation between bone and fingernail glycation content. Our findings provide evidence that the degradation pattern of bone and fingernail properties go hand-in-hand in individuals with T2DM. Hence, the fingernail compositional/material properties might serve as a non-invasive surrogate marker of bone quality in T2DM; however, further large-scale studies need to be undertaken

Regulation Of Long-Range Planar Cell Polarity By Fat- Dachsous Signaling

Planar cell polarity (PCP) is the organization of cellular characteristics within the plane of a tissue. PCP manifests both structurally, as in the directionality of insect bristles or mammalian skin hair, or dynamically, as in vertebrate neurulation, gastrulation, and oriented cell division in the kidney. Two well-conserved pathways are known to regulate PCP in invertebrates and in vertebrates: the Frizzled/PCP pathway and the Fat-Dachsous (Ft-Ds) pathway. The latter consists of the cadherins Ft and Ds, along with the Golgi kinase Four-jointed (Fj) and the transcriptional co-repressor Atrophin (Atro). Ft and Ds can bind each other, suggesting a mechanism for signal transduction. Fj phosphorylates Ft and Ds, modulating their binding affinities for each other. Atro is proposed to link Ft-Ds signaling with downstream events in the nucleus during eye development. The details of Ft-Ds binding, and the consequences of their interactions with other members of the pathway are poorly understood. In this work, I quantitatively analyzed Ft-Ds pathway mutant clones for their effects on ommatidial polarity in the Drosophila eye. My findings suggest that the Ft-Ds pathway regulates PCP independently of asymmetric cellular accumulation of Ft or Ds. I found that Atro has a position-specific role in regulating polarity in the eye, that Fj dampens clonal polarity signals, and that asymmetric accumulation of the atypical myosin Dachs is not essential for production and propagation of a long-range PCP signal. My observations suggest that Ft and Ds interact to modulate a secondary signal that regulates long-range polarity, that signaling by the Ds intracellular domain is dependent on Ft, and that ommatidial fate specification is genetically separable from long-range signaling.Ph

EUS-Assisted Evaluation of Rectal Varices before Banding

Rectal varices are an important cause of bleed. The bleeding can be sometimes fatal. Endoscopic management is possible and is generally done in emergency situation. Rectal variceal banding is useful. Hemodynamic evaluation has shown that the blood flow in rectal varices is from above downwards; however, the site of banding of rectal varices is unclear. This case series shows that the rectal varices should be banded at the highest point of inflow

Modeling craniofacial development reveals spatiotemporal constraints on robust patterning of the mandibular arch

How does pattern formation occur accurately when confronted with tissue growth and stochastic fluctuations (noise) in gene expression? Dorso-ventral (D-V) patterning of the mandibular arch specifies upper versus lower jaw skeletal elements through a combination of Bone morphogenetic protein (Bmp), Endothelin-1 (Edn1), and Notch signaling, and this system is highly robust. We combine NanoString experiments of early D-V gene expression with live imaging of arch development in zebrafish to construct a computational model of the D-V mandibular patterning network. The model recapitulates published genetic perturbations in arch development. Patterning is most sensitive to changes in Bmp signaling, and the temporal order of gene expression modulates the response of the patterning network to noise. Thus, our integrated systems biology approach reveals non-intuitive features of the complex signaling system crucial for craniofacial development, including novel insights into roles of gene expression timing and stochasticity in signaling and gene regulation

Modeling craniofacial development reveals spatiotemporal constraints on robust patterning of the mandibular arch.

How does pattern formation occur accurately when confronted with tissue growth and stochastic fluctuations (noise) in gene expression? Dorso-ventral (D-V) patterning of the mandibular arch specifies upper versus lower jaw skeletal elements through a combination of Bone morphogenetic protein (Bmp), Endothelin-1 (Edn1), and Notch signaling, and this system is highly robust. We combine NanoString experiments of early D-V gene expression with live imaging of arch development in zebrafish to construct a computational model of the D-V mandibular patterning network. The model recapitulates published genetic perturbations in arch development. Patterning is most sensitive to changes in Bmp signaling, and the temporal order of gene expression modulates the response of the patterning network to noise. Thus, our integrated systems biology approach reveals non-intuitive features of the complex signaling system crucial for craniofacial development, including novel insights into roles of gene expression timing and stochasticity in signaling and gene regulation