A core function for p120-catenin in cadherin turnover

p120-catenin stabilizes epithelial cadherin (E-cadherin) in SW48 cells, but the mechanism has not been established. Here, we show that p120 acts at the cell surface to control cadherin turnover, thereby regulating cadherin levels. p120 knockdown by siRNA expression resulted in dose-dependent elimination of epithelial, placental, neuronal, and vascular endothelial cadherins, and complete loss of cell–cell adhesion. ARVCF and δ-catenin were functionally redundant, suggesting that proper cadherin-dependent adhesion requires the presence of at least one p120 family member. The data reveal a core function of p120 in cadherin complexes, and strongly predict a dose-dependent loss of E-cadherin in tumors that partially or completely down-regulate p120

Novel SGCE mutation in a patient with myoclonus-dystonia: A case report

OBJECTIVES: Characterize the presentation, workup, and management of METHODS: A woman with myoclonus and dystonia was identified based on clinical history and physical examination. Workup was conducted to determine the cause of her symptoms, including whole-exome sequencing. Myoclonus-dystonia is associated with more than 100 distinct mutations in MYC/DYT RESULTS: Childhood onset myoclonus and worsening dystonia with age were identified in a young woman. She underwent screening for common causes of twitching movements, followed by whole-exome sequencing which identified a de novo novel variant in the DISCUSSION: Myoclonus-dystonia should be considered in patients with symptoms of head and upper extremity myoclonus early in life, especially with co-occurring dystonia, even in the absence of a family history of similar symptoms. Diagnosis of this condition should take place using sequencing, as new mutations continue to be discovered

p120-Catenin Mediates Inflammatory Responses in the Skin

SummaryAlthough p120-catenin regulates adherens junction (AJ) stability in cultured cells, genetic studies in lower eukaryotes have not revealed a role for this protein in vivo. Using conditional targeting in mice, we show that p120 null neonatal epidermis exhibits reduced intercellular AJ components but no overt disruption in barrier function or intercellular adhesion. As the mice age, however, they display epidermal hyperplasia and chronic inflammation, typified by hair degeneration and loss of body fat. Using skin engraftments and anti-inflammatory drugs, we show that these features are not attributable to reductions in junctional cadherins and catenins, but rather NFkB activation. Both in vivo and in vitro, p120 null epidermal cells activate nuclear NFkB, triggering a cascade of proinflammatory NFkB targets. Although the underlying mechanism is likely complex, we show that p120 affects NFkB activation and immune homeostasis in part through regulation of Rho GTPases. These findings provide important new insights into p120 function

MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology

OBJECTIVE: Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer\u27s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. METHODS: Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid-beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. RESULTS: Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. INTERPRETATION: MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies

Growing Scale-Free Networks with Tunable Clustering

We extend the standard scale-free network model to include a ``triad formation step''. We analyze the geometric properties of networks generated by this algorithm both analytically and by numerical calculations, and find that our model possesses the same characteristics as the standard scale-free networks like the power-law degree distribution and the small average geodesic length, but with the high-clustering at the same time. In our model, the clustering coefficient is also shown to be tunable simply by changing a control parameter - the average number of triad formation trials per time step.Comment: Accepted for publication in Phys. Rev.

Network Landscape from a Brownian Particle's Perspective

Given a complex biological or social network, how many clusters should it be decomposed into? We define the distance $d_{i,j}$ from node $i$ to node $j$ as the average number of steps a Brownian particle takes to reach $j$ from $i$. Node $j$ is a global attractor of $i$ if $d_{i,j}\leq d_{i,k}$ for any $k$ of the graph; it is a local attractor of $i$, if $j\in E_i$ (the set of nearest-neighbors of $i$) and $d_{i,j}\leq d_{i,l}$ for any $l\in E_i$. Based on the intuition that each node should have a high probability to be in the same community as its global (local) attractor on the global (local) scale, we present a simple method to uncover a network's community structure. This method is applied to several real networks and some discussion on its possible extensions is made.Comment: 5 pages, 4 color-figures. REVTeX 4 format. To appear in PR

Infectious Default Model with Recovery and Continuous Limit

We introduce an infectious default and recovery model for N obligors. Obligors are assumed to be exchangeable and their states are described by N Bernoulli random variables S_{i} (i=1,...,N). They are expressed by multiplying independent Bernoulli variables X_{i},Y_{ij},Y'_{ij}, and default and recovery infections are described by Y_{ij} and Y'_{ij}. We obtain the default probability function P(k) for k defaults. Taking its continuous limit, we find two nontrivial probability distributions with the reflection symmetry of S_{i} \leftrightarrow 1-S_{i}. Their profiles are singular and oscillating and we understand it theoretically. We also compare P(k) with an implied default distribution function inferred from the quotes of iTraxx-CJ. In order to explain the behavior of the implied distribution, the recovery effect may be necessary.Comment: 13 pages, 7 figure

Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson’s Disease

BACKGROUND: Most sequencing studies in Parkinson’s disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815). RESULTS: Disease-causing variants in the SNCA,LRRK2 and PARK2 genes were found in 2 % of PD patients. The LRRK2, p.G2019S mutation was found in 0.6 % of sporadic PD and 4.8 % of familial PD cases. Gene-based analysis suggests that additional variants in the LRRK2 gene also contribute to PD risk. The SNCA duplication was found in 0.8 % of familial PD patients. Novel variants were found in 0.8 % of PD cases and 0.6 % of controls. Heterozygous Gaucher disease-causing mutations in the GBA gene were found in 7.1 % of PD patients. Here, we established that the GBA variant (p.T408M) is associated with PD risk and age at onset. Additionally, gene-based and single-variant analyses demostrated that GBA gene variants (p.L483P, p.R83C, p.N409S, p.H294Q and p.E365K) increase PD risk. CONCLUSIONS: Our data suggest that the impact of additional untested coding variants in the GBA and LRRK2 genes is higher than previously estimated. Our data also provide compelling evidence of the existence of additional untested variants in the primary Mendelian and PD GWAS genes that contribute to the genetic etiology of sporadic PD

Measuring the dark side (with weak lensing)

We introduce a convenient parametrization of dark energy models that is general enough to include several modified gravity models and generalized forms of dark energy. In particular we take into account the linear perturbation growth factor, the anisotropic stress and the modified Poisson equation. We discuss the sensitivity of large scale weak lensing surveys like the proposed DUNE satellite to these parameters. We find that a large-scale weak-lensing tomographic survey is able to easily distinguish the Dvali-Gabadadze-Porrati model from LCDM and to determine the perturbation growth index to an absolute error of 0.02-0.03.Comment: 19 pages, 11 figure