Local Disruption Research Articles

The pathogenesis of multifocal motor neuropathy and an update on current management options.

Multifocal motor neuropathy (MMN) is a rare and disabling disease. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis, although underlying mechanisms in MMN seem to be very specific, mainly because of the presence of IgM anti-GM1 serum antibodies and the dramatic response to intravenous immunoglobulins (IVIg). The origin of antiganglioside antibodies and the way in which they act at the molecular level remain unclear. Several studies have demonstrated the key role of complement activation in the underlying mechanisms of MMN, as well as in animal models of acute motor axonal neuropathy (AMAN). Deposition of the membrane attack complex may disrupt the architecture of the nodes of Ranvier and paranodal areas, causing local disruption of nodal sodium-channel clusters. In patients with MMN, muscle weakness is the consequence of conduction blocks (CB), which leads to secondary axonal degeneration, consequently the aim of the treatment is to reverse CB at early stages of the disease. High-dose immunoglobulin is to date the only therapy which has proven efficacy in MMN patients in providing transient improvement of muscle strength, but long-term follow-up studies show a progressive motor decline. Therefore, other therapies are needed to improve the conduction nerve properties in long-term design. The reduction of complement activation and more generally the gain in paranodal stabilization could be directions for future therapeutic strategies.

Effect of pointlike impurities ondx2−y2charge-density waves in cuprate superconductors

Many cuprate superconductors possess an unusual charge-ordered phase that is characterized by an approximate ${d}_{{x}^{2}\ensuremath{-}{y}^{2}}$ intraunit cell form factor and a finite modulation wave vector ${\mathbf{q}}^{*}$. We study the effects of impurities on this charge-ordered phase via a single-band model in which bond order is the analog of charge order in the cuprates. Impurities are assumed to be pointlike and are treated within the self-consistent $t$-matrix approximation. We show that suppression of bond order by impurities occurs through the local disruption of the ${d}_{{x}^{2}\ensuremath{-}{y}^{2}}$ form factor near individual impurities. Unlike $d$-wave superconductors, where the sensitivity of ${T}_{c}$ to impurities can be traced to a vanishing average of the ${d}_{{x}^{2}\ensuremath{-}{y}^{2}}$ order parameter over the Fermi surface, the response of bond order to impurities is dictated by a few Fermi surface ``hotspots.'' The bond order transition temperature ${T}_{\mathrm{bo}}$ thus follows a different universal dependence on impurity concentration ${n}_{i}$ than does the superconducting ${T}_{c}$. In particular, ${T}_{\mathrm{bo}}$ decreases more rapidly than ${T}_{c}$ with increasing ${n}_{i}$ when there is a nonzero Fermi surface curvature at the hotspots. Based on experimental evidence that the pseudogap is insensitive to Zn doping, we conclude that a direct connection between charge order and the pseudogap is unlikely. Furthermore, the enhancement of stripe correlations in the La-based cuprates by Zn doping is evidence that this charge order is also distinct from stripes.

Mechanochromic luminescence of copper iodide clusters.

Luminescent mechanochromic materials are particularly appealing for the development of stimuli-responsive materials. Establishing the mechanism responsible for the mechanochromism is always an issue owing to the difficulty in characterizing the ground phase. Herein, the study of real crystalline polymorphs of a mechanochromic and thermochromic luminescent copper iodide cluster permits us to clearly establish the mechanism involved. The local disruption of the crystal packing induces changes in the cluster geometry and in particular the modification of the cuprophilic interactions, which consequently modify the emissive states. This study constitutes a step further toward the understanding of the mechanism involved in the mechanochromic luminescent properties of multimetallic coordination complexes.

On the risk-averse optimization of service level in a supply chain under disruption risks

The worst-case optimization of service level in the presence of supply chain disruption risks is considered for the two different service levels measures: the expected worst-case demand fulfillment rate and the expected worst-case order fulfillment rate. The optimization problem is formulated as a joint selection of suppliers and stochastic scheduling of customer orders under random disruptions of supplies. The suppliers are located in different geographic regions and the supplies are subject to random local and regional disruptions. The obtained combinatorial stochastic optimization problem is formulated as a mixed integer program with conditional service-at-risk as a worst-case service level measure. The risk-averse solutions that optimize the worst-case performance of a supply chain are compared for the two service level measures. In addition, to demonstrate the impact on the cost in the process of optimizing the worst-case service level, a joint optimization of expected cost and conditional service-at-risk using a weighted-sum approach is considered and illustrated with numerical examples. The findings indicate that the worst-case order fulfillment rate shows a higher service performance than the worst-case demand fulfillment rate. Maximization of the expected worst-case fraction of fulfilled customer orders better mitigates the impact of disruption risks. The supply portfolio is more diversified and the expected worst-case fraction of fulfilled orders is greater for most confidence levels. Finally, the results clearly show that worst-case service level is in opposition to cost.

A longitudinal EEG study of Alzheimer's disease progression based on a complex network approach.

A complex network approach is combined with time dynamics in order to conduct a space-time analysis applicable to longitudinal studies aimed to characterize the progression of Alzheimer's disease (AD) in individual patients. The network analysis reveals how patient-specific patterns are associated with disease progression, also capturing the widespread effect of local disruptions. This longitudinal study is carried out on resting electroence phalography (EEGs) of seven AD patients. The test is repeated after a three months' period. The proposed methodology allows to extract some averaged information and regularities on the patients' cohort and to quantify concisely the disease evolution. From the functional viewpoint, the progression of AD is shown to be characterized by a loss of connected areas here measured in terms of network parameters (characteristic path length, clustering coefficient, global efficiency, degree of connectivity and connectivity density). The differences found between baseline and at follow-up are statistically significant. Finally, an original topographic multiscale approach is proposed that yields additional results.

Combined local blood-brain barrier opening and systemic methotrexate for the treatment of brain tumors.

Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme patients, in part due to poor penetration of most drugs across the blood-brain barrier (BBB). We propose a minimal-invasive combined treatment approach consisting of local BBB disruption in the tumor in parallel to systemic drug administration. Local BBB disruption is obtained by convection-enhanced delivery of a novel BBB disruption agent, enabling efficient/targeted delivery of the systemically administered drug by the tumors own vasculature. Various human serum albumin (HSA) analogs were synthesized and screened for BBB disruption efficacy in custom in vitro systems. The candidate analogs were then delivered into naïve rat brains by convection-enhanced delivery and screened for maximal BBB disruption and minimal brain toxicity. These studies found a noncationized/neutralized analog, ethylamine (EA)-HSA, to be the optimal BBB-opening agent. Immunocytochemical studies suggested that BBB disruption by EA-HSA may be explained by alterations in occludin expression. Finally, an efficacy study in rats bearing intracranial gliomas was performed. The rats were treated by convection-enhanced delivery of EA-HSA in parallel to systemic administration of Methotrexate, showing significant antineoplastic effects of the combined approached reflected in suppressed tumor growth and significantly (~x3) prolonged survival.

Detergent-resistant membrane association of NS2 and E2 during hepatitis C virus replication.

Previously, we demonstrated that the efficiency of hepatitis C virus (HCV) E2-p7 processing regulates p7-dependent NS2 localization to putative virus assembly sites near lipid droplets (LD). In this study, we have employed subcellular fractionations and membrane flotation assays to demonstrate that NS2 associates with detergent-resistant membranes (DRM) in a p7-dependent manner. However, p7 likely plays an indirect role in this process, since only the background level of p7 was detectable in the DRM fractions. Our data also suggest that the p7-NS2 precursor is not involved in NS2 recruitment to the DRM, despite its apparent targeting to this location. Deletion of NS2 specifically inhibited E2 localization to the DRM, indicating that NS2 regulates this process. Treatment of cells with methyl-β-cyclodextrin (MβCD) significantly reduced the DRM association of Core, NS2, and E2 and reduced infectious HCV production. Since disruption of the DRM localization of NS2 and E2, either due to p7 and NS2 defects, respectively, or by MβCD treatment, inhibited infectious HCV production, these proteins' associations with the DRM likely play an important role during HCV assembly. Interestingly, we detected the HCV replication-dependent accumulation of ApoE in the DRM fractions. Taking into consideration the facts that ApoE was shown to be a major determinant for infectious HCV particle production at the postenvelopment step and that the HCV Core protein strongly associates with the DRM, recruitment of E2 and ApoE to the DRM may allow the efficient coordination of Core particle envelopment and postenvelopment events at the DRM to generate infectious HCV production. The biochemical nature of HCV assembly sites is currently unknown. In this study, we investigated the correlation between NS2 and E2 localization to the detergent-resistant membranes (DRM) and HCV particle assembly. We determined that although NS2's DRM localization is dependent on p7, p7 was not targeted to these membranes. We then showed that NS2 regulates E2 localization to the DRM, consistent with its role in recruiting E2 to the virus assembly sites. We also showed that short-term treatment with the cholesterol-extracting agent methyl-β-cyclodextrin (MβCD) not only disrupted the DRM localization of Core, NS2, and E2 but also specifically inhibited intracellular virus assembly without affecting HCV RNA replication. Thus, our data support the role of the DRM as a platform for particle assembly process.

Mode-locked ultrashort pulse generation from on-chip normal dispersion microresonators.

We describe generation of stable mode-locked pulse trains from on-chip normal dispersion microresonators. The excitation of hyperparametric oscillation is facilitated by the local dispersion disruptions induced by mode interactions. The system is then driven from hyperparametric oscillation to the mode-locked state with over 200nm spectral width by controlled pump power and detuning. With the continuous-wave-driven nonlinearity, the pulses sit on a pedestal, akin to a cavity soliton. We identify the importance of pump detuning and wavelength-dependent quality factors in stabilizing and shaping the pulse structure, to achieve a single pulse inside the cavity. We examine the mode-locking dynamics by numerically solving the master equation and provide analytic solutions under appropriate approximations.

Spatially Localized Disruptions of Voltage Activated Calcium Release in Mtm1-Deficient Muscle Fibers

Mutations in the gene encoding the phosphoinositide phosphatase myotubularin (Mtm1) are responsible for myotubular myopathy. We previously showed that muscle fibers from Mtm1-deficient mouse suffer from defective excitation-contraction coupling. Here we measured voltage-clamp activated Ca2+ signals in fibers from the flexor digitorum brevis muscles of 4 week-old wild type (WT) and Mtm1-ko mice under line-scan confocal microscopy using the dye rhod-2. Ca2+ release in the diseased fibers was deficient over the full range of activation: fitting the voltage dependence of the peak rate of rise of the line-averaged rhod-2 F/F0 signals with a Boltzmann function gave mean values for maximum rate, midpoint voltage and slope of 0.29 ± 0.02 and 0.14 ± 0.02 F/F0.ms−1, −8.8 ± 1.5 and 0.95 ± 2.3 mV, 7.0 ± 0.4 and 9.2 ± 0.7 mV in WT (n=22) and Mtm1-ko fibers (n=15), respectively. Furthermore, the mean time to peak rate was significantly delayed by 5-10 ms in Mtm1-ko as compared to WT fibers. These global alterations were associated with severe spatial inhomogeneity of Ca2+ release in the diseased fibers with rhod-2 transients yielding localized disruptions along the scanned line including reduced peak amplitude but also delayed or slower rate of onset, suggestive of specific alteration of the early peak component of the rate of Ca2+ release. In fibers treated with wortmannin and LY294002, the properties of the line-averaged rhod-2 F/F0 signals were unchanged in WT fibers but the mean maximum rate of rise of the rhod-2 signal was enhanced by 60% in Mtm1-deficient fibers. Results show that Mtm1-deficiency provokes EC coupling failure through accumulation of spatially localized disruptions of Ca2+ release. They also suggest that pharmacological inhibition of PtdIns-3-kinase activity has the potency to alleviate defective EC coupling in the diseased fibers.

Metal Erosion under Plasma Flow Typical for ITER Transient Regimes

Theoretical models of movement of a fast melt metal layer (up to v ∼ 10 m/s) and droplet erosion are developed for power density pulses typical for tokamak plasma edge localized modes (ELM) and disruption. Fast melt metal movement and droplet erosion were shown to be possible only at plasma flow pressure P > 1 atm. The secondary shielding plasma near the target has a high density, a relatively low temperature and a much higher pressure than that of the original plasma flow. Even if initial plasma flow has a pressure below the threshold of fast melt layer movement and droplet erosion, the secondary shielding plasma can cause fast melt metal movement and droplet erosion.

Ruptured Arteriovenous Malformation Presenting with Kernohan's Notch.

AVMs are congenital lesions that predispose patients to intracranial hemorrhage and resultant neurological deficits. These deficits are often focal and due to the presence of local neurologic disruption from hemorrhage in the contralateral cerebral hemisphere. We present a rare case of a patient with ipsilateral neurological deficits due to Kernohan's Notch phenomenon resulting from hemorrhage from an AVM. A 31-year-old woman with seizures underwent MR and angiographic imaging which confirmed an unruptured left parietal AVM. The patient declined treatment and presented with obtundation 4 years later. Imaging revealed an acute left parietal ICH and SDH with significant mass effect. The patient underwent emergent hemicraniectomy and hematoma evacuation. Postoperatively, she made significant improvement and was following commands contralaterally with ipsilateral hemiplegia. MR imaging revealed right Kernohan's Notch. The patient had significant rehabilitation with neurological improvement. She eventually underwent elective embolization followed by subsequent surgical resection and bone replacement. Three years from the initial hemorrhage, the patient had only mild left-sided weakness and ambulates without assistance. A false localizing sign, Kernohan's Notch phenomenon, should be considered in the setting of AVM hemorrhage with paradoxical motor impairment and can be identified through MRI.

Pelvic Solitary Plasmacytoma: Computed Tomography and Magnetic Resonance Imaging Findings with Histopathologic Correlation

ObjectiveTo describe the imaging features of pelvic solitary plasmacytoma and to correlate them with the pathologic grade.Materials and MethodsA retrospective study was performed on the imaging features of 10 patients with a histological diagnosis of pelvic solitary plasmacytoma. The imaging studies were assessed for bone expansion, cortical destruction, signal intensity/density of soft tissue mass and enhancement manifestations, which were then correlated to the pathologic grade.ResultsThe imaging features of pelvic solitary plasmacytoma revealed 3 different types: multilocular type (n = 5), unilocular type (n = 2) and complete osteolytic destruction type (n = 3) on computed tomography and MRI. Pathologically, the tumors were classified into low, intermediate and high grades. Features such as multilocular change, perilesional osteosclerosis, slight expansion, local bone cortex disruptions and masses inside bone destruction, often suggest a low-grade solitary plasmacytoma; complete osteolytic destruction, huge soft tissue mass, and osseous defects imply a higher pathologic grade.ConclusionPelvic solitary plasmacytoma has various imaging manifestations, while a slight expansile osteolytic feature with multilocular change or homogeneous enhancement highly suggests its diagnosis. The distinctive imaging features of pelvic solitary plasmacytoma are well correlated to the pathologic grade.

Extra-Coding Characteristics of hERG mRNA are Essential for Channel Function

The KCNH2 gene encodes the hERG protein, the alpha subunit of the rapid delayed rectifying potassium channel. This potassium channel plays an essential role in cardiac repolarization, and malfunction of this channel caused by mutation leads to Long QT Syndrome, type 2 (LQT2). LQT2 causes increased repolarization time in the heart, leading to ventricular arrhythmias, syncope and sudden death. There are over 600 documented mutations in KCNH2 associated with Long QT syndrome, with more mutations being reported regularly. These mutations occur throughout the length of the gene, without definitive mutational hotspots.While much investigation has been done to characterize the impact that these mutations have on the hERG channel function, little investigation has been focused on what causes the hERG channel to be intolerant to mutation. Our hypothesis is that “extra-coding” characteristics on the mRNA level, such as GC content, rare codon usage and mRNA structure play a critical role in determining correct protein synthesis for the hERG channel, and that mutational changes that disrupt these characteristics lead to Long QT Syndrome. To investigate this hypothesis first, hERG SNPs will be analyzed to both identify trends in disease-causing SNPs, and to find differences between disease-causing and benign SNPs such as changes in local GC content or disruption of codon usage frequency. Secondly, using a codon-modified hERG mRNA with decreased rare codon usage, GC content and CpG islands when compared to native hERG mRNA, the role of mRNA structure and ribosomal movement in determining secondary and tertiary protein structure will be investigated.

Ventricular Wall Stress Predicts Disruption of Cardiomyocyte T-Tubule Structure and Ca2+ Homeostasis across the Infarcted Heart

Invaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation-contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure promotes dyssynchronous, slowed Ca2+ release and reduced power of the heartbeat. While the triggers of t-tubule disruption remain poorly understood, recent evidence suggests that loss of junctophilin-2, a t-tubule anchor, may be critically involved. We presently investigated whether ventricular wall stress following myocardial infarction predicts loss of junctophilin-2, t-tubular structure, and disruption of Ca2+ homeostasis. Phase contrast MRI and blood pressure measurements were employed to examine regional ventricular wall stress in the left ventricle of failing, post-infarction, rat hearts in comparison with sham-operated controls. Markedly elevated diastolic blood pressure resulted in increased wall stress in failing hearts, particularly in regions proximal to the infarct where the ventricular wall was thinned (Wall stress = 61.8±6.4kN/m2 proximal zone vs 31.6±4.0kN/m2 sham). Wall stress measurements across failing hearts correlated strongly with junctophilin-2 expression, which was reduced in the proximal but not distal zones. A corresponding disruption of t-tubule organization and density was observed in the proximal zone (t-tubule fraction = 18.9±0.4% sham vs 17.1±0.6% proximal zone), and Ca2+ transients were significantly desynchronized and slowed. In agreement with local disruption of cardiomyocyte structure and Ca2+ homeostasis, in vivo strain was dramatically reduced in the proximal zone, with near isometric contraction observed. Strain measurements in the distal zone of infarcted hearts were unaltered from equivalent regions in sham. Thus, regional in vivo wall stress effectively predicts cardiomyocyte-level disruption of structure and function in the post-infarction failing heart, which in turn promotes reduced in vivo contractile function. These findings are consistent with a key role of mechanotransduction in signaling cardiomyocyte structural degradation during heart failure.

AFM Reveals Age-Dependent Micromechanical Degradation of Cardiopulmonary Tissues in a Mouse Model of Marfan Syndrome

Marfan syndrome (MFS) is caused by mutation of the FBN1 gene encoding the extracellular matrix (ECM) protein fibrillin-1 that forms elastic microfibrils. This study aims to characterize the micromechanics of aortic and lung tissues from wild type (WT) and FBN1-deficient mutant (MT) mice to identify biophysical determinants of cardiopulmonary disease in MFS. For testing by atomic force microscopy (AFM), full-thickness sections of ascending aorta were dissected from young (0.5-mo) and adult (2-mo) WT and MT mice, mounted flat with the lumen facing up, and indented with a 15-μm spherical probe at 3-5 sites per sample from 1-4 animals per condition. Indentation force-depth curves were analyzed using a hybrid theoretical and finite element analysis to determine the elastic modulus of intima (Eint) and media (Emed) layers. The Kolmogorov-Smirnov test was performed for pairwise statistical analysis; p<0.008 was considered significant based on the Bonferroni correction. Emed at 0.5-mo showed no difference between WT (10.1±2.7kPa, n=8; mean±SEM for n-curves) and MT (7.5±0.6kPa, n=80). Emed increased with age (p<0.0006), but was significantly softer in MT (21.3±1.4kPa, n=112) vs WT (37.4±2.2kPa, n=65, p<0.0001). Eint also increased with age (p<0.003) from ∼2kPa to ∼5-10kPa, but showed no significant difference between WT and MT at matched ages. Similar nano-indentation studies, using a pyramidal probe on lung parenchyma isolated from 2-mo WT and MT mice, showed Elung for MT (1.7±0.1 kPa, n=92) was significantly softer than WT (4.8±0.3kPa, n=91, p<0.0001). In conclusion, AFM revealed age-dependent softening of micro-elastic modulus in elastin-rich tissues including lung parenchyma and aortic media, but not in the aortic intima. In contrast to macro-scale measurements of aortic stiffening in MFS, these micro-scale AFM findings appear consistent with histological observations of local disruption of ECM microstructure in MFS.

Integrated Supply Chain Scheduling under Multi-Level Disruptions

A stochastic mixed integer programming formulation is proposed for integrated supplier selection and production and distribution scheduling in the presence of supply chain disruption risks. The suppliers are located in different geographic regions and the supplies are subject to multi-level local disruptions of each supplier individually and to two-level regional disruptions of all suppliers in the same region. The two conflicting objectives are considered: expected cost and expected service level, and optimized simultaneously using the weighted- sum aggregation approach. Numerical examples are presented and some managerial insights are reported. The main findings indicate that the service-oriented supply portfolio is more diversified than the cost-oriented portfolio. For the minimum cost objective the cheapest supplier from among the most reliable suppliers is usually selected, while for the maximum service level objective most reliable and most expensive suppliers dominate in the supply portfolio.

On the fair optimization of cost and customer service level in a supply chain under disruption risks

This paper presents a new decision-making problem of a fair optimization with respect to the two equally important conflicting objective functions: cost and customer service level, in the presence of supply chain disruption risks. Given a set of customer orders for products, the decision maker needs to select suppliers of parts required to complete the orders, allocate the demand for parts among the selected suppliers, and schedule the orders over the planning horizon, to equitably optimize expected cost and expected customer service level. The supplies of parts are subject to independent random local and regional disruptions. The fair decision-making aims at achieving the normalized expected cost and customer service level values as much close to each other as possible. The obtained combinatorial stochastic optimization problem is formulated as a stochastic mixed integer program with the ordered weighted averaging aggregation of the two conflicting objective functions. Numerical examples and computational results, in particular comparison with the weighted-sum aggregation of the two objective functions are presented and some managerial insights are reported. The findings indicate that for the minimum cost objective the cheapest supplier is usually selected, and for the maximum service level objective a subset of most reliable and most expensive suppliers is usually chosen, whereas the equitably efficient supply portfolio usually combines the most reliable and the cheapest suppliers. While the minimum cost objective function leads to the largest expected unfulfilled demand and the expected production schedule for the maximum service level follows the customer demand with the smallest expected unfulfilled demand, the equitably efficient solution ensures a reasonable value of expected unfulfilled demand.

The application of magnetic nanoparticles for the treatment of brain tumors.

Glioblastoma (GBM), a World Health Organization (WHO) grade IV astrocytoma, is the most common and difficult primary brain tumor to treat (Braun et al., 2012). Even when detected early, the median survival rate for patients is 12–15 months (Adamson et al., 2009; Johnson and O'Neill, 2012). The challenge in treating GBM arises from its resistance to therapies such as radiotherapy and chemotherapy. GBM tumors are quite infiltrative into the surrounding normal brain permitting tumors to recur locally in the majority of patients. The current standard of care treatment for GBM involves surgery and radiation, with concurrent and adjuvant chemotherapy (Stupp et al., 2005). Surgery permits the bulk of a GBM tumor to be removed in most cases. All patients have residual tumor cells residing away from the resection cavity that eventually lead to local tumor recurrence and the demise of the majority of patients (Hou et al., 2006). The infiltrating GBM cells reside centimeters away from the main tumor mass in normal brain making it difficult for complete surgical removal (Kim et al., 2014). Chemotherapy and radiotherapy of patients after surgery attempts to target these cells to prolong overall patient survival. The blood brain barrier (BBB) represents another challenge to the treatment of GBM tumors by preventing the accumulation of most chemotherapeutics into the brain to target the infiltrative cancer cells (Salazar et al., 1976; Bidros and Vogelbaum, 2009). Surgery and adjuvant therapies pose risks to the patient such as neurologic deficits and systemic toxicities. Known side effects of radiation therapy with chemotherapy for brain tumors include chronic fatigue, nausea, and cognitive deficits (Loehrer et al., 2011). The BBB remains a formidable challenge in the treatment of GBM and malignant brain tumors. Its selective permeability is due to the presence of specialized endothelial cells, astrocytes, pericytes, and neuronal terminals (Tajes et al., 2014). The semi-permeable membrane that comprises the BBB prevents sufficient exposure of tumors to most chemotherapeutic drugs that are commonly used to fight tumor progression (Liu et al., 2010). Local disruption of the BBB is found within GBM tumors. The tumor vessels in GBM tumors are abnormal both structurally and functionally (Batchelor et al., 2007). The abnormal tumor vessels further impair delivery of therapeutics and create a hypoxic microenvironment that can reduce the effectiveness of radiation and chemotherapy. Antiangiogenic therapy attempts to normalize the tumor vasculature and improve the tumor microenvironment (Jain, 2001, 2005). Outside of the main tumor mass, the BBB is intact where brain cancer cells infiltrate into the surrounding normal brain. The oral chemotherapy agent, temozolomide (Temodar), can penetrate the BBB and has resulted in prolongation of overall survival patient survival by several months (Stupp et al., 2005). The challenges associated with the treatment of GBM tumors require novel approaches for a greater impact on patient survival and quality of life for patients.

Small Ubiquitin-like Modifier (SUMO)-mediated Repression of the Xenopus Oocyte 5 S rRNA Genes

The 5 S rRNA gene-specific transcription factor IIIA (TFIIIA) interacts with the small ubiquitin-like modifier (SUMO) E3 ligase PIAS2b and with one of its targets, the transcriptional corepressor, XCtBP. PIAS2b is restricted to the cytoplasm of Xenopus oocytes but relocates to the nucleus immediately after fertilization. Following the midblastula transition, PIAS2b and XCtBP are present on oocyte-type, but not somatic-type, 5 S rRNA genes up through the neurula stage, as is a limiting amount of TFIIIA. Histone H3 methylation, coincident with the binding of XCtBP, also occurs exclusively on the oocyte-type genes. Immunohistochemical staining of embryos confirms the occupancy of a subset of the oocyte-type genes by TFIIIA that become positioned at the nuclear periphery shortly after the midblastula transition. Inhibition of SUMOylation activity relieves repression of oocyte-type 5 S rRNA genes and is correlated with a decrease in methylation of H3K9 and H3K27 and disruption of subnuclear localization. These results reveal a novel function for TFIIIA as a negative regulator that recruits histone modification activity through the CtBP repressor complex exclusively to the oocyte-type 5 S rRNA genes, leading to their terminal repression.

Effects of Beta-Amyloid on Resting State Functional Connectivity Within and Between Networks Reflect Known Patterns of Regional Vulnerability.

Beta-amyloid (Aβ) deposition is one of the hallmarks of Alzheimer's disease (AD). However, it is also present in some cognitively normal elderly adults and may represent a preclinical disease state. While AD patients exhibit disrupted functional connectivity (FC) both within and between resting-state networks, studies of preclinical cases have focused primarily on the default mode network (DMN). The extent to which Aβ-related effects occur outside of the DMN and between networks remains unclear. In the present study, we examine how within- and between-network FC are related to both global and regional Aβ deposition as measured by [(11)C]PIB-PET in 92 cognitively normal older people. We found that within-network FC changes occurred in multiple networks, including the DMN. Changes of between-network FC were also apparent, suggesting that regions maintaining connections to multiple networks may be particularly susceptible to Aβ-induced alterations. Cortical regions showing altered FC clustered in parietal and temporal cortex, areas known to be susceptible to AD pathology. These results likely represent a mix of local network disruption, compensatory reorganization, and impaired control network function. They indicate the presence of Aβ-related dysfunction of neural systems in cognitively normal people well before these areas become hypometabolic with the onset of cognitive decline.