Ten years ago, the United States stood at the forefront of the Internet revolution. With some of the fastest speeds and lowest prices in the world for high-speed Internet access, the nation was ...poised to be the global leader in the new knowledge-based economy. Today that global competitive advantage has all but vanished because of a series of government decisions and resulting monopolies that have allowed dozens of countries, including Japan and South Korea, to pass us in both speed and price of broadband. This steady slide backward not only deprives consumers of vital services needed in a competitive employment and business market-it also threatens the economic future of the nation.
This important book by leading telecommunications policy expert Susan Crawford explores why Americans are now paying much more but getting much less when it comes to high-speed Internet access. Using the 2011 merger between Comcast and NBC Universal as a lens, Crawford examines how we have created the biggest monopoly since the breakup of Standard Oil a century ago. In the clearest terms, this book explores how telecommunications monopolies have affected the daily lives of consumers and America's global economic standing.
Motor and gestural skills of children with autism spectrum disorders (ASD), developmental coordination disorder (DCD), and/or attention deficit hyperactivity disorder (ADHD) were investigated. A ...total of 49 children with ASD, 46 children with DCD, 38 children with DCD+ADHD, 27 children with ADHD, and 78 typically developing control children participated. Motor skills were assessed with the Bruininks-Oseretsky Test of Motor Proficiency Short Form, and gestural skills were assessed using a test that required children to produce meaningful gestures to command and imitation. Children with ASD, DCD, and DCD+ADHD were significantly impaired on motor coordination skills; however, only children with ASD showed a generalized impairment in gestural performance. Examination of types of gestural errors revealed that children with ASD made significantly more incorrect action and orientation errors to command, and significantly more orientation and distortion errors to imitation than children with DCD, DCD+ADHD, ADHD, and typically developing control children. These findings suggest that gestural impairments displayed by the children with ASD were not solely attributable to deficits in motor coordination skills.
FIRST AMENDMENT COMMON SENSE Crawford, Susan
Harvard law review,
06/2014, Letnik:
127, Številka:
8
Journal Article
Recenzirano
In 'Verizon v. FCC', high-speed Internet access provider Verizon asserted that the December 2010 Federal Communications Commission (FCC) Open Internet Rules were subject to heightened scrutiny under ...the First Amendment. Verizon's claim was that because it reserves the right to edit what users access across its high-speed Internet connections, any regulation (and thus, necessarily, any statute) limiting that discretion amounts to compelled speech. (Verizon also claimed that it did not in fact carry out such editing.) The cable industry, for its part, has long maintained that when it is selling high-speed Internet access its activities are shielded by the First Amendment, and that any nondiscrimination obligation aimed at cable Internet access providers "would not only encroach upon but would obliterate the boundaries established by the First Amendment and would surely be subject to at least 'heightened scrutiny' by the courts." Commentators working with think tanks such as the Free State Foundation have said that they agree with the idea that private providers of Internet access services should enjoy the same First Amendment protection from government oversight as do newspapers.
Objective To characterize white matter alterations in children with isolated or concurrent developmental coordination disorder and/or attention-deficit/hyperactivity disorder (ADHD) compared with ...typically-developing controls, and to determine whether group differences on motor and attention tasks could be explained by differences in diffusion tensor imaging (DTI) measures. Study design In a cohort of children (n = 85) with developmental coordination disorder, ADHD, or combined developmental coordination disorder+ADHD, we examined 3 major white matter tracts involved in attention and motor processes. Using DTI, the corpus callosum, superior longitudinal fasciculus, and cingulum were analyzed with respect to measures of white matter integrity. Differences in fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity were analyzed using ANOVA. Motor and attentional functioning was assessed using standardized tests, and correlated to DTI measures. Results FA reductions were noted in the frontal regions of the corpus callosum for children with ADHD ( P = .039), whereas children with developmental coordination disorder displayed similar reductions in regions of the corpus callosum underlying parietal brain regions ( P = .040), as well as the left superior longitudinal fasciculus ( P = .026). White matter integrity was impacted in both frontal and parietal regions for children with comorbid developmental coordination disorder+ADHD ( P = .029; .046). FA was positively correlated with scores on both motor and attentional assessments in a region-specific manner. Conclusion Our findings suggest that alterations in the corpus callosum underlie difficulties in motor and attention functioning. These changes are functionally and regionally distinct and could reflect a neurobiological basis for motor and attention disorders in children.
The retinal pigment epithelium (RPE) expresses the
gene to produce pigment epithelium-derived factor (PEDF), a retinoprotective protein that is downregulated with cell senescence, aging and retinal ...degenerations. We determined the expression of senescence-associated genes in the RPE of 3-month-old mice that lack the
gene and found that
deletion induced
for histone H2AX protein,
for p21 protein, and
gene for β-galactosidase. Senescence-associated β-galactosidase activity increased in the
null RPE when compared with wild-type RPE. We evaluated the subcellular morphology of the RPE and found that ablation of
increased the volume of the nuclei and the nucleoli number of RPE cells, implying chromatin reorganization. Given that the RPE phagocytic function declines with aging, we assessed the expression of the
gene, which is required for the degradation of photoreceptor outer segments by the RPE. We found that both the
gene and its protein PEDF-R declined with the
gene ablation. Moreover, we determined the levels of phagocytosed rhodopsin and lipids in the RPE of the
null mice. The RPE of the
null mice accumulated rhodopsin and lipids compared to littermate controls, implying an association of PEDF deficiency with RPE phagocytosis dysfunction. Our findings establish PEDF loss as a cause of senescence-like changes in the RPE, highlighting PEDF as both a retinoprotective and a regulatory protein of aging-like changes associated with defective degradation of the photoreceptor outer segment in the RPE.
The gene Serpinf1 encodes for Pigment Epithelium‐Derived Factor (PEDF), which protects photoreceptors from cell death. The Serpinf1 null mouse exhibits normal retinal function; however, PEDF ...deficiency increases retinal degeneration susceptibility in rd10 mouse. CRX is a transcription factor that regulates expression of several photoreceptor specific genes, including opsins and phosphodiesterase. This study aims to explore whether regulation of CRX activation is one mechanism by which PEDF exerts photoreceptor survival.
Serpinf1‐/‐, Serpinf1+/‐ and Serpinf1+/+ mice at 3 months of age were used. We prepared cultures of mouse retinal explants. They were treated with recombinant human PEDF. Zaprinast (a PDE inhibitor) was added to induce photoreceptor death. We determined cell death using PSVue‐550, a visible fluorescent probe for detection of phosphatidylserine on the surface of cells. Subcellular distribution of CRX, PDE6A and pan‐acetylation was detected by immunofluorescence. The transcriptional levels of Crx, Pde6a, Opn1mw and Opn1sw were assessed using qPCR.
PEDF treatment induced the expression of Crx and its regulated genes Pde6a, Opn1mw and Opn1sw. PEDF also enhanced the CRX immunoreactivity in the nuclei of photoreceptors. In contrast, the nuclear CRX immunoreactivity was suppressed in photoreceptors from retinas of Serpinf1‐/‐ mice deficient of PEDF. PDE6A immunoreactivity also decreased in Serpinf1‐/‐ photoreceptors compared to those from Serpinf1+/+ mice. Histone acetylation was detected in discrete photoreceptors in Serpinf1+/+ but was undetectable in the Serpinf1‐/‐ retinas. Zaprinast‐induced photoreceptor death was more pronounced in Serpinf1‐/‐ retinal explants than in wild type controls. PEDF pre‐treatment prior to the zaprinast treatment improved photoreceptor survival and enhanced CRX immunoreactivity in both Serpinf1‐/‐ and Serpinf1+/+ retinal explants. Deletion in PEDF in the Serpinf1 null mice accelerated retinal degeneration induced by zaprinast, which was prevented by exogenous addition of PEDF in retinal explants.
The findings imply that PEDF activated the CRX‐associated transcription factor network. They provide a novel insight linking extracellular PEDF to nuclear CRX during photoreceptor survival.
The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background ...with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.
Background
Carcinoma–associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the ...mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub‐populations of human prostate CAF can be identified and functionally characterized.
Methods
Single‐cell RNA‐seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non‐tumorigenic, initiated prostate epithelial BPH‐1 cells. Resultant grafts were assessed for inflammatory cell recruitment.
Results
Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub‐renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine‐related genes of individual clusters. Migration of THP‐1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF‐derived chemokine CCL2 may be responsible for CAF‐stimulated migration of THP‐1 cells, since neutralization of this chemokine abrogates migration capacity.
Conclusions
CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued.
Lipid droplet (LD) accumulation in cancer results from aberrant metabolic reprograming due to increased lipid uptake, diminished lipolysis and/or de novo lipid synthesis. Initially implicated in ...storage and lipid trafficking in adipocytes, LDs are more recently recognized to fuel key functions associated with carcinogenesis and progression of several cancers, including prostate cancer (PCa). However, the mechanisms controlling LD accumulation in cancer are largely unknown. EPHB2, a tyrosine kinase (TKR) ephrin receptor has been proposed to have tumor suppressor functions in PCa, although the mechanisms responsible for these effects are unclear. Given that dysregulation in TRK signaling can result in glutaminolysis we postulated that EPHB2 might have potential effects on lipid metabolism. Knockdown strategies for EPHB2 were performed in prostate cancer cells to analyze the impact on the net lipid balance, proliferation, triacylglycerol-regulating proteins, effect on LD biogenesis, and intracellular localization of LDs. We found that EPHB2 protein expression in a panel of human-derived prostate cancer cell lines was inversely associated with in vivo cell aggressiveness. EPHB2 silencing increased the proliferation of prostate cancer cells and concurrently induced de novo LD accumulation in both cytoplasmic and nuclear compartments as well as a “shift” on LD size distribution in newly formed lipid-rich organelles. Lipid challenge using oleic acid exacerbated the effects on the LD phenotype. Loss of EPHB2 directly regulated key proteins involved in maintaining lipid homeostasis including, increasing lipogenic DGAT1, DGAT2 and PLIN2 and decreasing lipolytic ATGL and PEDF. A DGAT1-specific inhibitor abrogated LD accumulation and proliferative effects induced by EPHB2 loss. In conclusion, we highlight a new anti-tumor function of EPHB2 in lipid metabolism through regulation of DGAT1 and ATGL in prostate cancer. Blockade of DGAT1 in EPHB2-deficient tumors appears to be effective in restoring the lipid balance and reducing tumor growth.
EPHB2 deficiency in prostate cancer cells leads to alterations of the triacylglyceride (TAG) synthesis pathway involved in lipogenesis and lipolysis. These changes initiate de novo cytoplasmic and intranuclear lipid droplets accumulation associated with increased proliferative capacity. Targeting the TAG pathway molecule DGAT1 diminishes the deleterious effects exerted by EPHB2 silencing.
Aims/hypothesis
Youth with type 1 diabetes are at high risk for loss to follow-up during the transition from paediatric to adult diabetes care. Our aim was to assess the effect of a communication ...technology enhanced transition coordinator intervention compared with usual care on clinic attendance among transitioning youth with type 1 diabetes.
Methods
In this open label, pragmatic clinical trial of youth with type 1 diabetes, aged 17–18 years, transitioning from paediatric to adult diabetes care, the intervention group received support from a transition coordinator who used communication technology and the control group received usual care. The primary outcome was the proportion of individuals that did not attend at least one routine clinic visit in adult diabetes care within 1 year after transfer. Secondary outcomes included diabetes-related clinical outcomes and quality of life measures.
Results
There were no baseline differences in age, sex, HbA
1c
and number of follow-up visits, emergency department visits and diabetic ketoacidosis admissions in the 1 year prior to transition between the usual care (
n
= 101) and intervention (
n
= 102) groups. In the year following transfer, 47.1% in the usual care group vs 11.9% in the intervention group did not attend any outpatient diabetes appointments (
p
< 0.01). There were no differences in glycaemic control or diabetic ketoacidosis post transfer.
Conclusions/interpretation
Our intervention was successful in improving clinic attendance among transitioning youth with type 1 diabetes. Importantly, this programme used simple, readily accessible communication technologies, which increases the sustainability and transferability of this strategy.
Trial registration
isrctn.org
ISRCTN13459962
Graphical abstract
PDF
