Binary and Millisecond Pulsars at the New Millennium

We review the properties and applications of binary and millisecond pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1300. There are now 56 binary and millisecond pulsars in the Galactic disk and a further 47 in globular clusters. This review is concerned primarily with the results and spin-offs from these surveys which are of particular interest to the relativity community.Comment: 59 pages, 26 figures, 5 tables. Accepted for publication in Living Reviews in Relativity (http://www.livingreviews.org

Nuclear and cytoplasmic WDR-23 isoforms mediate differential effects on GEN-1 and SKN-1 substrates

Maintaining a healthy cellular environment requires the constant control of proteostasis. E3 ubiquitin ligase complexes facilitate the post-translational addition of ubiquitin, which based on the quantity and specific lysine linkages, results in different outcomes. Our studies reveal the CUL4-DDB1 substrate receptor, WDR23, as both a positive and a negative regulator in cellular stress responses. These opposing roles are mediated by two distinct isoforms: WDR-23A in the cytoplasm and WDR-23B in the nucleus. C. elegans expressing only WDR-23A display activation of SKN-1 and enhanced survival to oxidative stress, whereas animals with restricted WDR-23B expression do not. Additionally, we identify GEN-1, a Holliday junction resolvase, as an evolutionarily conserved WDR-23 substrate and find that the nuclear and cytoplasmic isoforms of WDR-23 differentially affect double-strand break repair. Our results suggest that through differential ubiquitination, nuclear WDR-23B inhibits the activity of substrates, most likely by promoting protein turnover, while cytoplasmic WDR-23A performs a proteasome-independent role. Together, our results establish a cooperative role between two spatially distinct isoforms of WDR-23 in ensuring proper regulation of WDR-23 substrates.</p

Genome-wide association analysis identifies six new loci associated with forced vital capacity

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR129-2–HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease

Does interference between self and other perspectives in Theory of Mind Tasks reflect a common underlying process? Evidence from individual differences in theory of mind and inhibitory control

Theory of mind (ToM), the ability to understand that other agents have different beliefs, desires, and knowledge than oneself, has been extensively researched. Theory of mind tasks involve participants dealing with interference between their self-perspective and another agent’s perspective, and this interference has been related to executive function, particularly to inhibitory control. This study assessed whether there are individual differences in self–other interference, and whether these effects are due to individual differences in executive function. A total of 142 participants completed two ToM (the director task and a Level 1 visual perspective-taking task), which both involve self–other interference, and a battery of inhibitory control tasks. The relationships between the tasks were examined using path analysis. Results showed that the self–other interference effects of the two ToM tasks were dissociable, with individual differences in performance on the ToM tasks being unrelated and performance in each predicted by different inhibitory control tasks. We suggest that self–other differences are part of the nature of ToM tasks, but self–other interference is not a unitary construct. Instead, self–other differences result in interference effects in various ways and at different stages of processing, and these effects may not be a major limiting step for adults’ performance on typical ToM tasks. Further work is needed to assess other factors that may limit adults’ ToM performance and hence explain individual differences in social ability.</p

Bevacizumab intravítreo como tratamiento de maculopatías miópicas neovasculares

Introducción. La miopía patológica es una causa importante de pérdida de visión irreversible y es la cuarta a novena causa más frecuente de ceguera en el mundo. Es también conocida como miopía alta, degenerativa o maligna; condición en la que los individuos tienen una longitud axial superior a 25,5 - 26,5mm, y/o un error de refracción de por lo menos -5.0 dioptrías, acompañado por cambios patológicos. La neovascularización coroidea (NVC) asociada a miopía patológica puede resultar en la pérdida significativa de la visión y/o la ceguera. La NVC suele ser subfoveal y es una importante complicación, desarrollándose en aproximadamente 5-10% de ojos con miopía patológica. De manera similar que en otras enfermedades maculares asociadas a NVC, se ha encontrado un aumento del nivel del factor de crecimiento de endotelial (VEGF) en NVC miópicas, y por lo tanto, la terapia anti-VEGF sería útil. Desde la introducción en oftalmología de agentes anti factor de crecimiento de endotelial (anti-VEGF), el tratamiento anti-angiogénico con antiVEGF intravítreo se ha convertido en el tratamiento de primera línea para la NVC miópica. El bevacizumab es un anticuerpo monoclonal humano, anti factor de crecimiento endotelial (anti-VEGF), que inhibe la proliferación de nuevas células endoteliales produciendo un bloqueo de la fosforilación de las uniones estrechas (tight junctions) de las mismas. Este mecanismo produciría&nbsp;una mejoría anatómica-funcional en los pacientes e impediría una de las complicaciones más importantes de esta patología como lo es la neovascularización. Objetivo. Evaluar la eficacia de bevacizumab intravítreo (Avastin ®™) como tratamiento de la neovascularización coroidea (NVC) en miopías patológicas. Pacientes y métodos. Se evaluaron retrospectivamente 22 pacientes con diagnóstico de maculopatía miópica neovascular tratados mediante inyección intravítrea de bevacizumab, con un seguimiento mínimo de 12 meses. La agudeza visual se evaluó mediante tabla de Snellen y se convirtió en unidades LogMAR. El espesor macular se evaluó mediante tomografía de coherencia óptica (OCT). Las variables cuantitativas se analizaron mediante medidas de tendencia central, dispersión y forma. Los cambios en la agudeza visual se calcularon utilizando la prueba de Wilcoxon para variables apareadas y con la prueba de Mann Whitneypara comparar variables independientes. Las diferencias entre variables continuas con distribución normal y de muestras independientes fueron calculadas mediante la prueba T de Student. Resultado. Se estudiaron 22 pacientes con diagnóstico de maculopatía miópica neovascular, cuya edad promedio fue de 59,68 (DE 11,75; rango 34,00 – 85,00), de los cuales 7 (31,8%) fueron hombres y 15 (68,2%) fueron mujeres. El tiempo de seguimiento fue de 12 meses. El tiempo promedio transcurrido entre el comienzo de los síntomas y el inicio del tratamiento fue 38,68 (DE 34,63) días. El 68,2% (15) de los pacientes consultaron por disminución brusca de la agudeza visual del ojo afectado y 31,8% (7) consultaron por metamorfopsias. Todos los pacientes presentaron miopía patológica (&gt; 5.0 dioptrías). La cantidad total de inyecciones durante el seguimiento tuvo una media de 4,27 (DE 1.86; Rango 2,00 – 9,00), con un máximo de 9 inyecciones y un mínimo de 2 inyecciones. Durante los primeros 6 meses se realizaron la mayor parte de las inyecciones con una media de 3,36 (DE 1,22; Rango 1,00 – 6,00). La mediana de la AV al momento del tratamiento fue de 1,00 (P25-75=0,40- 1,00). Al analizar la totalidad de los pacientes se encontró que existe una diferencia significativa al comparar las agudezas visuales previas al tratamiento y a los 12 meses de tratamiento (p=&lt;0.0001)..La mejoría&nbsp;franca de la AV se observó entre el primer mes (mediana= 1.00 RIQ= 0,6) y los 3 meses de tratamiento (mediana= 0,60 RIQ= 0,6) (p= 0,0002), mientras que no hubo diferencias significativas en la variación de la AV más allá de los 3 meses de seguimiento (p= 0,09). Al estudiar los espesores maculares antes del tratamiento, encontramos una mediana de 290 (RIQ=105); mientras que a los 12 meses de seguimiento fue de 269,50 (RIQ= 91). Teniendo en cuenta el total de los pacientes estudiados, no hubo diferencias significativas en el análisis del espesor macular medido por OCT antes y después del tratamiento (p=0,8812). Conclusiones. El bevacizumab fue eficaz en el tratamiento de la maculopatía miópica, si bien no se encontraron diferencias significativas en la variación del espesor macular. En nuestra serie no hubo complicaciones oculares ni sistémicas vinculadas al tratamiento

Bevacizumab intravítreo como tratamiento de maculopatías miópicas neovasculares Intravitreal bevacizumab for neovascular myopic maculopathy

Ningun

Acute fatal presentation of ornithine transcarbamylase deficiency in a previously healthy male

Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle defect. While hemizygous males typically present with hyperammonemic coma in infancy, reports of rare late-onset presentations exist, with poor outcomes in males up to 58 years old. Relatives with mutations identical to affected patients often remain asymptomatic, and it is likely that environmental and genetic factors influence disease penetrance and expression. Here, we present our investigation of a patient with late-onset presentation, and we emphasize the potential role of environmental and genetic factors on disease expression. The patient was a previously healthy 62-year-old man who developed mental slowing, refractory seizures, and coma over an 8-day period. Interestingly, the patient had recently used home gardening fertilizers and pesticides. Evaluations for drug and alcohol use, infections, and liver disease were negative. Despite aggressive therapy, blood NH3 concentration peaked at 2,050 μM and the patient died from cerebral edema and cerebellar herniation. Analysis of the OTC gene showed a Pro-225-Thr (P225T) change in exon 7, a mutation that has been previously implicated in OTC deficiency. This case illustrates that OTC deficiency can cause acute, severe hyperammonemia in a previously healthy adult and that the P225T mutation can be associated with late-onset OTC deficiency. We speculate that exposure to organic chemicals might have contributed to the onset of symptoms in this patient. This case also emphasizes that persistent hyperammonemia may cause irreversible neurologic damage and that after the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle disorders and other causes of hyperammonemic encephalopathy

JISTIC: Identification of Significant Targets in Cancer

<p>Abstract</p> <p>Background</p> <p>Cancer is caused through a multistep process, in which a succession of genetic changes, each conferring a competitive advantage for growth and proliferation, leads to the progressive conversion of normal human cells into malignant cancer cells. Interrogation of cancer genomes holds the promise of understanding this process, thus revolutionizing cancer research and treatment. As datasets measuring copy number aberrations in tumors accumulate, a major challenge has become to distinguish between those mutations that drive the cancer versus those passenger mutations that have no effect.</p> <p>Results</p> <p>We present JISTIC, a tool for analyzing datasets of genome-wide copy number variation to identify driver aberrations in cancer. JISTIC is an improvement over the widely used GISTIC algorithm. We compared the performance of JISTIC versus GISTIC on a dataset of glioblastoma copy number variation, JISTIC finds 173 significant regions, whereas GISTIC only finds 103 significant regions. Importantly, the additional regions detected by JISTIC are enriched for oncogenes and genes involved in cell-cycle and proliferation.</p> <p>Conclusions</p> <p>JISTIC is an easy-to-install platform independent implementation of GISTIC that outperforms the original algorithm detecting more relevant candidate genes and regions. The software and documentation are freely available and can be found at: <url>http://www.c2b2.columbia.edu/danapeerlab/html/software.html</url></p

Sparsity-based single-shot sub-wavelength coherent diffractive imaging

We present the experimental reconstruction of sub-wavelength features from the far-field intensity of sparse optical objects: sparsity-based sub-wavelength imaging combined with phase-retrieval. As examples, we demonstrate the recovery of random and ordered arrangements of 100 nm features with the resolution of 30 nm, with an illuminating wavelength of 532 nm. Our algorithmic technique relies on minimizing the number of degrees of freedom; it works in real-time, requires no scanning, and can be implemented in all existing microscopes - optical and non-optical

An Epithelial Serine Protease, AgESP, Is Required for Plasmodium Invasion in the Mosquito Anopheles gambiae

Background: Plasmodium parasites need to cross the midgut and salivary gland epithelia to complete their life cycle in the mosquito. However, our understanding of the molecular mechanism and the mosquito genes that participate in this process is still very limited. Methodology/Principal Findings: We identified an Anopheles gambiae epithelial serine protease (AgESP) that is constitutively expressed in the submicrovillar region of mosquito midgut epithelial cells and in the basal side of the salivary glands that is critical for Plasmodium parasites to cross these two epithelial barriers. AgESP silencing greatly reduces Plasmodium berghei and Plasmodium falciparum midgut invasion and prevents the transcriptional activation of gelsolin, a key regulator of actin remodeling and a reported Plasmodium agonist. AgESP expression is highly induced in midgut cells invaded by Plasmodium, suggesting that this protease also participates in the apoptotic response to invasion. In salivary gland epithelial cells, AgESP is localized on the basal side–the surface with which sporozoites interact. AgESP expression in the salivary gland is also induced in response to P. berghei and P. falciparum sporozoite invasion, and AgESP silencing significantly reduces the number of sporozoites that invade this organ. Conclusion: Our findings indicate that AgESP is required for Plasmodium parasites to effectively traverse the midgut and salivary gland epithelial barriers. Plasmodium parasites need to modify the actin cytoskeleton of mosquito epithelial cells t