gebhart/patrepeval huggingface dataset:
13 Exploring mechanisms of tumour lymphangiogenesis to potentiate immunotherapies in melanoma (2018)

Introduction Tumour lymphangiogenesis correlates with poor prognosis and metastasis in melanoma and other cancers, yet its functional roles in regulating antitumor immunity have remained largely unexplored. Recently, we showed that despite its pro-metastatic effects, tumour lymphangiogenesis potentiates immunotherapies in melanoma. Here, we sought to further explore mechanisms of potentiation of immunotherapies and develop means to exploit the lymphatic growth factor VEGF-C therapeutically. Material and methods For this study, we used two mouse melanoma models: the injected B16F10 and the BrafV600E-PTEN-/- (±β-CAT-STA) autochthonous models. Lymphangiogenesis was inhibited using VEGFR-3 blocking antibodies, or promoted through either1 viral transduction of B16F10 with VEGF-C or2 intratumoral injections of a matrix-binding form of VEGF-C. Immunotherapies included PD-1 blockade, immune adjuvants (CpG-B and Poly I:C), or adoptive T cell transfer. For mechanistic studies, we used Batf3-/- mice, which lack cross-presenting dendritic cells (DCs) and fail to mount a potent antitumor CD8+ T cell response. Moreover, using gene expression analysis from The Cancer Genome Atlas (TCGA) database, we correlated VEGFC expression with the expression of genes associated with cross-presenting DCs such as BATF3, IRF8 and ZBTB46. Results and discussions In addition to reducing T cell infiltrates, VEGFR3 blockade in both models of melanoma reduced the number of cross-presenting DCs. Moreover, in tumours with low T cell infiltrates (coldtumours), and thus unresponsive to immunotherapies, the intratumoral delivery of matrix-binding VEGF-C increased T cell infiltration and restored the ability to respond to immunotherapies. Lymphangiogenic potentiation of immunotherapies was not observed in Batf3-/- mice, indicating the importance of cross-presenting dendritic cells and subsequent generation of tumor-specific endogenous CD8+ T cells. Finally, in the TCGA database, we found that VEGFC expression correlated with genes associated with cross-presenting DCs in human primary melanomas. Conclusion Our findings indicate that tumour lymphangiogenesis promotes recruitment of T cells and DCs into the microenvironment. By using an engineered variant of VEGF-C, we were able to transform the tumour microenvironment from a cold one to a hot one, thereby restoring responsiveness to immunotherapies. Further studies are needed to further develop this therapeutic approach.
Pore Scale Geochemical Processes (2015)

This RiMG (Reviews in Mineralogy &amp; Geochemistry) volume includes contributions that review experimental, characterization, and modeling advances in our understanding of pore-scale geochemical processes. The volume had its origins in a special theme session at the 2015 Goldschmidt Conference in Prague. From a diversity of pore-scale topics that ranged from multi-scale characterization to modeling, this work summarizes the state-of-the-science in this subject.Topics include: modification of thermodynamics and kinetics in small pores. chemo-mechanical processes and how they affect porosity evolution in geological media. small angle neutron scattering (SANS) techniques. how isotopic gradients across fluidâmineral boundaries can develop and how these provide insight into pore-scale processes. Information on an important class of models referred to as "pore network" and much more. The material in this book is accessible for graduate students, researchers, and professionals in the earth, material, environmental, hydrological, and biological sciences.The pore scale is readily recognizable to geochemists, and yet in the past it has not received a great deal of attention as a distinct scale or environment that is associated with its own set of questions and challenges. Is the pore scale merely an environment in which smaller scale (molecular) processes aggregate, or are there emergent phenomena unique to this scale? Is it simply a finer-grained version of the "continuum" scale that is addressed in larger-scale models and interpretations? The scale is important because it accounts for the pore architecture within which such diverse processes as multi-mineral reaction networks, microbial community interaction, and transport play out, giving rise to new geochemical behavior that might not be understood or predicted by considering smaller or larger scales alone.
Mechanisms of Spatial and Temporal Development of Autoimmune Vitiligo in Tyrosinase-Specific TCR Transgenic Mice (2010)

Generalized vitiligo is thought to have an autoimmune etiology and has been correlated with the presence of CD8 T cells specific for melanocyte differentiation Ag. However, limited animal models for the disease have hampered its understanding. Thus, we generated TCR transgenic mice that recognize an epitope of the melanocyte protein, tyrosinase. These animals develop vitiligo with strikingly similar characteristics to the human disease. Vitiligo develops temporally and spatially, with juvenile lesions forming bilaterally in head and facial areas, and only arising later in the body of adult animals. Vitiligo is entirely dependent on CD8 T cells, whereas CD4 T cells exert a negative regulatory effect. Importantly, CD8 T cells can be pervasively present in the skin in the steady state without inducing vitiligo in most areas. This points to developmental differences in melanocyte susceptibility and/or immunological effector mechanisms over time, or in different body locations. Disease is strongly dependent on both IFN-gamma and CXCR3, whereas dependence on CCR5 is more limited, and both CCR4 and perforin are dispensable. Genetic ablation of CXCR3 or IFN-gamma also resulted in scarce CD8 T cell infiltration into the skin. Our results identify unexpected complexity in vitiligo development and point toward possible therapeutic interventions.
Disruption of Fgf13 Causes Synaptic Excitatory-Inhibitory Imbalance and Genetic Epilepsy and Febrile Seizures Plus (2015)

We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability.
Selective response of rat peripheral sympathetic nervous system to various stimuli (1979)

1. We utilized the induction of tyrosine hydroxylase, a catecholamine‐synthesizing enzyme, in sympathetic ganglia and adrenal medullae to explore the central and peripheral mechanisms through which choline, various environmental stresses, and drugs that alter blood pressure or central neurotransmission affect various portions of the sympathetic nervous system. Animals received each treatment chronically, and enzyme activity was measured in the superior cervical, stellate, and coeliac ganglia and in the adrenal medullae. 2. Choline administration increased tyrosine hydroxylase activity in all four tissues, probably by increasing the release of acetylcholine from preganglionic sympathetic neurones that synapse on catecholamine‐producing ganglion and chromaffin cells; carbachol and nicotine had similar effects. 3. Insulin enhanced tyrosine hydroxylase activity primarily in the coeliac ganglion and the adrenal medullae, but not in the superior cervical ganglia. 4. Reserpine and phenoxybenzamine increased the activity of the enzyme in all four tissues. 5. Prolonged exposure to a cold environment increased enzyme activity in all four tissues, but especially in the stellate and coeliac ganglia; forced swimming affected tyrosine hydroxylase only in these two ganglia. 6. Several drugs known to modify central neurotransmission were found to increase tyrosine hydroxylase activity in some portions of the sympathetic nervous system but not in others. 5,7‐Dihydroxytryptamine, which destroys terminals of serotoninergic neurones, enhanced enzyme activity in all four tissues, but primarily in the coeliac ganglion and adrenal medullae. ET‐495 (a dopaminergic agonist), D ‐amphetamine, and morphine induced tyrosine hydroxylase activity in the adrenal medullae and the coeliac ganglion, but not in the superior cervical ganglia. Oxotremorine, a centrally acting muscarinic agonist, increased tyrosine hydroxylase activity only in the adrenal medullae; its effect was not blocked by methylatropine, a peripheral muscarinic blocker. 7. These data indicate that specific neurones in the central nervous system, which utilize specific neurotransmitters and which are differentially affected by drugs and environmental inputs, selectively influence the outflows through the various zones of the sympathetic nervous system.
Genome-Scale CRISPR Screens Identify Human Pluripotency-Specific Genes (2019)

Human pluripotent stem cells (hPSCs) generate a variety of disease-relevant cells that can be used to improve the translation of preclinical research. Despite the potential of hPSCs, their use for genetic screening has been limited by technical challenges. We developed a scalable and renewable Cas9 and sgRNA-hPSC library in which loss-of-function mutations can be induced at will. Our inducible mutant hPSC library can be used for multiple genome-wide CRISPR screens in a variety of hPSC-induced cell types. As proof of concept, we performed three screens for regulators of properties fundamental to hPSCs: their ability to self-renew and/or survive (fitness), their inability to survive as single-cell clones, and their capacity to differentiate. We identified the majority of known genes and pathways involved in these processes, as well as a plethora of genes with unidentified roles. This resource will increase the understanding of human development and genetics. This approach will be a powerful tool to identify disease-modifying genes and pathways.
Compressed Sensing Vs. Active Learning (2006)

Compressive sampling (CS), or Compressed Sensing, has generated a tremendous amount of excitement in the signal processing community. Compressive sampling, which involves non-traditional samples in the form of randomized projections, can capture most of the salient information in a signal with a relatively small number of samples, often far fewer samples than required using traditional sampling schemes. Adaptive sampling (AS), also called Active Learning, uses information gleaned from previous observations (e.g., feedback) to focus the sampling process. Theoretical and experimental results have shown that adaptive sampling can dramatically outperform conventional (non-adaptive) sampling schemes. This paper compares the theoretical performance of compressive and adaptive sampling in noisy conditions, and it is shown that for certain classes of piecewise constant signals and high SNR regimes both CS and AS are near-optimal. This result is remarkable since it is the first evidence that shows that compressive sampling, which is non-adaptive, cannot be significantly outperformed by any other method (including adaptive sampling procedures), even in presence of noise.
Optical Fibre with an Aerogel-Filled Core (2009)

Get PDF Email Share Share with Facebook Tweet This Post on reddit Share with LinkedIn Add to CiteULike Add to Mendeley Add to BibSonomy Get Citation Copy Citation Text M. D. W. Grogan, S. G. Leon-Saval, R. Williams, R. England, and T. A. Birks, "Optical Fibre with an Aerogel-Filled Core," in Conference on Lasers and Electro-Optics/International Quantum Electronics Conference, OSA Technical Digest (CD) (Optica Publishing Group, 2009), paper CMW3. Export Citation BibTex Endnote (RIS) HTML Plain Text Citation alert Save article
ChemInform Abstract: Selenocyclizations of Homoallylic Sulfonamides: A Highly Stereoselective Route to Both cis‐ and trans‐2,5‐Dihydropyrroles. (1999)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Relationship between Immunological Markers and Short-Term Brain Volume Changes in Patients with Relapsing-Remitting Multiple Sclerosis Receiving Interferon Beta-1a (P3.146) (2014)

Objective: Compare percent brain volume change (PBVC) between patients with relapsing-remitting multiple sclerosis (RRMS) treated over 6 months with thrice-weekly interferon beta-1a subcutaneously (IFN beta-1a SC) and healthy controls (HCs); analyze correlations between immunological markers and short-term volume changes among treated patients. Background: Chronic RRMS progression is associated with decreased brain volume (atrophy). Over the short term, brain volume may change via inflammation-related hydrodynamic changes, which subside following anti-inflammatory therapy (pseudoatrophy). Responses to such therapy may be influenced by patients’ immunological status before and during treatment. Design/Methods: This 24-week, two-arm (23 RRMS patients receiving IFN beta-1a SC, 15 HCs) pilot study (NCT01085318) evaluated magnetic resonance imaging (MRI) at baseline and 3 and 6 months, and immunological measures at baseline and 6 months. PBVC using SIENA over 0-3, 3-6 and 0-6 months was assessed within groups using Wilcoxon signed-rank test; differences between RRMS patients and HCs were assessed by Wilcoxon rank-sum test. Spearman correlation coefficients were calculated between PBVC and changes in immunological markers in RRMS patients. Results: PBVC between baseline and 3 months was -0.95% (standard deviation, 1.712%) among RRMS patients (p=0.03) and 0.24% (standard deviation, 1.068%) in HCs (p=0.36); between-group difference was significant (p=0.02). No significant PBVC was seen with either group over Months 3-6 or 0-6. Decreased percentage of CD4+ T-cells producing interleukin (IL)-17F over Months 0-6 was significantly correlated with reduced brain volume over Months 0-6 (r=0.51; p=0.02) in RRMS patients. Conclusion: IFN beta-1a SC is associated with reduced brain volume over the first 3 months of treatment, but not over 3-6 months, an effect consistent with treatment-induced pseudoatrophy. Correlation between decreased percentage of CD4+ T-cells producing inflammatory IL-17F and volume reduction is supportive of an early anti-inflammatory therapeutic effect of IFN beta-1a SC. Study supported by: EMD Serono, Inc., Rockland, MA, a subsidiary of Merck KGaA, Darmstadt, Germany, and Pfizer Inc, New York, USA.
The deacetylase HDAC4 controls myocyte enhancing factor‐2‐dependent structural gene expression in response to neural activity (2008)

Histone deacetylase 4 (HDAC4) binds and inhibits activation of the critical muscle transcription factor myocyte enhancer factor-2 (MEF2). However, the physiological significance of the HDAC4-MEF2 complex in skeletal muscle has not been established. Here we show that in skeletal muscle, HDAC4 is a critical modulator of MEF2-dependent structural and contractile gene expression in response to neural activity. We present evidence that loss of neural input leads to concomitant nuclear accumulation of HDAC4 and transcriptional reduction of MEF2-regulated gene expression. Cell-based assays show that HDAC4 represses structural gene expression via direct binding to AT-rich MEF2 response elements. Notably, using both surgical denervation and the neuromuscular disease amyotrophic lateral sclerosis (ALS) model, we found that elevated levels of HDAC4 are required for efficient repression of MEF2-dependent structural gene expression, indicating a link between the pathological induction of HDAC4 and subsequent MEF2 target gene suppression. Supporting this supposition, we show that ectopic expression of HDAC4 in muscle fibers is sufficient to induce muscle damage in mice. Our study identifies HDAC4 as an activity-dependent regulator of MEF2 function and suggests that activation of HDAC4 in response to chronically reduced neural activity suppresses MEF2-dependent gene expression and contributes to progressive muscle dysfunction observed in neuromuscular diseases.
The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors (2011)

We analyzed the association between achievement of early complete cytogenetic response (CCyR) and event-free survival (EFS) and overall survival (OS) in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib 400 mg (n = 73), or imatinib 800 mg daily (n = 208), or second- generation tyrosine kinase inhibitors (n = 154). The overall CCyR rates were 87%, 91%, and 96%, respectively (P = .06); and major molecular response (MMR) rates were 77%, 87%, and 89%, respectively (P = .05). Their 3-year EFS rates were 85%, 92%, and 97% (P = .01), and OS rates were 93%, 97%, and 100% (P = .18), respectively. By landmark analysis, patients with 3-, 6-, and 12-month CCyR had significantly better outcome: 3-year EFS rates of 98%, 97%, and 98% and OS rates of 99%, 99%, and 99%, respectively, compared with 83%, 72%, and 67% and 95%, 90%, and 94%, in patients who did not achieve a CCyR. Among patients achieving CCyR at 12 months, the depth of molecular response was not associated with differences in OS or EFS. In conclusion, second tyrosine kinase inhibitors induced higher rates of CCyR and MMR than imatinib. The achievement of early CCyR remains a major determinant of chronic myeloid leukemia outcome regardless of whether MMR is achieved or not.
Optimal gradient clock synchronization in dynamic networks (2010)

We study the problem of clock synchronization in highly dynamic networks, where communication links can appear or disappear at any time. The nodes in the network are equipped with hardware clocks, but the rate of the hardware clocks can vary arbitrarily within specific bounds, and the estimates that nodes can obtain about the clock values of other nodes are inherently inaccurate. Our goal in this setting is to output a logical clock at each node, such that the logical clocks of any two nodes are not too far apart, and nodes that remain close to each other in the network for a long time are better synchronized than distant nodes. This property is called gradient clock synchronization.
Molecular Cloning of a Glycosylphosphatidylinositol-Anchored Molecule CDw108 (1999)

CDw108, also known as the John-Milton-Hagen human blood group Ag, is an 80-kDa glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein that is preferentially expressed on activated lymphocytes and E. The molecular characteristics and biological function of the CDw108 were not clarified previously. In this manuscript, we identify the cDNA clone containing the entire coding sequence of the CDw108 gene and report its molecular characteristics. The 1998-base pairs of the open reading frame of the cloned cDNA encoded a protein of 666 amino acids (aa), including the 46 aa of the signal peptide and the 19 aa of the GPI-anchor motif. Thus, the membrane-anchoring form of CDw108 was the 602 aa, and the estimated molecular mass of the unglycosylated form was 68 kDa. The RGD (Arg-Gly-Asp) cell attachment sequence and the five potential N-linked glycosylation sites were located on the membrane-anchoring form. Flow cytometric and immunoprecipitation analyses of the CDw108 cDNA transfectants confirmed that the cloned cDNA encoded the native form of CDw108. The CDw108 mRNA was expressed in activated PBMCs as well as in the spleen, thymus, testis, placenta, and brain, but was not expressed in any other tissues tested. Radiation hybrid mapping indicated that the CDw108 gene was located in the middle of the long arm of chromosome 15 (15q23-24). This molecular information will be critical for understanding the biological function of the CDw108 Ag.
Past Experiences of Getting Bullied and Assaulted and Posttraumatic Stress Disorder (PTSD) after a Severe Traumatic Event in Adulthood: A Study of World Trade Center (WTC) Responders (2019)

Although experiencing bullying and other forms of assault is associated with adverse physical, emotional, and psychological consequences, the long-term consequences, especially in the aftermath of a severe trauma in adulthood, is not known. This study examined the relationship between history of being bullied and/or assaulted and posttraumatic stress disorder (PTSD) symptoms among responders to the World Trade Center (WTC) disaster. During 2015-16, a modified life events checklist was administered to responders at Stony Brook WTC Health Program. WTC-related PTSD symptoms were assessed by PTSD checklist (PCL). Longitudinal mixed models examined associations between bullying, other forms of assault, and severity and chronicity of PTSD symptoms. Approximately 13% of 920 responders had probable WTC-PTSD (PCL≥44). Being bullied in childhood was associated with increased odds of WTC-PTSD (adjusted odds ratio [aOR] =7.34; 95% confidence interval [CI] = 2.12-25.34), adjusted for demographics, other stressors, and WTC exposures. PTSD odds decreased over time among those not bullied (aOR 0.82; 95% CI: 0.73-0.92), but not among victims. Experiencing physical, sexual, or verbal assaults during adulthood, also had a significant association with WTC-PTSD (aOR 4.64; 95% CI: 1.98-10.92). Findings suggest being bullied in childhood and/or assaulted in adulthood can increase PTSD risk and progression after mass trauma.
Understanding the contribution of mode area and slow light to the effective Kerr nonlinearity of waveguides (2013)

We resolve the ambiguity in existing definitions of the effective area of a waveguide mode that have been reported in the literature by examining which definition leads to an accurate evaluation of the effective Kerr nonlinearity. We show that the effective nonlinear coefficient of a waveguide mode can be written as the product of a suitable average of the nonlinear coefficients of the waveguide’s constituent materials, the mode’s group velocity and a new suitably defined effective mode area. None of these parameters on their own completely describe the strength of the nonlinear effects of a waveguide.