Emerging targets in human lymphoma: targeting the MYD88 mutation

B cell neoplasms co-opt the molecular machinery of normal B cells for their survival. Technological advances in cancer genomics has significantly contributed to uncovering the root cause of aggressive lymphomas, revealing a previously unknown link between TLR signaling and B cell neoplasm. Recurrent oncogenic mutations in MYD88 have been found in 39% of the activated B cell-like subtype of diffuse large B cell lymphoma (ABC DLBCL). Interestingly, 29% of ABC DLBCL have a single amino acid substitution of proline for the leucine at position 265 (L265P), and the exact same variant has also been identified in a number of lymphoid malignancies. The MYD88 L265P variant was recently identified in 90% of Wadenstrom's macroglobulinemia patients. These recent developments warrant the need for novel diagnostic tools as well as targeted therapeutics. In this review, we discuss the physiological functions of MYD88 and focus on its role in B cell lymphomas, evaluating the potential for targeting oncogenic MYD88 in lymphoma

Backscatter and spontaneous four-wave mixing in micro-ring resonators

We model backscatter for electric fields propagating through optical micro-ring resonators, as occurring both in-ring and in-coupler. These provide useful tools for modelling transmission and in-ring fields in these optical devices. We then discuss spontaneous four-wave mixing and use the models to obtain heralding efficiencies and rates. We observe a trade-off between these, which becomes more extreme as the rings become more strongly backscattered.Comment: 8 pages, 8 figures - matches version published in J. Phys. Photonic

Backscatter and spontaneous four-wave mixing in micro-ring resonators

We model backscatter for electric fields propagating through optical micro-ring resonators, as occurring both in-ring and in-coupler. These provide useful tools for modelling transmission and in-ring fields in these optical devices. We then discuss spontaneous four-wave mixing and use the models to obtain heralding efficiencies and rates. We observe a trade-off between these, which becomes more extreme as the rings become more strongly backscattered

Determination of total plasma oxysterols by enzymatic hydrolysis, solid phase extraction and liquid chromatography coupled to mass-spectrometry

The potential use of cholesterol esterases was tested to avoid alkaline hydrolysis for cleavage of plasma esterified oxysterols. The enzymatic hydrolysis was optimized by testing two sources of enzyme—Pseudomonas and bovine pancreas, presence of surfactants, incubation time and amount of enzyme. Free forms of 4ß-, 7-, 24-, 25- and 27-hydroxycholesterol (HC) as well 7-ketocholesterol (7-KC) were analyzed by liquid chromatography and mass-spectrometry using the deuterated internal standard, 25-HC(d6). Enzymatic hydrolysis was more effective using the Pseudomonas enzyme and in presence of surfactants. Compared to alkaline hydrolysis, it generated a cleaner chromatographic baseline and better recovery of the internal standard. Oxysterols were assayed with detection limits between 7 and 31 pg/mL. Interassay coefficients of variation were lower than 10% and extraction recovery efficiencies, higher than 90%. The procedure was used to characterize plasma levels of Cyp7b1-deficient rat, where it showed increased plasma levels of 7, 24 and 25-HC. Due to the low volume of sample required, it may be used in other animal models, particularly rodents, as well as in pediatric samples where sample amount is always a problem. Thus, the proposed new method offers mild enzymatic processing that greatly facilitates oxysterol determinations to delineate their role in physiopathology

Integrated photon sources for quantum information science applications

Ring resonators are used as photon pair sources by taking advantage of the materials second or third order non-linearities through the processes of spontaneous parametric downconversion and spontaneous four wave mixing respectively. Two materials of interest for these applications are silicon for the infrared and aluminum nitride for the ultraviolet through the infrared. When fabricated into ring type sources they are capable of producing pairs of indistinguishable photons but typically suffer from an effective 50% loss. By slightly decoupling the input waveguide from the ring, the drop port coincidence ratio can be significantly increased with the trade-off being that the pump is less efficiently coupled into the ring. Ring resonators with this design have been demonstrated having coincidence ratios of 96% but requiring a factor of ∼10 increase in the pump power. Through the modification of the coupling design that relies on additional spectral dependence, it is possible to achieve similar coincidence ratios without the increased pumping requirement. This can be achieved by coupling the input waveguide to the ring multiple times, thus creating a Mach-Zehnder interferometer. This coupler design can be used on both sides of the ring resonator so that resonances supported by one of the couplers are suppressed by the other. This is the ideal configuration for a photon-pair source as it can only support the pump photons at the input side while only allowing the generated photons to leave through the output side. Recently, this device has been realized with preliminary results exhibiting the desired spectral dependence and with a coincidence ratio as high as ∼ 97% while allowing the pump to be nearly critically coupled to the ring. The demonstrated near unity coincidence ratio infers a near maximal heralding efficiency from the fabricated device. This device has the potential to greatly improve the scalability and performance of quantum computing and communication systems.National Science Foundation (U.S.) (Grant ECCS- 1542081)National Science Foundation (U.S.) (Award No. ECCS14052481

Inflammasome-Associated Nucleotide-Binding Domain, Leucine-Rich Repeat Proteins and Inflammatory Diseases

The nucleotide-binding domain, leucine-rich repeat (NLR) proteins are a recently discovered family of intracellular pathogen and danger signal sensors. NLRs have emerged as important contributors to innate immunity in animals. The physiological impact of these genes is increasingly evident, underscored by the genetic association of variant family members with an array of inflammatory diseases. The association of mutations in NLR genes with autoinflammatory diseases indicates an important function of these genes in inflammation in vivo. This review summarizes the role of the inflammasome NLR proteins in innate immunity and inflammatory diseases and explores the possible utility of some of these NLRs as pharmacological targets

Sterolomics in biology, biochemistry, medicine

In mammalian systems “sterolomics” can be regarded as the quantitative or semi-quantitative profiling of all metabolites derived from cholesterol and its cyclic precursors. The system can be further complicated by metabolites derived from ingested phytosterols or pharmaceuticals, but this is beyond the scope of this article. “Sterolomics” can be performed on either an unbiased global format, or more usually, exploiting a targeted format. Here we discuss the different mass spectrometry-based analytical techniques used in “sterolomics” giving specific examples in the context of neurodegenerative disease and for the diagnosis of inborn errors of metabolism. We pay particular attention to the profiling of cholesterol metabolites in the bile acid biosynthesis pathways, although the analytical techniques discussed are also appropriate for analysis of hormonal steroids

Oncogenic signaling and mechanisms of immune evasion in aggressive B-cell lymphomas

B cel lymfomen kunnen ontstaan tijdens verschillende fasen van de B cel ontwikkeling en vormen een zeer heterogene groep maligniteiten. Diffuus grootcellig B cel lymfoom (DLBCL) en mantelcellymfoom (MCL) vallen beiden onder de groep van de agressieve non-Hodgkin lymfomen. Aberrante activatie van diverse oncogene signaleringsroutes speelt een belangrijke rol in de pathogenese van zowel DLBCL als MCL. Herkenning van een antigen door de B-cel receptor (BCR), een membraan gebonden antilichaam, stimuleert intrinsieke signaleringsroutes die zorgen voor B cel activatie en celdeling. Daarnaast brengen B cellen Toll-like receptoren (TLRs) tot expressie waarmee ze potentieel pathogene micro-organismen of lichaamseigen stoffen die bij schade vrijkomen, kunnen herkennen. Verstoorde activatie van zowel BCR als TLR gedreven signaleringsroutes als gevolg van mutaties of epigenetische veranderingen, komt voor bij een groot deel van DLBCL en MCL gevallen. Primaire grootcellige B cel lymfomen die voorkomen op extranodale locaties waar het afweersysteem zeer sterk gereguleerd wordt, worden gekenmerkt door een hoge frequentie van activerende MYD88 en CD79B mutaties. Daarnaast maken deze lymfomen vaak gebruik van verschillende mechanismen om herkenning en eliminatie door het afweersysteem van de gastheer te ontwijken. Het beter begrijpen van de pathobiologie van deze lymfomen kan bijdragen aan de ontwikkeling van specifieke therapieën voor de behandeling van deze agressieve lymfomen

ANALYSIS OF THE \u3ci\u3eCRMP\u3c/i\u3e GENE IN \u3ci\u3eDROSOPHILA\u3c/i\u3e: DETERMINING THE REGULATORY ROLE OF CRMP IN SIGNALING AND BEHAVIOR

The mammalian genome encodes five collapsin response mediator protein (CRMP) isoforms. Cell culture studies have shown that the CRMPs mediate growth cone dynamics and neuron polarity through associations with a variety of signal transduction components and cytoskeletal elements. CRMP is also a member of a protein family including the presumably ancestral dihydropyrimidinase (DHP) protein that catalyzes the second step in pyrimidine degradation. In Drosophila, CRMP and DHP proteins are produced by alternatively spliced transcripts of the CRMP gene. The alternative protein forms have a 91% sequence identity, but unique expression patterns. CRMP is found exclusively in neuronal tissues and DHP is ubiquitously expressed in non-neuronal tissues. Comparative analysis of CRMP homologous sequences from insect taxa show CRMP alternative splicing is a common feature and probably represents the ancestral state of this gene family. To investigate the regulatory role of CRMP, loss-of-function mutations of CRMP that lack both proteins were isolated; homozygous animals display DHP-null phenotypes but exhibit no overt developmental or neurological defects. To determine possible interactions of Drosophila CRMP with signaling pathways in which mammalian CRMP has been shown to act, the UAS-GAL4 system was utilized. Phenotypes produced by misexpression of a variety of UAS signal transduction mediator responders were modified in a CRMP mutant background. The modification entails enhancement or suppression of a specific phenotype in a direction that corresponds to the hypothesized involvement of mammalian CRMP in signaling pathways that regulate growth cone dynamics. These data suggest that Drosophila CRMP has a role in cell signaling pathways similar to the role of the mammalian CRMPs. Furthermore, recent findings demonstrate that CRMP plays an important role in learning and memory of mice, leading to the assessment of new phenotypes in the Drosophila CRMP mutants. Tests utilizing the Pavlovian olfactory conditioning assay reveal that loss of CRMP function leads to significant learning, 3 hour memory, and long term memory deficits. Preliminary data also suggest that Drosophila CRMP may be required for normal circadian locomotor rhythms. Collectively, the data presented here demonstrate CRMP’s role in adult behavioral processes and regulating signaling events comparable to mammalian CRMP signaling