Effects of Lorentz invariance violation on cosmic ray photon emission and gamma ray decay processes

In this work, we use Lorentz invariance violation (LIV) introduced as a generic modification to particle dispersion relations to study some consequences of single photon emission, known as vacuum Cherenkov radiation, and photon decay processes in cosmic and gamma rays. These processes are forbidden in a Lorentz invariant theory but allowed under the hypothesis of LIV. We show that the emission rate have a dependency on the cosmic ray primary mass and the electric charge that could modify the UHECR spectrum. Furthermore, LIV dramatically enhances photon decay into an electro-positron pair above certain energy threshold. This last effect can then be used to set limits to the LIV energy scale from the direct observation of very high energy cosmic photon events by telescopes of gamma-rays.Comment: Proceedings of the 35th International Cosmic Ray Conference (ICRC 2017), Busan, Kore

Murine Plasma <i>N</i>‑Glycosylation Traits Associated with Sex and Strain

Glycosylation is an abundant and important protein modification with large influence on the properties and interactions of glycoconjugates. Human plasma <i>N</i>-glycosylation has been the subject of frequent investigation, revealing strong associations with physiological and pathological conditions. Less well-characterized is the plasma <i>N</i>-glycosylation of the mouse, the most commonly used animal model for studying human diseases, particularly with regard to differences between strains and sexes. For this reason, we used MALDI-TOF­(/TOF)-MS­(/MS) assisted by linkage-specific derivatization of the sialic acids to comparatively analyze the plasma <i>N</i>-glycosylation of both male and female mice originating from BALB/c, CD57BL/6, CD-1, and Swiss Webster strains. The combined use of this analytical method and the recently developed data processing software named MassyTools allowed the relative quantification of the <i>N</i>-glycan species within plasma, the distinction between α2,3- and α2,6-linked <i>N</i>-glycolylneuraminic acids (due to respective lactonization and ethyl esterification), the detection of sialic acid <i>O</i>-acetylation, as well as the characterization of branching sialylation (Neu5Gcα2,3-Hex-[Neu5Gcα2,6-]­HexNAc). When analyzing the glycosylation according to mouse sex, we found that female mice present a considerably higher degree of core fucosylation (2–4-fold depending on the strain), galactosylation, α2,6-linked sialylation, and larger high-mannose type glycan species compared with their male counterparts. Male mice, on the contrary, showed on average higher α2,3-linked sialylation, branching sialylation, and putative bisection. These differences together with sialic acid acetylation proved to be strain-specific as well. Interestingly, the outbred strains CD-1 and Swiss Webster displayed considerably larger interindividual variation than inbred strains BALB/c and CD57BL/6, suggesting a strong hereditable component of the observed plasma <i>N</i>-glycome

Murine Plasma <i>N</i>‑Glycosylation Traits Associated with Sex and Strain

Glycosylation is an abundant and important protein modification with large influence on the properties and interactions of glycoconjugates. Human plasma <i>N</i>-glycosylation has been the subject of frequent investigation, revealing strong associations with physiological and pathological conditions. Less well-characterized is the plasma <i>N</i>-glycosylation of the mouse, the most commonly used animal model for studying human diseases, particularly with regard to differences between strains and sexes. For this reason, we used MALDI-TOF­(/TOF)-MS­(/MS) assisted by linkage-specific derivatization of the sialic acids to comparatively analyze the plasma <i>N</i>-glycosylation of both male and female mice originating from BALB/c, CD57BL/6, CD-1, and Swiss Webster strains. The combined use of this analytical method and the recently developed data processing software named MassyTools allowed the relative quantification of the <i>N</i>-glycan species within plasma, the distinction between α2,3- and α2,6-linked <i>N</i>-glycolylneuraminic acids (due to respective lactonization and ethyl esterification), the detection of sialic acid <i>O</i>-acetylation, as well as the characterization of branching sialylation (Neu5Gcα2,3-Hex-[Neu5Gcα2,6-]­HexNAc). When analyzing the glycosylation according to mouse sex, we found that female mice present a considerably higher degree of core fucosylation (2–4-fold depending on the strain), galactosylation, α2,6-linked sialylation, and larger high-mannose type glycan species compared with their male counterparts. Male mice, on the contrary, showed on average higher α2,3-linked sialylation, branching sialylation, and putative bisection. These differences together with sialic acid acetylation proved to be strain-specific as well. Interestingly, the outbred strains CD-1 and Swiss Webster displayed considerably larger interindividual variation than inbred strains BALB/c and CD57BL/6, suggesting a strong hereditable component of the observed plasma <i>N</i>-glycome

Additional file 2: of Fab glycosylation of immunoglobulin G does not associate with improvement of rheumatoid arthritis during pregnancy

Data used for analysis. Contains the relative abundances of the observed glycans and the calculated glycosylation traits for the RA patients and healthy controls used in the current study. (XLSX 120 kb

High-Throughput Profiling of Protein N‑Glycosylation by MALDI-TOF-MS Employing Linkage-Specific Sialic Acid Esterification

Protein glycosylation is an important post-translational modification associated, among others, with diseases and the efficacy of biopharmaceuticals. Matrix-assisted laser desorption/ionization (MALDI) time-of-fight (TOF) mass spectrometry (MS) can be performed to study glycosylation in a high-throughput manner, but is hampered by the instability and ionization bias experienced by sialylated glycan species. Stabilization and neutralization of these sialic acids can be achieved by permethylation or by specific carboxyl group derivatization with the possibility of discrimination between α2,3- and α2,6-linked sialic acids. However, these methods typically require relatively pure glycan samples, show sensitivity to side reactions, and need harsh conditions or long reaction times. We established a rapid, robust and linkage-specific high-throughput method for sialic acid stabilization and MALDI-TOF-MS analysis, to allow direct modification of impure glycan-containing mixtures such as PNGase F-released human plasma N-glycome. Using a combination of carboxylic acid activators in ethanol achieved near-complete ethyl esterification of α2,6-linked sialic acids and lactonization of α2,3-linked variants, in short time using mild conditions. Glycans were recovered by hydrophilic interaction liquid chromatography solid phase extraction and analyzed by MALDI-TOF-MS in reflectron positive mode with 2,5-dihydroxybenzoic acid as the matrix substance. Analysis of the human plasma N-glycome allowed high-throughput detection and relative quantitation of more than 100 distinct N-glycan compositions with varying sialic acid linkages

Changes in Healthy Human IgG Fc-Glycosylation after Birth and during Early Childhood

Glycosylation on the fragment crystallizable (Fc) region of immunoglobulin G (IgG) has a large influence on the interaction of the antibody with Fc gamma receptors (FcγRs). IgG consists of four subclasses that all have distinct affinities for the different FcγRs. Knowledge about the Fc-glycosylation in healthy human is valuable as reference for new biomarkers and in the design of biopharmaceuticals that rely on IgG Fc-glycosylation. Previously, subclass-specific characterization of IgG Fc-glycosylation was performed for healthy adults, pregnant women, and newborns. For young healthy children, however, the subclass-specific description of IgG Fc-glycosylation is still lacking. Therefore, we performed the IgG subclass-specific analysis of the Fc-glycosylation of 130 healthy humans between birth and 40 years of age, including 22 samples derived from the umbilical cords of newborns. The analysis was performed by a previously published matrix-assisted laser desorption/ionization (MALDI)-time-of-flight (TOF)-mass spectrometry (MS) workflow, including a derivatization step for the linkage-specific stabilization of sialic acids. The characterization revealed that when children start to produce their own IgG they have a decreased galactosylation, sialylation, and bisection and an increased fucosylation compared with newborns. During childhood, the fucosylation and sialylation decrease, whereas bisection increases and galactosylation stays constant

Image_2_Concanavalin A staining: a potential biomarker to predict cytarabine sensitivity in acute myeloid leukemia.tif

Acute myeloid leukemia (AML) is a cancer of the myeloid lineage of blood cells, with an overall 5-year survival rate of 25%, mainly due to therapy-resistant relapses in > 50% of patients. The standard treatment for AML comprises cytarabine (AraC) with anthracyclines. Biomarkers to determine AraC sensitivity are currently lacking, thus hampering the rational choice of optimal treatment protocols, which would be especially warranted in the case of primary refractory disease. In the current study, we hypothesized that AraC-resistant AML cells harbor a different “sugar decoration”, i.e., glycosylation profile, compared with sensitive cells, which could be used as biomarker for AraC sensitivity. Therefore, we analyzed the expression of glycosylation-related genes in publicly available AML datasets, whereby the high expression of mannosylation-related genes (6 out of 13) was significantly associated with a worse survival in patients treated with AraC-based intensive chemotherapy protocols. In line with these data, the AraC-resistant AML cells expressed higher levels of high mannose N-glycans, as detected by mass spectrometry-based glycomics. Concanavalin A (ConA), a lectin that specifically recognizes α-mannoses in N-glycans, bound more strongly to AraC-resistant cells, and the extent of the ConA binding was correlated with AraC sensitivity in a panel of AML cell lines. Furthermore, the ConA staining could discriminate AraC sensitivity in vitro between two patient-derived AML samples taken at diagnosis. Therefore, the ConA staining may be a potential novel biomarker to predict AraC sensitivity in AML.</p

Image_1_Concanavalin A staining: a potential biomarker to predict cytarabine sensitivity in acute myeloid leukemia.tif

Acute myeloid leukemia (AML) is a cancer of the myeloid lineage of blood cells, with an overall 5-year survival rate of 25%, mainly due to therapy-resistant relapses in > 50% of patients. The standard treatment for AML comprises cytarabine (AraC) with anthracyclines. Biomarkers to determine AraC sensitivity are currently lacking, thus hampering the rational choice of optimal treatment protocols, which would be especially warranted in the case of primary refractory disease. In the current study, we hypothesized that AraC-resistant AML cells harbor a different “sugar decoration”, i.e., glycosylation profile, compared with sensitive cells, which could be used as biomarker for AraC sensitivity. Therefore, we analyzed the expression of glycosylation-related genes in publicly available AML datasets, whereby the high expression of mannosylation-related genes (6 out of 13) was significantly associated with a worse survival in patients treated with AraC-based intensive chemotherapy protocols. In line with these data, the AraC-resistant AML cells expressed higher levels of high mannose N-glycans, as detected by mass spectrometry-based glycomics. Concanavalin A (ConA), a lectin that specifically recognizes α-mannoses in N-glycans, bound more strongly to AraC-resistant cells, and the extent of the ConA binding was correlated with AraC sensitivity in a panel of AML cell lines. Furthermore, the ConA staining could discriminate AraC sensitivity in vitro between two patient-derived AML samples taken at diagnosis. Therefore, the ConA staining may be a potential novel biomarker to predict AraC sensitivity in AML.</p

Detailed Characterization of Monoclonal Antibody Receptor Interaction Using Affinity Liquid Chromatography Hyphenated to Native Mass Spectrometry

We report on the online coupling of FcRn affinity liquid chromatography (LC) with electrospray ionization mass spectrometry (ESI-MS) in native conditions to study the influence of modifications on the interaction of recombinant mAbs with the immobilized FcRn receptor domain. The analysis conditions were designed to fit the requirements of both affinity LC and ESI-MS. The mobile phase composition was optimized to maintain the proteins studied in native conditions and enable sharp pH changes in order to mimic properly IgGs Fc domain/FcRn receptor interaction. Mobile phase components needed to be sufficiently volatile to achieve native MS analysis. MS data demonstrated the conservation of the pseudonative form of IgGs and allowed identification of the separated variants. Native FcRn affinity LC–ESI-MS was performed on a therapeutic mAb undergoing various oxidation stress. Native MS detection was used to determine the sample oxidation level. Lower retention was observed for mAbs oxidized variants compared to their intact counterparts indicating decreased affinities for the receptor. This methodology proved to be suitable to identify and quantify post-translational modifications at native protein level in order to correlate their influence on the binding to the FcRn receptor. Native FcRn affinity LC–ESI-MS can tremendously reduce the time required to assess the biological relevance of the IgG microheterogeneities thus providing valuable information for biopharmaceutical research and development

Table_1_Immunoglobulin G Fragment Crystallizable Glycosylation After Hematopoietic Stem Cell Transplantation Is Dissimilar to Donor Profiles.XLSX

<p>Immunoglobulin G (IgG) fragment crystallizable (Fc) N-glycosylation has a large influence on the affinity of the antibody for binding to Fcγ-receptors (FcγRs) and C1q protein, thereby influencing immune effector functions. IgG Fc glycosylation is known to be partly regulated by genetics and partly by stimuli in the microenvironment of the B cell. Following allogeneic hematopoietic stem cell transplantation (HSCT), and in the presence of (almost) complete donor chimerism, IgG is expected to be produced by, and glycosylated in, B cells of donor origin. We investigated to what extent IgG glycosylation in patients after transplantation is determined by factors of the donor (genetics) or the recipient (environment). Using an IgG subclass-specific liquid chromatography–mass spectrometry method, we analyzed the plasma/serum IgG Fc glycosylation profiles of 34 pediatric patients pre-HSCT and at 6 and 12 months post-HSCT and compared these to the profiles of their donors and age-matched healthy controls. Patients treated for hematological malignancies as well as for non-malignant hematological diseases showed after transplantation a lower Fc galactosylation than their donors. Especially for the patients treated for leukemia, the post-HSCT Fc glycosylation profiles were more similar to the pre-HSCT recipient profiles than to profiles of the donors. Pre-HSCT, the leukemia patient group showed as distinctive feature a decrease in sialylation and in hybrid-type glycans as compared to healthy controls, which both normalized after transplantation. Our data suggest that IgG Fc glycosylation in children after HSCT does not directly mimic the donor profile, but is rather determined by persisting environmental factors of the host.</p