This thesis aimed to provide evidence that supports a central role for NGCs in CVD by studying the expression, regulation and function of neuronal guidance cues (NGCs) in endothelial cells and... Show moreThis thesis aimed to provide evidence that supports a central role for NGCs in CVD by studying the expression, regulation and function of neuronal guidance cues (NGCs) in endothelial cells and monocytes, the 2 cells types that play main role in development of atherosclerosis. The findings laid the foundation for future research of NGCs as novel tar- gets for intervention of atherosclerosis. Show less
Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we... Show moreGenetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets. Show less
The Innovative Medicines Initiative Consortium RESOLUTE has started to develop tools and produce data sets to de-orphanize transporters in the solute carrier protein (SLC) superfamily, thereby... Show moreThe Innovative Medicines Initiative Consortium RESOLUTE has started to develop tools and produce data sets to de-orphanize transporters in the solute carrier protein (SLC) superfamily, thereby lowering the barrier for the scientific community to explore SLCs as an attractive drug target class Show less
Nature uses a special class of histone proteins, histone variants, to modulate the properties of chromatin at defined genomic locations. H2A.B is one of the most divergent H2A variants and is... Show moreNature uses a special class of histone proteins, histone variants, to modulate the properties of chromatin at defined genomic locations. H2A.B is one of the most divergent H2A variants and is involved in important cellular functions, such as transcription and mRNA splicing. Incorporation of H2A.B in nucleosomes causes unwrapping of ~15 bp entry/ exit nucleosomal DNA from the histone octamer core. Yet, the molecular basis of such peculiar nucleosome conformation is unclear. The work described in this thesis aimed to determine the impact of H2A.B incorporation on the structural and dynamical properties of the nucleosome, primarily using nuclear magnetic resonance (NMR) spectroscopy. Show less
Side effect is one of the main factors affecting the success of cancer therapies in clinic. Patients treated with photodynamic therapy (PDT) suffer mainly from the phototoxicity due to the... Show moreSide effect is one of the main factors affecting the success of cancer therapies in clinic. Patients treated with photodynamic therapy (PDT) suffer mainly from the phototoxicity due to the relatively long time blood circulation of the tumor enrichment and they have also to be protected from background light for days after the treatment. Here we introduce a new design of nanophotosensitizers in which the luminescence upconversion nanoparticles loaded with photosensitizers are self-assembled into a nanoball with the aid of a specific pH-sensitive polymer layer containing overloaded photosensitizers and quenching molecules. This design makes the therapy function "off/on" possible, i.e. only imaging during the circulation of the nanoballs ascribing to the near-infrared (NIR) photon upconversion of the nanoballs and the pH-sensitive shell. Activation of PDT solely occurs once the nanoballs are taken up by the cancer cells due to the acidic microenvironment. This design prevents effectively the photodamage of the photosensitizers during enrichment and targeting process of tumor, as validated in vitro and in vivo, which enables imaging-guided PDT treatment of deep-seated tumor in a much more relax and comfortable way for patients. This patient-friendly nanomaterial construction strategy can also be extended to other therapies. Show less
The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor... Show moreThe clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing. Show less
A broad-based interlaboratory study of glycosylation profiles of a reference and modified IgG antibody involving 103 reports from 76 laboratories.Glycosylation is a topic of intense current... Show moreA broad-based interlaboratory study of glycosylation profiles of a reference and modified IgG antibody involving 103 reports from 76 laboratories.Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submitted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide community-derived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods. Show less
Bruikman, C.; Vreeken, D.; Zhang, H.; Zonneveld, A.J. van; Hovingh, K.; Gils, J. van 2019
ImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk... Show moreImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research. Show less
Feng, Y.S.; Wu, Y.N.; Zuo, J.; Tu, L.P.; Que, I.; Chang, Y.L.; ... ; Zhang, H. 2019
Intergroup conflict contributes to human discrimination and violence, but persists because individuals make costly contributions to their group’s fighting capacity. Yet, how group members... Show moreIntergroup conflict contributes to human discrimination and violence, but persists because individuals make costly contributions to their group’s fighting capacity. Yet, how group members effectively coordinate their contributions during intergroup conflict remains poorly understood. Here, we examine the role of oxytocin for (the coordination of) contributions to group attack or defense in multi-round, real-time feedback intergroup contests. In a double-blind placebo-controlled study with N = 480 males in Intergroup Attacker-Defender Contests, we found that oxytocin reduced contributions to attack and over time increased attacker’s within-group coordination of contributions. However, rather than becoming peaceful, attackers given oxytocin better tracked their rival’s historical defense and coordinated their contributions into well-timed and hence more profitable attacks. Our results reveal coordination of contributions as a critical component of successful attacks and subscribe to the possibility that oxytocin enables individuals to contribute to in-group efficiency and prosperity even when doing so implies outsiders are excluded or harmed. Show less
