Objective. To characterize its dose-response relationship, BI 655064 (an anti-CD40 monoclonal antibody) was tested as an add-on to mycophenolate and glucocorticoids in patients with active lupus... Show moreObjective. To characterize its dose-response relationship, BI 655064 (an anti-CD40 monoclonal antibody) was tested as an add-on to mycophenolate and glucocorticoids in patients with active lupus nephritis (LN).Methods. A total of 121 patients were randomized (2:1:1:2) to receive placebo or BI 655064 120, 180, or 240 mg and received a weekly loading dose for 3 weeks followed by dosing every 2 weeks for the 120 and 180 mg groups, and 120 mg weekly for the 240 mg group. The primary endpoint was complete renal response (CRR) at week 52. Secondary endpoints included CRR at week 26.Results. A dose-response relationship with CRR at week 52 was not shown (BI 655064 120 mg, 38.3%; 180 mg, 45.0%; 240 mg, 44.6%; placebo, 48.3%). At week 26, 28.6% (120 mg), 50.0% (180 mg), 35.0% (240 mg), and 37.5% (placebo) achieved CRR. The unexpected high placebo response prompted a post hoc analysis evaluating confirmed CRR (cCRR, at weeks 46 and 52). cCRR was achieved in 22.5% (120 mg), 44.3% (180 mg), 38.2% (240 mg), and 29.1% (placebo) of patients. Most patients reported >= 1 adverse event (BI 655064, 85.7-95.0%; placebo, 97.5%), most frequently infections and infestations (BI 655064 61.9-75.0%; placebo 60%). Compared with other groups, higher rates of serious (20% vs. 7.5-10%) and severe infections (10% vs. 4.8-5.0%) were reported with 240 mg BI 655064.Conclusion. The trial failed to demonstrate a dose-response relationship for the primary CRR endpoint. Post hoc analyses suggest a potential benefit of BI 655064 180 mg in patients with active LN. Show less
This dissertation examines the Malayic varieties spoken in Kelantan and Terengganu, two Malaysian states located on the northeast coast of the Malay Peninsula. It focuses on three varieties, namely... Show moreThis dissertation examines the Malayic varieties spoken in Kelantan and Terengganu, two Malaysian states located on the northeast coast of the Malay Peninsula. It focuses on three varieties, namely Kelantan Malay, Coastal Terengganu Malay and Inland Terengganu Malay, all belonging to the Malayic subgroup within the Austronesian language family. On the basis of data gathered through linguistic fieldwork undertaken by the author, this dissertation provides the most comprehensive description of these languages to date and offers an analysis of their historical developments.The three Malayic varieties under investigation display notable similarities in their phonological and morphosyntactic patterns, characterised by significant phonological and morphological reduction. Despite these common features, however, it is concluded that these varieties do not form a discrete subgroup within the Malayic languages. The common changes observed in their consonant systems must have followed distinct developments in the vowel systems. Furthermore, the morphological reduction was primarily driven by internal phonological changes, and no clear traces of substrate influences have been found.It is proposed that Inland Terengganu Malay represents a separate variety, distinct from Kelantan Malay and Coastal Terengganu Malay. A two-wave migration pattern is suggested: speakers of Inland Terengganu Malay likely arrived in the region earlier, whereas the speakers of Kelantan Malay and Coastal Terengganu Malay arrived at a later stage. Show less
Herein, we investigated to which extent metallic nanoparticles (MNPs) affect the trophic transfer of other coexisting MNPs from lettuce to terrestrial snails and the associated tissue-specific... Show moreHerein, we investigated to which extent metallic nanoparticles (MNPs) affect the trophic transfer of other coexisting MNPs from lettuce to terrestrial snails and the associated tissue-specific distribution using toxicokinetic (TK) modeling and single-particle inductively coupled plasma mass spectrometry. During a period of 22 days, snails were fed with lettuce leaves that were root exposed to AgNO3 (0.05 mg/L), AgNPs (0.75 mg/L), TiO2NPs (200 mg/L), and a mixture of AgNPs and TiO2NPs (equivalent doses as for single NPs). The uptake rate constants (ku) were 0.08 and 0.11 kg leaves/kg snail/d for Ag and 1.63 and 1.79 kg leaves/kg snail/d for Ti in snails fed with NPs single- and mixture-exposed lettuce, respectively. The elimination rate constants (ke) of Ag in snails exposed to single AgNPs and mixed AgNPs were comparable to the corresponding ku, while the ke for Ti were lower than the corresponding ku. As a result, single TiO2NP treatments as well as exposure to mixtures containing TiO2NPs induced significant biomagnification from lettuce to snails with kinetic trophic transfer factors (TTFk) of 7.99 and 6.46. The TTFk of Ag in the single AgNPs treatment (1.15 kg leaves/kg snail) was significantly greater than the TTFk in the mixture treatment (0.85 kg leaves/kg snail), while the fraction of Ag remaining in the body of snails after AgNPs exposure (36%) was lower than the Ag fraction remaining after mixture exposure (50%). These results indicated that the presence of TiO2NPs inhibited the trophic transfer of AgNPs from lettuce to snails but enhanced the retention of AgNPs in snails. Biomagnification of AgNPs from lettuce to snails was observed in an AgNPs single treatment using AgNPs number as the dose metric, which was reflected by the particle number-based TTFs of AgNPs in snails (1.67, i.e., higher than 1). The size distribution of AgNPs was shifted across the lettuce-snail food chain. By making use of particle-specific measurements and fitting TK processes, this research provides important implications for potential risks associated with the trophic transfer of MNP mixtures. Show less
The goal of the current study was to quantify the trophic transfer of copper nanoparticles (CuNPs) in a food chain consisting of the microalga Pseudokirchneriella subcapitata as the representative... Show moreThe goal of the current study was to quantify the trophic transfer of copper nanoparticles (CuNPs) in a food chain consisting of the microalga Pseudokirchneriella subcapitata as the representative of primary producer, the grazer Daphnia magna, and the omnivorous mysid Limnomysis benedeni. To quantify the size and number concentration of CuNPs in the biota, tissue extraction with tetramethylammonium hydroxide (TMAH) was performed and quantification was done by single particle inductively coupled plasma mass spectrometry (sp-ICP-MS). The bioconcentration factor (BCF) of the test species for CuNPs varied between 102 - 103 L/kg dry weight when expressing the internal concentration on a mass basis, which was lower than BCF values reported for Cu2+ (103 - 104 L/kg dry weight). The particle size of CuNPs determined by sp-ICP-MS ranged from 22 to 40 nm in the species. No significant changes in the particle size were measured throughout the food chain. Moreover, the measured number of CuNPs in each trophic level was in the order of 1013 particles/kg wet weight. The calculated trophic transfer factor (mass concentration basis) was > 1. This indicates biomagnification of particulate Cu from P. subcapitata to L. benedeni. It was also found that the uptake of particulate Cu (based on the particle number concentration) was mainly from the dietary route rather than from direct aqueous exposure. Furthermore, dietary exposure to CuNPs had a significant effect on the feeding rate of mysid during their transfer from daphnia to mysid and from alga through daphnia to mysid. This work emphasizes the importance of tracing the particulate fraction of metal-based engineered nanoparticles when studying their uptake and trophic transfer. Show less
Nanoparticles (NPs), heavy metals and natural organic matter may co-exist in the water bodies. Currently, knowledge on their interaction effects on the behaviors and fates of NPs and heavy metal... Show moreNanoparticles (NPs), heavy metals and natural organic matter may co-exist in the water bodies. Currently, knowledge on their interaction effects on the behaviors and fates of NPs and heavy metal ions is rather limited, which is critical to comprehensively understand their environmental risk. In this study, the aggregation, solubility and Cd-adsorption of CuO NPs co-existing with humic acid (HA) and Cd2+ upon different solution pH and contact sequences were determined. In the ternary systems of CuO NPs, HA and Cd2+, pH was more important than the contact sequence of the components in affecting the NP aggregation, while the contact sequence was a predominant factor in determining the NP solubility. Pre-equilibration of CuO NPs and HA before addition of Cd2+ resulted in the highest solubility and lowest aggregation of the NPs, relative to other sequences of addition of the components. The adsorption capacity of CuO NPs for Cd-ions increased with an increasing pH value from 5 to 9. HA significantly enhanced the Cd-adsorption capacity of CuO NPs at pH 7 and 9, while at pH 5 a non-significant effect was observed. The results are helpful to better estimate the behaviors and fates of CuO NPs and Cd2+ when they coexisting in natural waters. Show less
Gotlieb, R.J.M.; Hickey-Moody, A.; Güroglu, B.; Burnard, P.; Horn, C.; Willcox, M.; ... ; Zhou, J. 2022
The rapidly increasing commercial application of metallic nanoparticles within products will inevitably enhance the amount of NPs being released into soil. Assessment of the impact of metallic... Show moreThe rapidly increasing commercial application of metallic nanoparticles within products will inevitably enhance the amount of NPs being released into soil. Assessment of the impact of metallic nanoparticles (NPs) in soil ecosystems is a necessity for ensuring their safe and sustainable application. In this thesis, we integrated exposure routes and exposure dynamics of NPs to investigate the uptake, translocation and impacts of metallic NPs in plants upon long-term exposure. We furthermore investigated the long-term impacts of NPs on the rhizosphere soil bacterial community and the potential transfer and biomagnification within the lettuce - terrestrial snails food chain. Our results demonstrate that 1) root exposure induced more phytotoxicity than foliar exposure at equal exposure concentrations; 2) the phytotoxicity and accumulation of AgNPs in plants was shape- and size-dependent; 3) nanoparticulate Ag present in AgNPs suspensions that predominantly drive their impacts on green leafy plants; 4) the dissolution of AgNPs in soil is the dominant process influencing Ag uptake and translocation in lettuce; 5) long-term exposure to high concentrations of AgNPs altered the structure and composition of rhizosphere bacterial community; 6) NPs can be transferred from lettuce leaves to snails, as associated with increased potential risks to higher trophic level organisms. Show less
Adolescence is a developmental period characterized by substantial biological, neural, behavioral, and social changes. Learning to navigate the complex social world requires adaptive skills.... Show moreAdolescence is a developmental period characterized by substantial biological, neural, behavioral, and social changes. Learning to navigate the complex social world requires adaptive skills. Although anticipation of social situations can serve an adaptive function, providing opportunity to adjust behavior, socially anxious individuals may engage in maladaptive anticipatory processing. Importantly, elevated social anxiety often coincides with adolescence. This study investigated cortical electroencephalogram (EEG) responses during anticipation of evaluative feedback in 106 healthy adolescents aged 12-17 years. We examined differences in anticipatory event-related potentials (i.e., stimulus preceding negativity [SPN]) in relation to social anxiety levels and pubertal maturation. As expected, the right frontal SPN was more negative during feedback anticipation, particularly for adolescents with higher social anxiety and adolescents who were at a more advanced pubertal stage. Effects for the left posterior SPN were the opposite of those for the right frontal SPN consistent with a dipole. Anticipatory reactivity in adolescence was related to social anxiety symptom severity, especially in females, and pubertal maturation in a social evaluative situation. This study provides evidence for the development of social anticipatory processes in adolescence and potential mechanisms underlying maladaptive anticipation in social anxiety. Show less
Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could... Show moreNeurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures. Show less
The objective of this paper was to study the cognitive processes underlying cross-dialectal novel word borrowing and loanword establishment in a Standard-Chinese-to-Shanghainese (SC-SH) auditory... Show moreThe objective of this paper was to study the cognitive processes underlying cross-dialectal novel word borrowing and loanword establishment in a Standard-Chinese-to-Shanghainese (SC-SH) auditory lexical learning and borrowing experiment. To investigate these underlying cognitive processes, SC-SH bi-dialectals were compared with SC monolectals as well as bi-dialectals of SC and other Chinese dialects (OD) to investigate the influence of short-term and long-term linguistic experience. Both comprehension and production borrowings were tested. This study found that early and proficient bi-dialectism, even if it is not directly related to the recipient dialect of lexical borrowing, has a protective effect on the ability of cross-dialectal lexical borrowing in early adulthood. Bi-dialectals tend to add separate lexical representations for incidentally encountered dialectal variants, while monolectals tend to assimilate dialectal variants to standard forms. Bi-dialectals, but not monolectals, use etymologically related morphemes between the source and recipient dialects to create nonce-borrowing compounds. Dialectal variability facilitates lexical borrowing via enriching instead of increasing the short-term lexical experience of learners. The long-term bi-dialectal experience of individuals, as well as their short-term exposure to each specific loanword, may collectively shape the route of lexical evolution of co-evolving linguistic varieties. Show less
Direct and indirect reciprocity are two fundamental mechanisms that promote prosocial behavior within groups and across societies. Here, we review recent work that illustrates how a (direct and... Show moreDirect and indirect reciprocity are two fundamental mechanisms that promote prosocial behavior within groups and across societies. Here, we review recent work that illustrates how a (direct and indirect) reciprocity framework can illuminate our understanding of several factors related to prosocial behavior — namely group membership, gossip, and third-party punishment. We propose that each of these factors can promote prosocial behavior via proximate psychological mechanisms related to direct and indirect reciprocity: reputational concern, expectations, and anticipation of future interaction. Finally, we discuss the implications of adopting such a framework and highlight a number of avenues for future research. Show less
Deodhar, A.; Sliwinska-Stanczyk, P.; Xu, H.J.; Baraliakos, X.; Gensler, L.S.; Fleishaker, D.; ... ; Heijde, D. van der 2021
Objective To assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS).Methods This phase III, randomised, double-blind, placebo-controlled study enrolled... Show moreObjective To assess the efficacy/safety of tofacitinib in adult patients with active ankylosing spondylitis (AS).Methods This phase III, randomised, double-blind, placebo-controlled study enrolled patients aged >= 18 years diagnosed with active AS, meeting the modified New York criteria, with centrally read radiographs, and an inadequate response or intolerance to >= 2 non-steroidal anti-inflammatory drugs. Patients were randomised 1:1 to receive tofacitinib 5 mg two times per day or placebo for 16 weeks. After week 16, all patients received open-label tofacitinib until week 48. The primary and key secondary endpoints were Assessment of SpondyloArthritis international Society >= 20% improvement (ASAS20) and >= 40% improvement (ASAS40) responses, respectively, at week 16. Safety was assessed throughout.Results 269 patients were randomised and treated: tofacitinib, n=133; placebo, n=136. At week 16, the ASAS20 response rate was significantly (p<0.0001) greater with tofacitinib (56.4%, 75 of 133) versus placebo (29.4%, 40 of 136), and the ASAS40 response rate was significantly (p<0.0001) greater with tofacitinib (40.6%, 54 of 133) versus placebo (12.5%, 17 of 136). Up to week 16, with tofacitinib and placebo, respectively, 73 of 133 (54.9%) and 70 of 136 (51.5%) patients had adverse events; 2 of 133 (1.5%) and 1 of 136 (0.7%) had serious adverse events. Up to week 48, with tofacitinib, 3 of 133 (2.3%) patients had adjudicated hepatic events, 3 of 133 (2.3%) had non-serious herpes zoster, and 1 of 133 (0.8%) had a serious infection; with placebo -> tofacitinib, 2 (1.5%) patients had non-serious herpes zoster. There were no deaths, malignancies, major adverse cardiovascular events, thromboembolic events or opportunistic infections.Conclusions In adults with active AS, tofacitinib demonstrated significantly greater efficacy versus placebo. No new potential safety risks were identified. Show less
This research aims to study the dynamic interaction between education and poetic identity, with a reference to the Obscure poets that came to the fore in the late 1970s and the early 1980s in... Show moreThis research aims to study the dynamic interaction between education and poetic identity, with a reference to the Obscure poets that came to the fore in the late 1970s and the early 1980s in Mainland China. It has been a prevailing idea that “successful” schooling in China has killed creativity and produced many unimaginative minds.Michelle Yeh’s and Maghiel van Crevel’s localized redefinition of poetic identity and Ivan Illich’s idea of deschooling, enable us to take a different perspective. I adopt mixed methods and use various resources such as oeuvre and textbooks. It shows that school education, family education, peer education, and mentor education have impacted on the forming of Obscure Poetry, and there is a fascinating “complicity” in the relationship between Obscure Poetry and Political Lyricism. There is definitely a relation between educational background and poetic identity, and it is not just, or even primarily, a negative relation. Literary traditions pass from one generation to another through various kinds of education. The complexity of the relationship between education and creative writing has often been reduced, overlooked and misconstrued, but the role of education remains a core perspective for our understanding of literature and of cultural traditions at large. Show less
