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
Gotlieb, R.J.M.; Hickey-Moody, A.; Güroglu, B.; Burnard, P.; Horn, C.; Willcox, M.; ... ; Zhou, J. 2022
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
Researchers use different approaches when collecting and managing primary language materials during fieldwork. Yet it is important that this work is done in a transparent way, so that it can be... Show moreResearchers use different approaches when collecting and managing primary language materials during fieldwork. Yet it is important that this work is done in a transparent way, so that it can be used by other researchers, who might have other aims, as well as by the speaker community who might want to use or take note of the collected materials. In this article we use our research experience in language data collection in and around Indonesia in fieldwork projects of three kinds: descriptive fieldwork, linguistic surveys, and projects investigating language contact. Our aim is to provide an introductory and practical guide for students and professionals who are embarking on fieldwork in or around Indonesia. Describing practical methods of language data collection, processing, and management, our aim is to provide a guide for any research which involves the collection of language materials, including linguistic research, oral history or literature, and ethnography. Show less
Phonological similarity affects bilingual lexical access of etymologically-related translation equivalents (ETEs). Jinan Mandarin (JM) and Standard Chinese (SC) are closely related and share many... Show morePhonological similarity affects bilingual lexical access of etymologically-related translation equivalents (ETEs). Jinan Mandarin (JM) and Standard Chinese (SC) are closely related and share many ETEs, which are usually orthographically and segmentally identical but vary in tonal similarity. Using an auditory lexical decision experiment and Generalised Additive Modelling, the present study investigates how cross-linguistic tonal similarity interacts with language of operation and how the switching of language across blocks influences SC-JM bilinguals’ auditory lexical processing of ETEs. Bilinguals showed a language dominance effect, indicating that ETEs are specified with separated word-form representations. Compared with SC tonal monolinguals, bilinguals showed a discontinuous bilingual auditory lexical advantage, instead of a classical bilingual lexical disadvantage. The dynamic role of cross-linguistic tonal similarity in auditory word processing is discussed in light of the bilinguals’ attentional shift with the change of language mode at the pre-lexical and lexical stages. Show less
The present study applied functional partition to investigate disyllabic lexical tonal pattern categories in an underresourced Chinese dialect, Jinan Mandarin. A two-stage partitioning procedure... Show moreThe present study applied functional partition to investigate disyllabic lexical tonal pattern categories in an underresourced Chinese dialect, Jinan Mandarin. A two-stage partitioning procedure was introduced to process a multi-speaker corpus that contains irregular lexical variants in a semi automatic way In the first stage, a program provides suggestions for the phonetician to decide the lexical tonal variants for the recordings of each word, based on the result of a functional k-means partitioning algorithm and tonal information from an available pronunciation dictionary of a related Chinese dialect, i.e. Standard Chinese. The second stage iterates a functional version of k-means partitioning with silhouette-based criteria to abstract an optimal number of tonal patterns from the whole corpus, which also allows the phoneticians to adjust the results of the automatic procedure in a controlled way and so redo partitioning for a subset of clusters.The procedure yielded eleven disyllabic tonal patterns for Jinan Mandarin, representing the tonal system used by contemporary Jinan Mandarin speakers from a wide range of age groups. The procedure used in this paper is different from previous linguistic descriptions which were based on more elderly speakers' pronunciations . This method incorporates phoneticians' linguistic knowledge and preliminary linguistic resources into the procedure of partitioning. It can improve the efficiency and objectivity in the investigation of lexical tonal pattern categories when building pronunciation dictionaries for underresourced languages. Show less
Xue, X.G.; Wu, J.; Ricklin, D.; Forneris, F.; Crescenzio, P. di; Schmidt, C.Q.; ... ; Gros, P. 2017
Both Standard Chinese (SC) high- and low-rising tones sound like the rising tone in Jinan Mandarin (JM) Chinese. Acoustically (Experiment 1), the JM rising tone overlaps with both SC rising tones,... Show moreBoth Standard Chinese (SC) high- and low-rising tones sound like the rising tone in Jinan Mandarin (JM) Chinese. Acoustically (Experiment 1), the JM rising tone overlaps with both SC rising tones, but more with the high-rising tone than with the low-rising tone. Perceptually (Experiment 2), the JM rising tone was more likely identified as the SC high-rising tone by SC monolinguals, as shown in Experiments 1 and 2. Experiment 3 examined the role of this two-to-one interlingual tonal mapping in bilingual lexical access. Final high-rising SC pseudo-words were more frequently and more quickly accepted as JM real words than final low-rising SC pseudo-words were. However, both high- and low-rising SC pseudo-words triggered equivalent facilitatory semantic priming on JM real-word targets. The results suggest that different tones are represented in the bilinguals’ mental lexicon in terms of fine-grained and sometimes overlapping acoustic specification. Lexical activation and semantic activation are partially independent. Show less
