Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in... Show moreEffector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases. Show less
Zhang, Z.; Du, C.; De Barsy, F.; Liem, M.; Liakopoulos, A.; Wezel, G.P. van; ... ; Rozen, D.E. 2020
One of the hallmark behaviors of social groups is division of labor, where different group members become specialized to carry out complementary tasks. By dividing labor, cooperative groups... Show moreOne of the hallmark behaviors of social groups is division of labor, where different group members become specialized to carry out complementary tasks. By dividing labor, cooperative groups increase efficiency, thereby raising group fitness even if these behaviors reduce individual fitness. We find that antibiotic production in colonies of Streptomyces coelicolor is coordinated by a division of labor. We show that S. coelicolor colonies are genetically heterogeneous because of amplifications and deletions to the chromosome. Cells with chromosomal changes produce diversified secondary metabolites and secrete more antibiotics; however, these changes reduced individual fitness, providing evidence for a trade-off between antibiotic production and fitness. Last, we show that colonies containing mixtures of mutants and their parents produce significantly more antibiotics, while colony-wide spore production remains unchanged. By generating specialized mutants that hyper-produce antibiotics, streptomycetes reduce the fitness costs of secreted secondary metabolites while maximizing the yield and diversity of these products. Show less
The unusual correlated state that emerges in URu2Si2 below THO = 17.5 K is known as “hidden order” because even basic characteristics of the order parameter, such as its dimensionality (whether it... Show moreThe unusual correlated state that emerges in URu2Si2 below THO = 17.5 K is known as “hidden order” because even basic characteristics of the order parameter, such as its dimensionality (whether it has one component or two), are “hidden.” We use resonant ultrasound spectroscopy to measure the symmetry-resolved elastic anomalies across THO. We observe no anomalies in the shear elastic moduli, providing strong thermodynamic evidence for a one-component order parameter. We develop a machine learning framework that reaches this conclusion directly from the raw data, even in a crystal that is too small for traditional resonant ultrasound. Our result rules out a broad class of theories of hidden order based on two-component order parameters, and constrains the nature of the fluctuations from which unconventional superconductivity emerges at lower temperature. Our machine learning framework is a powerful new tool for classifying the ubiquitous competing orders in correlated electron systems. Show less
Kuninty, P.R.; Bansal, R.; Geus, S.W.L. de; Mardhian, D.F.; Schnittert, J.; Baarlen, J. van; ... ; Prakash, J. 2019
Abundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to... Show moreAbundant desmoplastic stroma is the hallmark for pancreatic ductal adenocarcinoma (PDAC), which not only aggravates the tumor growth but also prevents tumor penetration of chemotherapy, leading to treatment failure. There is an unmet clinical need to develop therapeutic solutions to the tumor penetration problem. In this study, we investigated the therapeutic potential of integrin alpha 5 (ITGA5) receptor in the PDAC stroma. ITGA5 was over-expressed in the tumor stroma from PDAC patient samples, and overexpression was inversely correlated with overall survival. In vitro, knockdown of ITGA5 inhibited differentiation of human pancreatic stellate cells (hPSCs) and reduced desmoplasia in vivo. Our novel peptidomimetic AV3 against ITGA5 inhibited hPSC activation and enhanced the antitumor effect of gemcitabine in a 3D heterospheroid model. In vivo, AV3 showed a strong reduction of desmoplasia, leading to decompression of blood vasculature, enhanced tumor perfusion, and thereby the efficacy of gemcitabine in co-injection and patient-derived xenograft tumor models. Show less
Schoot, J.M.S. van der; Fennemann, F.L.; Valente, M.; Dolen, Y.; Hagemans, I.M.; Becker, A.M.D.; ... ; Scheeren, F.A. 2019
Stable, single-nanometer thin, and free-standing two-dimensional layers with controlled molecular architectures are desired for several applications ranging from (opto-)electronic devices to... Show moreStable, single-nanometer thin, and free-standing two-dimensional layers with controlled molecular architectures are desired for several applications ranging from (opto-)electronic devices to nanoparticle and single-biomolecule characterization. It is, however, challenging to construct these stable single molecular layers via self-assembly, as the cohesion of those systems is ensured only by in-plane bonds. We herein demonstrate that relatively weak noncovalent bonds of limited directionality such as dipole-dipole (-CN center dot center dot center dot NC-) interactions act in a synergistic fashion to stabilize crystalline monomolecular layers of tetrafunctional calixarenes. The monolayers produced, demonstrated to be freestanding, display a well-defined atomic structure on the single-nanometer scale and are robust under a wide range of conditions including photon and electron radiation. This work opens up new avenues for the fabrication of robust, single-component, and free-standing layers via bottom-up self-assembly. Show less
Alone and together, climatic changes, population growth, and economic scarcity create shared problems that can be tackled effectively through cooperation and coordination. Perhaps because... Show moreAlone and together, climatic changes, population growth, and economic scarcity create shared problems that can be tackled effectively through cooperation and coordination. Perhaps because cooperation is fragile and easily breaks down, societies also provide individual solutions to shared problems, such as privatized healthcare or retirement planning. But how does the availability of individual solutions affect free-riding and the efficient creation of public goods? We confronted groups of individuals with a shared problem that could be solved either individually or collectively. Across different cost-benefit ratios of individually versus collectively solving the shared problem, individuals display a remarkable tendency toward group-independent, individual solutions. This “individualism” leads to inefficient resource allocations and coordination failure. Introducing peer punishment further results in wasteful punishment feuds between “individualists” and “collectivists.” In the presence of individual solutions to shared problems, groups struggle to balance self-reliance and collective efficiency, leading to a “modern tragedy of the commons.” Show less
Dunning, T.; Grossman, G.; Humphreys, M.; Hyde, S.B.; McIntosh, C.; Nellis, G.; ... ; Sircar, N. 2019
Voters may be unable to hold politicians to account if they lack basic information about their representatives’ performance. Civil society groups and international donors therefore advocate using... Show moreVoters may be unable to hold politicians to account if they lack basic information about their representatives’ performance. Civil society groups and international donors therefore advocate using voter information campaigns to improve democratic accountability. Yet, are these campaigns effective? Limited replication, measurement heterogeneity, and publication biases may undermine the reliability of published research. We implemented a new approach to cumulative learning, coordinating the design of seven randomized controlled trials to be fielded in six countries by independent research teams. Uncommon for multisite trials in the social sciences, we jointly preregistered a meta-analysis of results in advance of seeing the data. We find no evidence overall that typical, nonpartisan voter information campaigns shape voter behavior, although exploratory and subgroup analyses suggest conditions under which informational campaigns could be more effective. Such null estimated effects are too seldom published, yet they can be critical for scientific progress and cumulative, policy-relevant learning. Show less
Li, R.Y.; Petit, L.; Franke, D.P.; Dehollain, J.P.; Helsen, J.; Steudtner, M.; ... ; Veldhorst, M. 2018
