Although vote intention polls are often used in the public debate as forecasts of future election outcomes, their predictive value has been subjected to scholarly inquiry. This research note... Show moreAlthough vote intention polls are often used in the public debate as forecasts of future election outcomes, their predictive value has been subjected to scholarly inquiry. This research note contributes to the literature by assessing the predictive value of vote intention polls simultaneously at the macro-level (polls), meso-level (parties), and micro-level (voters). We analyse polls presented by the main polling agencies in the Netherlands (covering seven election cycles between 1998 and 2021), as well as micro-level panel data (covering 27,572 respondents and 46 polls between 2006 and 2010, and 35,574 respondents and 31 polls between 2010 and 2012). We reach three main conclusions. First, vote intention polls in the Netherlands generally do not provide more information than the previous election outcome, until the last few weeks of an election cycle. Second, the predictive accuracy of vote intention polls is lower for challenger parties than for non-challenger parties, particularly midway through the election cycle. Third, the predictive value for individual voters is generally very low, until the last few months before the election. Show less
Perrin, P.; Janssen, L.; Janssen, H.; Broek, B. van den; Voortman, L.M.; Elsland, D. van; ... ; Neefjes, J. 2021
The endosomal system constitutes a highly dynamic vesicle network used to relay materials and signals between the cell and its environment. (1)Once internalized, endosomes gradually mature into... Show moreThe endosomal system constitutes a highly dynamic vesicle network used to relay materials and signals between the cell and its environment. (1)Once internalized, endosomes gradually mature into late acidic compartments and acquire a multivesicular body (MVB) organization through invagination of the limiting membrane (LM) to form intraluminal vesicles (ILVs). (2)Cargoes sequestered into ILVs can either be delivered to lysosomes for degradation or secreted following fusion of the MVB with the plasma membrane. (3)It has been speculated that commitment to ILVs is not a terminal event, and that a return pathway exists, allowing "back-fusion" or "retrofusion" of intraluminal membranes to the LM.(4) The existence of retrofusion as a way to support membrane equilibrium within the MVB has been widely speculated in various cell biological contexts, including exosome uptake(5) and major histocompatibility complex class II (MHC class II) antigen presentation. (6-9) Given the small physical scale, retrofusion of ILVs cannot be measured with conventional techniques. To circumvent this, we designed a chemically tunable cell-based system to monitor retrofusion in real time. Using this system, we demonstrate that retrofusion occurs as part of the natural MVB lifestyle, with attributes parallel to those of viral infection. Furthermore, we find that retrofusion and exocytosis coexist in an equilibrium, implying that ILVs inert to retrofusion comprise a significant fraction of exosomes destined for secretion. MVBs thus contain three types of ILVs: those committed to lysosomal degradation, those retrofusing ILVs, and those subject to secretion in the form of exosomes. Show less
HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8(+) T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options... Show moreHLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8(+) T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options for restoring HLA-I antigen presentation are limited, we aimed to identify druggable HLA-I pathway targets. Using iterative genome-wide screens, we uncovered that the cell surface glycosphingolipid (GSL) repertoire determines effective HLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5 enzyme activity, resulting in upregulation of surface neolacto-series GSLs. These GSLs sterically impeded antibody and receptor interactions with HLA-I and diminished CDS+ T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlated with decreased patient survival. We show that the immunomodulatory effect could be reversed through GSL synthesis inhibition using clinically approved drugs. Overall, our study identifies a GSL signature that inhibits immune recognition and represents a potential therapeutic target in cancer, infection, and autoimmunity. Show less
HLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8+ T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options... Show moreHLA class I (HLA-I) glycoproteins drive immune responses by presenting antigens to cognate CD8+ T cells. This process is often hijacked by tumors and pathogens for immune evasion. Because options for restoring HLA-I antigen presentation are limited, we aimed to identify druggable HLA-I pathway targets. Using iterative genome-wide screens, we uncovered that the cell surface glycosphingolipid (GSL) repertoire determines effective HLA-I antigen presentation. We show that absence of the protease SPPL3 augmented B3GNT5 enzyme activity, resulting in upregulation of surface neolacto-series GSLs. These GSLs sterically impeded antibody and receptor interactions with HLA-I and diminished CD8+ T cell activation. Furthermore, a disturbed SPPL3-B3GNT5 pathway in glioma correlated with decreased patient survival. We show that the immunomodulatory effect could be reversed through GSL synthesis inhibition using clinically approved drugs. Overall, our study identifies a GSL signature that inhibits immune recognition and represents a potential therapeutic target in cancer, infection, and autoimmunity. Show less
The invariant chain (Ii, also known as CD74) is a multifunctional regulator of adaptive immune responses and is responsible for sorting major histocompatibility complex class I and class II (MHCI... Show moreThe invariant chain (Ii, also known as CD74) is a multifunctional regulator of adaptive immune responses and is responsible for sorting major histocompatibility complex class I and class II (MHCI and MHCII, respectively) molecules, as well as other Ii-associated molecules, to a specific endosomal pathway. When Ii is expressed, endosomal maturation and proteolytic degradation of proteins are delayed and, in non-antigen presenting cells, the endosomal size increases, but the molecular mechanisms underlying this are not known. We identified that a SNARE, Vti1b, is essential for regulating these Ii-induced effects. Vti1b binds to Ii and is localized at the contact sites of fusing Ii-positive endosomes. Furthermore, truncated Ii lacking the cytoplasmic tail, which is not internalized from the plasma membrane, relocates Vti1b to the plasma membrane. Knockout of Ii in an antigen-presenting cell line was found to speed up endosomal maturation, whereas silencing of Vti1b inhibits the Ii-induced maturation delay. Our results suggest that Ii, by interacting with the SNARE Vti1b in antigen-presenting cells, directs specific Ii-associated SNARE-mediated fusion in the early part of the endosomal pathway that leads to a slower endosomal maturation for efficient antigen processing and MHC antigen loading. Show less
Jongsma, M.L.M.; Bakker, J.; Cabukusta, B.; Liv, N.; Elsland, D. van; Fermie, J.; ... ; Neefjes, J. 2020
The endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or "late" endosomes are designated by... Show moreThe endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or "late" endosomes are designated by small membrane-bound GTPases Rab7 and Arl8b, which can either operate independently or collaborate to form a joint compartment. Whether, and how, Rab7 and Arl8b resolve this hybrid identity compartment to regain functional autonomy is unknown. Here, we report that Arl8b employs its effector SKIP to instigate inactivation and removal of Rab7 from select membranes. We find that SKIP interacts with Rab7 and functions as its negative effector, delivering the cognate GAP, TBC1D15. Recruitment of TBC1D15 to SKIP occurs via the HOPS complex, whose assembly is facilitated by contacts between Rab7 and the KMI motif of SKIP. Consequently, SKIP mediates reinstatement of single identity Arl8b sub-compartment through an ordered Rab7-to-Arl8b handover, and, together with Rab7's positive effector RILP, enforces spatial, temporal and morphological compartmentalization of endolysosomal organelles. Show less
Jongsma, M.L.M.; Bakker, J.; Cabukusta, B.; Liv, N.; Elsland, D. van; Fermie, J.; ... ; Neefjes, J. 2020
The endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or "late" endosomes are designated by... Show moreThe endolysosomal system fulfils a myriad of cellular functions predicated on regulated membrane identity progressions, collectively termed maturation. Mature or "late" endosomes are designated by small membrane-bound GTPases Rab7 and Arl8b, which can either operate independently or collaborate to form a joint compartment. Whether, and how, Rab7 and Arl8b resolve this hybrid identity compartment to regain functional autonomy is unknown. Here, we report that Arl8b employs its effector SKIP to instigate inactivation and removal of Rab7 from select membranes. We find that SKIP interacts with Rab7 and functions as its negative effector, delivering the cognate GAP, TBC1D15. Recruitment of TBC1D15 to SKIP occurs via the HOPS complex, whose assembly is facilitated by contacts between Rab7 and the KMI motif of SKIP. Consequently, SKIP mediates reinstatement of single identity Arl8b sub-compartment through an ordered Rab7-to-Arl8b handover, and, together with Rab7's positive effector RILP, enforces spatial, temporal and morphological compartmentalization of endolysosomal organelles. Show less
Elfrink, S.; Winde, C.M. de; Brand, M. van den; Berendsen, M.; Roemer, M.G.M.; Arnold, F.; ... ; Spriel, A.B. van 2019
Tetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated... Show moreTetraspanin CD37 is predominantly expressed on the cell surface of mature B lymphocytes and is currently being studied as novel therapeutic target for B-cell lymphoma. Recently, we demonstrated that loss of CD37 induces spontaneous B-cell lymphoma in Cd37-knockout mice and correlates with inferior survival in patients with diffuse large B-cell lymphoma (DLBCL). Here, CD37 mutation analysis was performed in a cohort of 137 primary DLBCL samples, including 44 primary immune-privileged site-associated DLBCL (IP-DLBCL) samples originating in the testis or central nervous system. CD37 mutations were exclusively identified in IP-DLBCL cases (10/44, 23%) but absent in non-IP-DLBCL cases. The aberrations included 10 missense mutations, 1 deletion, and 3 splice-site CD37 mutations. Modeling and functional analysis of CD37 missense mutations revealed loss of function by impaired CD37 protein expression at the plasma membrane of human lymphoma B cells. This study provides novel insight into the molecular pathogenesis of IP-DLBCL and indicates that anti-CD37 therapies will be more beneficial for DLBCL patients without CD37 mutations. Show less
Phenomenon: Rising healthcare expenditures threaten the accessibility and affordability of healthcare systems. Research has demonstrated that teaching (junior) physicians to deliver high-value,... Show morePhenomenon: Rising healthcare expenditures threaten the accessibility and affordability of healthcare systems. Research has demonstrated that teaching (junior) physicians to deliver high-value, cost-conscious care can be effective when learning is situated in a supportive environment. This study aims to offer insight into how residents learn to provide high-value, cost-conscious care in the workplace and how the postgraduate training environment influences this learning. Approach: Six homogeneous focus groups were held between August 2015 and July 2016 with 36 residents from six residency programs (dermatology, n=5; elderly care, n=8; family medicine, n=5; internal medicine, n=6; orthopedic surgery, n=6; surgery, n=6). An iterative grounded theory approach was used to analyze the qualitative data. Findings: Influential factors in learning of high-value, cost-conscious care delivery operated on three levels: individual resident, training program, and the workplace. On the individual level, we discerned three types of beliefs regarding HV3C. At the training program level, perceived determinants of learning included resident-supervisor interactions, involvement in decision-making over time, and exposure to variation in care delivery. At the workplace level, learning depended on the availability of professional healthcare expertise and the presence of institutional policy. Insights: Residents struggle to seize high-value, cost-conscious care learning opportunities in the workplace setting. Both residency training programs and workplaces can contribute to creating these learning opportunities. An important starting point is being aware of the different personal beliefs of residents and the approaches to high-value, cost-conscious care on the level of the training program and workplace. Show less
Phenomenon: Rising healthcare expenditures threaten the accessibility and affordability of healthcare systems. Research has demonstrated that teaching (junior) physicians to deliver high-value,... Show morePhenomenon: Rising healthcare expenditures threaten the accessibility and affordability of healthcare systems. Research has demonstrated that teaching (junior) physicians to deliver high-value, cost-conscious care can be effective when learning is situated in a supportive environment. This study aims to offer insight into how residents learn to provide high-value, cost-conscious care in the workplace and how the postgraduate training environment influ- ences this learning. Approach: Six homogeneous focus groups were held between August 2015 and July 2016 with 36 residents from six residency programs (dermatology, n 1⁄4 5; eld- erly care, n1⁄48; family medicine, n1⁄45; internal medicine, n1⁄46; orthopedic surgery, n1⁄46; surgery, n 1⁄4 6). An iterative grounded theory approach was used to analyze the qualitative data. Findings: Influential factors in learning of high-value, cost-conscious care delivery oper- ated on three levels: individual resident, training program, and the workplace. On the indi- vidual level, we discerned three types of beliefs regarding HV3C. At the training program level, perceived determinants of learning included resident–supervisor interactions, involve- ment in decision-making over time, and exposure to variation in care delivery. At the work- place level, learning depended on the availability of professional healthcare expertise and the presence of institutional policy. Insights: Residents struggle to seize high-value, cost-con- scious care learning opportunities in the workplace setting. Both residency training pro- grams and workplaces can contribute to creating these learning opportunities. An important starting point is being aware of the different personal beliefs of residents and the approaches to high-value, cost-conscious care on the level of the training program and workplace. Show less
