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Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B 12 and molecular hallmarks of methionine starvation. Supplementation with vitamin B 12 increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B 12 levels, providing evidence for a link between B 12 levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B 12 supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B 12 , through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair., (© 2023. The Author(s).)

Background: Cardiovascular diseases are a leading cause of mortality and morbidity worldwide. Pregnancy imposes unique physiological changes on a woman's cardiovascular system., Materials and Methods: A cohort of 68 participants, comprising 30 pregnant women with cardiovascular risk and 38 without cardiovascular risk, was recruited for this study. These participants were prospectively followed during their pregnancies from 2020 to 2022 at the Obstetrics and Gynecology Department of the "Pius Brînzeu" Emergency County Clinical Hospital in Timişoara, Romania. All women included in this study underwent cesarean section deliveries at the same medical facility. Data regarding the gestational weeks at delivery, birth weight, and Apgar scores assessed by neonatologists were collected for each participant. Statistical analyses were performed to compare the neonatal effects between the two groups., Results: The results of this study revealed significant differences between the groups in terms of Apgar scores ( p = 0.0055), gestational weeks ( p = 0.0471), and baby birth weight ( p = 0.0392)., Conclusion: The findings underscore the importance of considering maternal cardiovascular health as a potential determinant of neonatal outcomes. Further research is needed to elucidate the underlying mechanisms and develop strategies for optimizing neonatal outcomes in high-risk pregnancies.

Despite the advance and success of precision oncology in gastrointestinal cancers, the frequency of molecular-informed therapy decisions in pancreatic ductal adenocarcinoma (PDAC) is currently neglectable. We present a longitudinal precision oncology platform based on functional model systems, including patient-derived organoids, to identify chemotherapy-induced vulnerabilities. We demonstrate that treatment-induced tumor cell plasticity in vivo distinctly changes responsiveness to targeted therapies, without the presence of a selectable genetic marker, indicating that tumor cell plasticity can be functionalized. By adding a mechanistic layer to precision oncology, adaptive processes of tumors under therapy can be exploited, particularly in highly plastic tumors, such as pancreatic cancer., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The naïve and primed states are the best characterized pluripotency states. Naïve pluripotent stem cells (PSCs) correspond to the early pre-implantation blastocyst and, in mice, constitute the optimal starting state for subsequent developmental applications. However, the stabilization of human naïve PSCs remains challenging because, after short-term culture, most current methods result in karyotypic abnormalities, aberrant DNA methylation patterns, loss of imprinting and severely compromised developmental potency. We have recently developed a novel method to induce and stabilize naïve human PSCs that consists in the simple addition of a chemical inhibitor for the closely related CDK8 and CDK19 kinases (CDK8/19i). Long-term cultured CDK8/19i-naïve human PSCs preserve their normal karyotype and do not show widespread DNA demethylation. Here, we investigate the long-term stability of allele-specific methylation at imprinted loci and the differentiation potency of CDK8/19i-naïve human PSCs. We report that long-term cultured CDK8/19i-naïve human PSCs retain the imprinting profile of their parental primed cells, and imprints are further retained upon differentiation in the context of teratoma formation. We have also tested the capacity of long-term cultured CDK8/19i-naïve human PSCs to differentiate into primordial germ cell (PGC)-like cells (PGCLCs) and trophoblast stem cells (TSCs), two cell types that are accessible from the naïve state. Interestingly, long-term cultured CDK8/19i-naïve human PSCs differentiated into PGCLCs with a similar efficiency to their primed counterparts. Also, long-term cultured CDK8/19i-naïve human PSCs were able to differentiate into TSCs, a transition that was not possible for primed PSCs. We conclude that inhibition of CDK8/19 stabilizes human PSCs in a functional naïve state that preserves imprinting and potency over long-term culture.

The complexity of homeless service users' characteristics and the contextual challenges faced by services can make the experience of working with people in homelessness stressful and can put providers' well-being at risk. In the current study, we investigated the association between service characteristics (i.e., the availability of training and supervision and the capability-fostering approach) and social service providers' work engagement and burnout. The study involved 497 social service providers working in homeless services in eight different European countries (62% women; mean age = 40.73, SD = 10.45) and was part of the Horizon 2020 European study "Homelessness as Unfairness (HOME_EU)." Using hierarchical linear modeling (HLM), findings showed that the availability of training and supervision were positively associated with providers' work engagement and negatively associated with burnout. However, results varied based on the perceived usefulness of the training and supervision provided within the service and the specific outcome considered. The most consistent finding was the association between the degree to which a service promotes users' capabilities and all the aspects of providers' well-being analyzed. Results are discussed in relation to their implications for how configuration of homeless services can promote social service providers' well-being and high-quality care., (© 2020 Society for Community Research and Action.)

Human naïve pluripotent stem cells (PSCs) represent an optimal homogenous starting point for molecular interventions and differentiation strategies. This is in contrast to the standard primed PSCs which fluctuate in identity and are transcriptionally heterogeneous. However, despite many efforts, the maintenance and expansion of human naïve PSCs remains a challenge. Here, we discuss our recent strategy for the stabilization of human PSC in the naïve state based on the use of a single chemical inhibitor of the related kinases CDK8 and CDK19. These kinases phosphorylate and negatively regulate the multiprotein Mediator complex, which is critical for enhancer-driven recruitment of RNA Pol II. The net effect of CDK8/19 inhibition is a global stimulation of enhancers, which in turn reinforces transcriptional programs including those related to cellular identity. In the case of pluripotent cells, the presence of CDK8/19i efficiently stabilizes the naïve state. Importantly, in contrast to previous chemical methods to induced the naïve state based on the inhibition of the FGF-MEK-ERK pathway, CDK8/19i-naïve human PSCs are chromosomally stable and retain developmental potential after long-term expansion. We suggest this could be related to the fact that CDK8/19 inhibition does not induce DNA demethylation. These principles may apply to other fate decisions., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Pluripotent stem cells (PSCs) transition between cell states in vitro, reflecting developmental changes in the early embryo. PSCs can be stabilized in the naive state by blocking extracellular differentiation stimuli, particularly FGF-MEK signalling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF-MEK signalling or global DNA methylation. Mechanistically, chemical inhibition of CDK8 and CDK19 (hereafter CDK8/19) kinases removes their ability to repress the Mediator complex at enhancers. CDK8/19 inhibition therefore increases Mediator-driven recruitment of RNA polymerase II (RNA Pol II) to promoters and enhancers. This efficiently stabilizes the naive transcriptional program and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with a reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be achieved in vitro by inhibiting CDK8/19 kinase activity. These principles may apply to other contexts of cellular plasticity.

Across Europe, as governments turn to housing-led strategies in attempts to reverse rising rates of homelessness, increasing numbers of Housing First (HF) programs are being implemented. As HF programs become more widespread, it is important to understand how service users experience them compared to the more prevalent traditional treatment-first approach to addressing long-term homelessness. Although there is a large body of research on service users' experiences of Housing First compared to treatment-first in North American contexts, comparatively less is known about how these two categories of homeless services are experienced in the European context. In a correlational and cross-sectional study, part of a larger examination of homelessness in Europe, participants (n = 520) engaged with either HF (n = 245) or traditional services (TS; n = 275) programs in seven countries completed measures of their experiences of services (consumer choice, housing quality, and service satisfaction) and recovery (time in independent housing, psychiatric symptoms, and community integration). Across the seven countries, participants engaged with HF programs reported experiencing more consumer choice, better perceived housing quality, and more satisfaction with services than participants engaged in TS programs. Participants in HF programs also reported a greater proportion of time in independent accommodation, fewer psychiatric symptoms, and more community integration. Varying patterns of association between experiences of services and recovery outcomes were observed. Findings indicate HF consistently predicts greater recovery than TS across diverse sociopolitical and economic contexts. Implications of findings for configurations of homeless services and homeless services policy are discussed., (© 2019 Society for Community Research and Action.)

Background: Homeless services expend considerable resources to provide for service users' most basic needs, such as food and shelter, but their track record for ending homelessness is disappointing. An alternative model, Housing First, reversed the order of services so that homeless individuals are offered immediate access to independent housing, with wraparound supports but no treatment or abstinence requirements. Although the evidence base for Housing First's effectiveness in ending homelessness is robust, less is known about its effectiveness in promoting recovery., Objective: The objective of this research is to compare rehabilitation- and recovery-related outcomes of homeless services users who are engaged in either Housing First or traditional staircase services in eight European countries: France, Ireland, Italy, the Netherlands, Poland, Portugal, Spain, and Sweden., Methods: A mixed methods, multi-site investigation of Housing First and traditional services will compare quantitative outcomes at two time points. Key rehabilitation outcomes include stable housing and psychiatric symptoms. Key growth outcomes include community integration and acquired capabilities. Semistructured interviews will be used to examine service users' experiences of environmental constraints and affordances on acquired capabilities to identify features of homeless services that enhance service users' capabilities sets. Multi-level modelling will be used to test for group differences-Housing First versus traditional services-on key outcome variables. Thematic analysis will be used to understand the ways in which service users make sense of internal and external affordances and constraints on capabilities., Results: The study is registered with the European Commission (registration number: H2020-SC6-REVINEQUAL-2016/ GA726997). Two press releases, a research report to the funding body, two peer-reviewed articles, and an e-book chapter are planned for dissemination of the final results. The project was funded from September 2016 through September 2019. Expected results will be disseminated in 2019 and 2020., Conclusions: We will use the findings from this research to formulate recommendations for European social policy on the configuration of homeless services and the scaling up and scaling out of Housing First programs. From our findings, we will draw conclusions about the setting features that promote individuals' exits from homelessness, rehabilitation, and recovery., International Registered Report Identifier (irrid): RR1-10.2196/14584., (©Ronni Michelle Greenwood, Rachel M Manning, Branagh R O'Shaughnessy, Oisin Cross, Maria J Vargas-Moniz, Pascal Auquier, Massimo Santinello, Judith R Wolf, Anna Bokszczanin, Roberto Bernad, Håkan Källmén, Frederik Spinnewijn, José Ornelas, HOME_EU Consortium. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 05.02.2020.)

The purpose of this study is to assess the utility value European citizens put on an innovative social program aimed at reducing homelessness. The Housing First (HF) model involves access to regular, scattered, independent and integrated housing in the community with the support of a multidisciplinary team. Currently, HF is not implemented by most European countries or funded by healthcare or social plans, but randomised controlled trials have stressed significant results for improved housing stability, recovery and healthcare services use. The broader implementation of HF across Europe would benefit from a better understanding of citizens' preferences and "willingness to pay" (WTP) for medico-social interventions like HF. We conducted a representative telephone survey between March and December 2017 in eight European countries (France, Ireland, Italy, the Netherlands, Poland, Portugal, Spain, and Sweden). Respondent's WTP for HF (N = 5631) was assessed through a contingent valuation method with a bidding algorithm. 42.3% of respondents were willing to pay more taxes to reduce homelessness through the HF model, and significant differences were found between countries (p < 0.001); 30.4% of respondents who did not value the HF model were protest zeros (either contested the payment vehicle-taxes- or the survey instrument). Respondents were willing to pay €28.2 (±11) through annual taxation for the HF model. Respondents with higher educational attainment, who paid national taxes, reported positive attitudes about homelessness, or reported practices to reduce homelessness (donations, volunteering) were more likely to value the HF model, with some countries' differences also related to factors at the environmental level. These findings inform key stakeholders that European citizens are aware of the issue of homelessness in their countries and that scaling up the HF model across Europe is both feasible and likely to have public support., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To examine the lifetime, 5-year and past-year prevalence of homelessness among European citizens in eight European nations., Design: A nationally representative telephone survey using trained bilingual interviewers and computer-assisted telephone interview software., Setting: The study was conducted in France, Ireland, Italy, the Netherlands, Poland, Portugal, Spain and Sweden., Participants: European adult citizens, selected from opt-in panels from March to December 2017. Total desired sample size was 5600, with 700 per country. Expected response rates of approximately 30% led to initial sample sizes of 2500 per country., Main Outcome Measures: History of homelessness was assessed for lifetime, past 5 years and past year. Sociodemographic data were collected to assess correlates of homelessness prevalence using generalised linear models for clustered and weighted samples., Results: Response rates ranged from 30.4% to 33.5% (n=5631). Homelessness prevalence was 4.96% for lifetime (95% CI 4.39% to 5.59%), 1.92% in the past 5 years (95% CI 1.57% to 2.33%) and 0.71% for the past year (95% CI 0.51% to 0.98%) and varied significantly between countries (pairwise comparison difference test, p<0.0001). Time spent homeless ranged between less than a week (21%) and more than a year (18%), with high contrasts between countries (p<0.0001). Male gender, age 45-54, lower secondary education, single status, unemployment and an urban environment were all independently strongly associated with lifetime homelessness (all OR >1.5)., Conclusions: The prevalence of homelessness among the surveyed nations is significantly higher than might be expected from point-in-time and homeless service use statistics. There was substantial variation in estimated prevalence across the eight nations. Coupled with the well-established health impacts of homelessness, medical professionals need to be aware of the increased health risks of those with experience of homelessness. These findings support policies aiming to improve health services for people exposed to homelessness., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Addressing Citizen's perspectives on homelessness is crucial for the design of effective and durable policy responses, and available research in Europe is not yet substantive. We aim to explore citizens' opinions about homelessness and to explain the differences in attitudes within the general population of eight European countries: France, Ireland, Italy, the Netherlands, Poland, Portugal, Spain, and Sweden., Methods: A nationally representative telephone survey of European citizens was conducted in 2017. Three domains were investigated: Knowledge, Attitudes, and Practices about homelessness. Based on a multiple correspondence analysis (MCA), a generalized linear model for clustered and weighted samples was used to probe the associations between groups with opposing attitudes., Results: Response rates ranged from 30.4% to 33.5% (N = 5,295). Most respondents (57%) had poor knowledge about homelessness. Respondents who thought the government spent too much on homelessness, people who are homeless should be responsible for housing, people remain homeless by choice, or homelessness keeps capabilities/empowerment intact (regarding meals, family contact, and access to work) clustered together (negative attitudes, 30%). Respondents who were willing to pay taxes, welcomed a shelter, or acknowledged people who are homeless may lack some capabilities (i.e. agreed on discrimination in hiring) made another cluster (positive attitudes, 58%). Respondents living in semi-urban or urban areas (ORs 1.33 and 1.34) and those engaged in practices to support people who are homeless (ORs > 1.4; p<0.005) were more likely to report positive attitudes, whereas those from France and Poland (p<0.001) were less likely to report positive attitudes., Conclusion: The majority of European citizens hold positive attitudes towards people who are homeless, however there remain significant differences between and within countries. Although it is clear that there is strong support for increased government action and more effective solutions for Europe's growing homelessness crisis, there also remain public opinion barriers rooted in enduring negative perceptions., Competing Interests: The authors have declared that no competing interests exist.

The RNA polymerase II-associated protein 1 (RPAP1) is conserved across metazoa and required for stem cell differentiation in plants; however, very little is known about its mechanism of action or its role in mammalian cells. Here, we report that RPAP1 is essential for the expression of cell identity genes and for cell viability. Depletion of RPAP1 triggers cell de-differentiation, facilitates reprogramming toward pluripotency, and impairs differentiation. Mechanistically, we show that RPAP1 is essential for the interaction between RNA polymerase II (RNA Pol II) and Mediator, as well as for the recruitment of important regulators, such as the Mediator-specific RNA Pol II factor Gdown1 and the C-terminal domain (CTD) phosphatase RPAP2. In agreement, depletion of RPAP1 diminishes the loading of total and Ser5-phosphorylated RNA Pol II on many genes, with super-enhancer-driven genes among the most significantly downregulated. We conclude that Mediator/RPAP1/RNA Pol II is an ancient module, conserved from plants to mammals, critical for establishing and maintaining cell identity., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Polμ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polμ (Polμ(-/-)) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polμ(-/-) mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polμ(-/-) deficiency on liver aging. We found that old Polμ(-/-) mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polμ(-/-) liver showed reduced genomic instability and increased apoptosis resistance. However, Polμ(-/-) mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polμ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.

Transdermal delivery of active principles is a versatile method widely used in medicine. The main drawback for the transdermal route, however, is the low efficiency achieved in the absorption of many drugs, mostly due to the complexity of the skin barrier. To improve drug delivery through the skin, we prepared and characterized liposomes loaded with ibuprofen and designed pharmaceutical formulations based on the extemporaneous addition of penetration enhancer (PE) surfactants. Afterwards, permeation and release studies were carried out. According to the permeation studies, the ibuprofen liposomal formulation supplemented with PEs exhibited similar therapeutic effects, but at lower doses (20%) comparing with a commercial formulation used as a reference. Atomic force microscopy (AFM) was used to investigate the effect caused by PEs on the adsorption mechanism of liposomal formulations onto the skin. Non-fused liposomes, bilayers and multilayered lipid structures were observed. The transformation of vesicles into planar structures is proposed as a possible rationale for explaining the lower doses required when a liposome formulation is supplemented with surfactant PEs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Centromeric protein A (CENP-A) is the epigenetic mark of centromeres. CENP-A replenishment is necessary in each cell cycle to compensate for the dilution associated to DNA replication, but how this is achieved mechanistically is largely unknown. We have developed an assay using Xenopus egg extracts that can recapitulate the spatial and temporal specificity of CENP-A deposition observed in human cells, providing us with a robust in vitro system amenable to molecular dissection. Here we show that this deposition depends on Xenopus Holliday junction-recognizing protein (xHJURP), a member of the HJURP/Scm3 family recently identified in yeast and human cells, further supporting the essential role of these chaperones in CENP-A loading. Despite little sequence homology, human HJURP can substitute for xHJURP. We also report that condensin II, but not condensin I, is required for CENP-A assembly and contributes to retention of centromeric CENP-A nucleosomes both in mitosis and interphase. We propose that the chromatin structure imposed by condensin II at centromeres enables CENP-A incorporation initiated by xHJURP.

Centromeres are the chromosomal loci that direct the formation of the kinetochores. These macromolecular assemblies mediate the interaction between chromosomes and spindle microtubules and thereby power chromosome movement during cell division. They are also the sites of extensive regulation of the chromosome segregation process. Except in the case of budding yeast, centromere identity does not rely on DNA sequence but on the presence of a special nucleosome that contains a histone H3 variant known as CenH3 or CENP-A (Centromere Protein A). It has been therefore proposed that CENP-A is the epigenetic mark of the centromere. Upon DNA replication the mark is diluted two-fold and must be replenished to maintain centromere identity. What distinguishes CENP-A nucleosomes from those containing histone H3, how CENP-A nucleosomes are incorporated specifically into centromeric chromatin, and how this incorporation is coordinated with other cell cycle events are key issues that have been the focus of intensive research over the last decade. Here we review some of the highlights of this research.

Genetic alterations causing constitutive tyrosine kinase activation are observed in a broad spectrum of cancers. Thus far, these mutant kinases have been localized to the plasma membrane or cytoplasm, where they engage proliferation and survival pathways. We report that the NUP214-ABL1 fusion is unique among these because of its requisite localization to the nuclear pore complex for its transforming potential. We show that NUP214-ABL1 displays attenuated transforming capacity as compared to BCR-ABL1 and that NUP214-ABL1 preferentially transforms T cells, which is in agreement with its unique occurrence in T cell acute lymphoblastic leukemia. Furthermore, NUP214-ABL1 differs from BCR-ABL1 in subcellular localization, initiation of kinase activity, and signaling and lacks phosphorylation on its activation loop. In addition to delineating an unusual mechanism for kinase activation, this study provides new insights into the spectrum of chromosomal translocations involving nucleoporins by indicating that the nuclear pore context itself may play a central role in transformation.

The nuclear pore complex (NPC) conducts macromolecular transport to and from the nucleus and provides a kinetic/hydrophobic barrier composed of phenylalanine-glycine (FG) repeats. Nuclear transport is achieved through permeation of this barrier by transport receptors. The transport receptor CRM1 facilitates export of a large variety of cargoes. Export of the preribosomal 60 S subunit follows this pathway through the adaptor protein NMD3. Using RNA interference, we depleted two FG-containing cytoplasmically oriented NPC complexes, Nup214-Nup88 and Nup358, and investigated CRM1-mediated export. A dramatic defect in NMD3-mediated export of preribosomes was found in Nup214-Nup88-depleted cells, whereas only minor export defects were evident in other CRM1 cargoes or upon depletion of Nup358. We show that the large C-terminal FG domain of Nup214 is not accessible to freely diffusing molecules from the nucleus, indicating that it does not conduct 60 S preribosomes through the NPC. Consistently, derivatives of Nup214 lacking the FG-repeat domain rescued the 60 S export defect. We show that the coiled-coil region of Nup214 is sufficient for 60 S nuclear export, coinciding with recruitment of Nup88 to the NPC. Our data indicate that Nup214 plays independent roles in NPC function by participating in the kinetic/hydrophobic barrier through its FG-rich domain and by enabling NPC gating through association with Nup88.

Leucine-rich nuclear export signals (NESs) mediate rapid nuclear export of proteins via interaction with CRM1. This interaction is stimulated by RanGTP but remains of a relatively low affinity. In order to identify strong signals, we screened a 15-mer random peptide library for CRM1 binding, both in the presence and absence of RanGTP. Under each condition, strikingly similar signals were enriched, conforming to the NES consensus sequence. A derivative of an NES selected in the absence of RanGTP exhibits very high affinity for CRM1 in vitro and stably binds without the requirement of RanGTP. Localisation studies and RNA interference demonstrate inefficient CRM1-mediated export and accumulation of CRM1 complexed with the high-affinity NES at nucleoporin Nup358. These results provide in vivo evidence for a nuclear export reaction intermediate. They suggest that NESs have evolved to maintain low affinity for CRM1 to allow efficient export complex disassembly and release from Nup358.

Nuclear pore complexes (NPCs) traverse the nuclear envelope (NE), providing a channel through which nucleocytoplasmic transport occurs. Nup358/RanBP2, Nup214/CAN, and Nup88 are components of the cytoplasmic face of the NPC. Here we show that Nup88 localizes midway between Nup358 and Nup214 and physically interacts with them. RNA interference of either Nup88 or Nup214 in human cells caused a strong reduction of Nup358 at the NE. Nup88 and Nup214 showed an interdependence at the NPC and were not affected by the absence of Nup358. These data indicate that Nup88 and Nup214 mediate the attachment of Nup358 to the NPC. We show that localization of the export receptor CRM1 at the cytoplasmic face of the NE is Nup358 dependent and represents its empty state. Also, removal of Nup358 causes a distinct reduction in nuclear export signal-dependent nuclear export. We propose that Nup358 provides both a platform for rapid disassembly of CRM1 export complexes and a binding site for empty CRM1 recycling into the nucleus.