A pilot study evaluating the preventive effects of platform-end lengthwise fencing on trespassing, person struck by train and traffic delays.

BACKGROUND: Trespassing at train tracks and "person under train" (PUT) incidents are serious health, societal and transportation concerns. There is a need for developing different measures to prevent these events. Here, we hypothesized that platform-end lengthwise fences (PLF) reduce trespassing, the number of PUT incidents (suicides and accidents), and train traffic delays. METHOD: PLFs were installed as the intervention at one station in Stockholm in 2020. The number of trespassers detected using CCTV-cameras was compared before and after at the intervention station over a total period of 29 months (using incidence rate ratio, IRR). The reduction in the number of PUT (over 20 years) and train traffic delays (over 9 years) was also investigated by IRR, and by using three control groups. RESULTS: After installation of PLF there was a significant ∼90% reduction in trespasses (IRR = 0.10, 95%CI 0.04-0.23; one-sided exact p < 0.0001). No PUT incident occurred at the intervention station after the installation, compared to 1.11 per year before installation (IRR = 0.32, 95%CI 0-1.82; one-sided exact p = 0.1216). There was a significant reduction in delay minutes post installation compared to before the installation (Mann Whitney U = 0, upper one-sided exact p = 0.0357). The effect of the PLF was also observable in comparison to the three control groups, suggesting that the preventive effect was not due to wider societal events affecting all stations. CONCLUSION: PLF had a large effect on reducing the number of trespasses and the number of delay minutes due to trespasses and PUT incidents. PLF may also have an effect of reducing PUT incidents. PRACTICAL APPLICATIONS: PLF is deemed to be relatively easy and cheap to install and thus scalable (as compared to full barriers, e.g., platform screen doors) and may be considered at platform-ends having an exit, provided there is enough space to install them.

A pilot study evaluating the effectiveness of preventing railway suicides by mid-track fencing, which restrict easy access to high-speed train tracks.

BACKGROUND: Suicides in the railway system is a serious health, societal, and transportation concern. Restriction of the access to suicide methods in the form of different physical barriers is a promising approach for suicide prevention. METHOD: Mid-track fencing, which is fencing placed in-between the high-speed and commuter train tracks, was installed at one out of seven stations along a train line outside of Stockholm in the years 2013/2014. The number of suicides at the intervention station was compared to six other stations used as controls, over a total period of 20 years (2002-2021). RESULTS: Suicides at high-speed tracks occurring at stations was the major cause of death on the investigated railway line. Prior to the year 2014, the intervention and control stations displayed similar time trends in the number of suicides. After installation of the mid-track fencing in 2014, there was a 62.5% reduction in the rate of suicides occurring at the intervention station. Compared to the six other control stations, the intervention station displayed a significant reduction in the number of suicides during the years 2014-2021 (OR = 0.14, 95%CI 0.013-0.95). Suicides at the railway lines in-between stations were not increased post-intervention. However, nearby control stations showed a 162% increase in suicides after the intervention, suggesting the induction of transfer effects. CONCLUSION: Mid-track fences restricting access to high-speed train tracks may have a large effect on reducing the number of railway suicides at intervention stations, but may also induce an increase in suicides at nearby stations without mid-track fences. PRACTICAL APPLICATIONS: Partial physical barriers such as mid-track fencing is deemed to be relatively easy and cheap to install (as compared to full barriers; e.g., full height platform screen doors) and should be considered at all stations on railway lines that have high-speed trains passing by.

Accident or suicide? Improvement in the classification of suicides among road traffic fatalities in Sweden by extended psychosocial investigations, during the years 2010-2019.

INTRODUCTION: Suicide is the second leading cause of death in the ages 15-29 worldwide, exceeded only by road injury. However, fatalities in road traffic may be either accidents or suicides. In 2010 Sweden began efforts to separately report deaths in road traffic as either accidents or suicides. METHOD: Three alternative criteria defining what constitutes a fatality by suicide were introduced. After exclusion of natural deaths, fatalities were also classified on a five-level graded scale, which distinguished between accident, undetermined, and suicide. The investigations of fatalities were complemented by extended psychosocial investigations in 2012. The improvement in the classification of suicide deaths was evaluated by an intra-year 2012 comparison, as well as using the 2010-2012 period as a control to evaluate the continued use of extended psychosocial investigations during the 2013-2019 period. RESULTS: The 2012 intra-year comparison showed a 63% increase in the number of identified suicides when using extended psychosocial investigations. The additional 14 suicides identified in 2012 were mainly attributed to a resolution of 12 "undetermined" causes of deaths. Suicides of all road fatalities increased from 5.7-6.8% in 2010-2011, to 11.2% in 2012. Over the subsequent period 2013-2019 with extended psychosocial investigations, suicides of all road fatalities averaged 10%, a 60% increase over prior years. An average of ∼9 additional suicides was identified each year during 2013-2019, which was accompanied by an annual reduction of ∼6 "undetermined" fatalities. CONCLUSION: The use of extended psychosocial investigations is of major importance for our knowledge about the occurrence of suicides in road traffic. Practical applications: A standardized and in-depth classification of suicide deaths is a basic prerequisite needed for the cooperation, implementation, and effect-evaluations of suicide intervention and prevention efforts, with potential to include the entire Swedish transportation system.

Polygenic risk scores for neuropsychiatric, inflammatory, and cardio-metabolic traits highlight possible genetic overlap with suicide attempt and treatment-emergent suicidal ideation.

Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co-occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio-metabolic traits/diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta-analyzed across samples, including a total of 688 patients with SA (Neff  = 2,258) and 214 with TWESI (Neff  = 785). Stratified genetic covariance analyses were performed to investigate functionally cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11-1.38; p = 1.73 × 10-4 ). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p = 4.6 × 10-3 ), loneliness (p = .009), or chronic pain (p = .016) and SA, PRSs for MDD or CAD and TWESI (p = .043 and p = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.

A candidate biological network formed by genes from genomic and hypothesis-free scans of suicide.

Information about genes and the biology of suicidal behavior (SB) is noisy due to heterogenous outcomes (suicide attempts or deaths), as well as many different genes and overlapping biological processes implicated. One approach to test the unbiased biological coherence of disease genes, is to use genes from hypothesis-free genetic scans and to investigate if they aggregate close to each other in cellular gene and protein interaction networks ("interactomes"). Therefore, we used network methods to study the biological coherence among genes (n = 229) from genome-wide association studies (GWAS) and whole exome sequencing (WES) of suicide outcome. Results showed that the suicide GWAS+WES genes has significant aggregation in three major interactome database assemblies, a hallmark of biological similarity and increased likelihood of being involved in the same outcome (suicide). This pinpointed e.g. genes on chromosome 19, which are also associated with lipid metabolism, schizophrenia and bipolar disorder. We identified a subset of GWAS+WES "core" genes (n = 54) which are the most proximal to each other in the context of three interactome assemblies, and present a candidate network module of suicide which is specific for nervous system tissues. The n = 54 most proximal "core" genes showed overrepresentation of synaptic and nervous system development genes, as well as network paths to other SB genes having increased evidence diversity. Overall, results suggested the existence of a coherent biology in suicide outcome and provide unbiased biological support concerning links to other SB genes, as well as e.g. bipolar disorder, excitatory/inhibitory function and ketamine treatment in SB.

Genetic origins of suicidality? A synopsis of genes in suicidal behaviours, with regard to evidence diversity, disorder specificity and neurodevelopmental brain transcriptomics.

With regard to suicidal behavior (SB) genetics, many novel genes have been implicated over the years, in particular by a variety of hypothesis-free genomic methods (e.g. GWAS and exome sequencing). In addition, many novel SB gene findings appear enigmatic in their biological relevance and have weak statistical support, e.g. lack direct replications. Adding to this is the comorbidity between psychiatric disorders and SB. Here we provide a synopsis of SB genes, by prioritization of 106 (out of ~2500) genes based on their highest level of evidence diversity across mainly five genetic evidence types (candidate/GWAS SNP, CNV, linkage and whole exome sequencing), supplemented by three functional categories. This is a representative set of both old and new SB gene candidates, implicated by all kinds of evidence. Furthermore, we define a subset of 40 SB "specific" genes, which are not found among ~3900 genes implicated in other neuropsychiatric disorders, e.g. Autism spectrum disorders (ASD) or Schizophrenia. Biological research of suicidality contains a major developmental focus, e.g. with regard to the gene-environment interactions and epigenetic effects during childhood. Less is known about early (fetal) development and SB genes. Inspired by huge efforts to understand the role early (fetal) neurodevelopment in e.g. ASD by using brain transcriptomic data, we here also characterize the 106 SB genes. We find interesting spatiotemporal expression differences and similarities between SB specific and non-specific genes during brain neurodevelopment. These aspects are of interest to investigate further, to better understand and counteract the genetic origins suicidality.

Gene-level associations in suicide attempter families show overrepresentation of synaptic genes and genes differentially expressed in brain development.

Suicidal behavior (SB) has a complex etiology involving different polygenic and environmental components. Here we used an excess of significant markers (ESM) test to study gene-level associations in previous genome-wide association studies (GWAS) SNP data from a family-based sample, having medically severe suicide attempt (SA) as main outcome in the offspring. In SA without major psychiatric disorders (N = 498), a screening of 5,316 genes across the genome suggested association 17 genes (at fdr < 0.05). Genes RETREG1 (a.k.a. FAM134B), GSN, GNAS, and CACNA1D were particularly robust to different methodological variations. Comparison with the more widely used Multi-marker Analysis of GenoMic Annotation (MAGMA) methods, mainly supported RETREG1, GSN, RNASEH2B, UBE2H, and CACNA1D by using the "mean" model, and ranked 13 of the same genes as ESM among its top-17. Complementing the ESM screen by using MAGMA to analyze 17,899 genes, we observed excess of genes with p < .05 by using the "top" model, and the "mean" model suggested additional genes with genome-wide fdr < 0.25. Overrepresentation analysis of 10 selected gene sets using all genes with p < .05, showed significant results for synaptic genes, genes differentially expressed in brain development and for ~12% of the SA polygenic association genes identified previously in this sample. Exploratory analysis linked some of the ESM top-17 genes to psychotropic drugs and we examined the allelic heterogeneity in the previous SA candidate GRIN2B. This study complemented previous GWAS on SB outcomes, implicating both previous candidate (e.g., GRIN2B and GNAS) and novel genes in SA outcomes, as well as synaptic functions and brain development.

Rare CNVs in Suicide Attempt include Schizophrenia-Associated Loci and Neurodevelopmental Genes: A Pilot Genome-Wide and Family-Based Study.

Suicidal behavior (SB) has a complex etiology involving genes and environment. One of the genetic components in SB could be copy number variations (CNVs), as CNVs are implicated in neurodevelopmental disorders. However, a recently published genome-wide and case-control study did not observe any significant role of CNVs in SB. Here we complemented these initial observations by instead using a family-based trio-sample that is robust to control biases, having severe suicide attempt (SA) in offspring as main outcome (n = 660 trios). We first tested for CNV associations on the genome-wide Illumina 1M SNP-array by using FBAT-CNV methodology, which allows for evaluating CNVs without reliance on CNV calling algorithms, analogous to a common SNP-based GWAS. We observed association of certain T-cell receptor markers, but this likely reflected inter-individual variation in somatic rearrangements rather than association with SA outcome. Next, we used the PennCNV software to call 385 putative rare (<1%) and large (>100 kb) CNVs, observed in n = 225 SA offspring. Nine SA offspring had rare CNV calls in a set of previously schizophrenia-associated loci, indicating the importance of such CNVs in certain SA subjects. Several additional, very large (>1MB) sized CNV calls in 15 other SA offspring also spanned pathogenic regions or other neural genes of interest. Overall, 45 SA had CNVs enriched for 65 medically relevant genes previously shown to be affected by CNVs, which were characterized by a neurodevelopmental biology. A neurodevelopmental implication was partly congruent with our previous SNP-based GWAS, but follow-up analysis here indicated that carriers of rare CNVs had a decreased burden of common SNP risk-alleles compared to non-carriers. In conclusion, while CNVs did not show genome-wide association by the FBAT-CNV methodology, our preliminary observations indicate rare pathogenic CNVs affecting neurodevelopmental functions in a subset of SA, who were distinct from SA having increased SNP risk-allele burden. These observations may open up new avenues in the genetic etiology of SB.

Genome-wide association studies of suicidal behaviors: a review.

Suicidal behaviors represent a fatal dimension of mental ill-health, involving both environmental and heritable (genetic) influences. The putative genetic components of suicidal behaviors have until recent years been mainly investigated by hypothesis-driven research (of "candidate genes"). But technological progress in genotyping has opened the possibilities towards (hypothesis-generating) genomic screens and novel opportunities to explore polygenetic perspectives, now spanning a wide array of possible analyses falling under the term Genome-Wide Association Study (GWAS). Here we introduce and discuss broadly some apparent limitations but also certain developing opportunities of GWAS. We summarize the results from all the eight GWAS conducted up to date focused on suicidality outcomes; treatment emergent suicidal ideation (3 studies), suicide attempts (4 studies) and completed suicides (1 study). Clearly, there are few (if any) genome-wide significant and reproducible findings yet to be demonstrated. We then discuss and pinpoint certain future considerations in relation to sample sizes, the units of genetic associations used, study designs and outcome definitions, psychiatric diagnoses or biological measures, as well as the use of genomic sequencing. We conclude that GWAS should have a lot more potential to show in the case of suicidal outcomes, than what has yet been realized.

Family-based study of AVPR1B association and interaction with stressful life events on depression and anxiety in suicide attempts.

The cortisol response to psychosocial stress may become dysregulated in stress-related disorders. It is potentiated by pituitary secretion of adrenocorticotropic hormone (ACTH), which is, in part, regulated by arginine vasopressin receptor-1B (AVPR1B). AVPR1B variants were previously reported to associate with mood and anxiety disorders. This study aims, for the first time, to investigate association of AVPR1B genetic variants with mood and anxiety outcomes in suicidal behavior.Using a family-based study design of 660 complete nuclear family trios with offspring who have made a suicide attempt (SA), we tested the direct association and linkage of AVPR1B single nucleotide polymorphisms (SNPs) with SA, as well as with depression and anxiety in SA. Main findings were the association and linkage of AVPR1B exon 1 SNP rs33990840 and a major 6-SNP haplotype representative of all common AVPR1B-SNPs, on the outcome of high Beck Depression Inventory scores in SA. By contrast, genetic associations with lifetime diagnoses of depression and anxiety in SA or gene-environment interactions between AVPR1B variants and stressful life events (SLEs) were not significant. An exploratory screen of interactions between AVPR1B and CRHR1 (corticotropin-releasing hormone receptor-1), the principal pituitary regulator of ACTH secretion, showed no support for gene-gene interactions on the studied outcomes. The results suggest that AVPR1B genetic variation, eg, non-synonymous SNP rs33990840 mediating putative consequences on ligand binding, has a role in SA etiology characterized by elevated depression symptoms, without involving AVPR1B-moderation of SLEs.

[The European Psychiatric Association (EPA) guidance on suicide treatment and prevention]. / Az Európai Pszichiátriai Szövetség (European Psychiatric Association, EPA) úmutatója az öngyilkosság kezelésére és megelözésére.

UNLABELLED: Suicide is a major public health problem in the WHO European Region accounting for over 150,000 deaths per year. Suicidal crisis: Acute intervention should start immediately in order to keep the patient alive. DIAGNOSIS: An underlying psychiatric disorder is present in up to 90% of people who completed suicide. Comorbidity with depression, anxiety, substance abuse and personality disorders is high. In order to achieve successful prevention of suicidality, adequate diagnostic procedures and appropriate treatment for the underlying disorder are essential. TREATMENT: Existing evidence supports the efficacy of pharmacological treatment and cognitive behavioural therapy (CBT) in preventing suicidal behaviour. Some other psychological treatments are promising, but the supporting evidence is currently insufficient. Studies show that antidepressant treatment decreases the risk for suicidality among depressed patients. However, the risk of suicidal behaviour in depressed patients treated with antidepressants exists during the first 10-14 days of treatment, which requires careful monitoring. Short-term supplementary medication with anxiolytics and hypnotics in the case of anxiety and insomnia is recommended. TREATMENT with antidepressants of children and adolescents should only be given under supervision of a specialist. Long-term treatment with lithium has been shown to be effective in preventing both suicide and attempted suicide in patients with unipolar and bipolar depression. TREATMENT with clozapine is effective in reducing suicidal behaviour in patients with schizophrenia. Other atypical antipsychotics are promising but more evidence is required. TREATMENT team: Multidisciplinary treatment teams including psychiatrist and other professionals such as psychologist, social worker, and occupational therapist are always preferable, as integration of pharmacological, psychological and social rehabilitation is recommended especially for patients with chronic suicidality. Family: The suicidal person independently of age should always be motivated to involve family in the treatment. Social support: Psychosocial treatment and support is recommended, as the majority of suicidal patients have problems with relationships, work, school and lack functioning social networks. SAFETY: A secure home, public and hospital environment, without access to suicidal means is a necessary strategy in suicide prevention. Each treatment option, prescription of medication and discharge of the patient from hospital should be carefully evaluated against the involved risks. Training of personnel: Training of general practitioners (GPs) is effective in the prevention of suicide. It improves treatment of depression and anxiety, quality of the provided care and attitudes towards suicide. Continuous training including discussions about ethical and legal issues is necessary for psychiatrists and other mental health professionals.

The exosome associates cotranscriptionally with the nascent pre-mRNP through interactions with heterogeneous nuclear ribonucleoproteins.

Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.

Nature and nurture in suicidal behavior, the role of genetics: some novel findings concerning personality traits and neural conduction.

Suicide affects about one million people each year, a phenomenon characterized by heterogeneous and complex causes. Often environmental factors such as negative life events may act as a significant contributor to suicidal behavior. However, in many cases the exposure to the same environmental stress does not result in increased suicidality. It is now well established that there is also a substantial genetic contribution to suicidal behavior. Here, functional and association studies which implicate specific genes in psychological traits and environmental factors are discussed, interactions which are related to completed suicide or suicide attempt, and our novel findings which need replication are presented. We found that genetic variation in the noradrenergic tyrosine hydroxylase gene was associated with the angry/hostility personality trait and vulnerability to stress. Similarly, we recently discovered that genetic variation in components of the stress-related hypothalamic pituitary adrenocortical axis, T-box 19 and corticotropin releasing hormone receptor 1, showed association and linkage to high anger/hostility in and male depression the suicidal offspring, respectively. Further results from our studies have revealed that genetic variation in genes with roles in basal mechanisms of neural conduction, voltage-gated sodium channel type VIII alpha and vesicle-associated membrane 4 protein, showed association and linkage among suicide attempters. Additionally, we have results which give support to the findings of others, implicating the serotonin transporter and serotonin receptor 1A in suicidal behavior. Our future studies aim at identifying and resolving complex patterns and mechanisms of neurobiological gene-environment interactions, which may contribute to suicide.

Association of the serotonin transporter promotor polymorphism with suicide attempters with a high medical damage.

Serotonergic neurotransmission has been implicated in suicidal behavior, including inconsistent results concerning the serotonin transporter promoter polymorphism (5-HTTLPR). Here, we analyzed the 5-HTTLPR in suicide attempters (n=85). Comparing the presence of SS with SL+LL genotypes showed a significantly higher prevalence of the SS genotype in suicide attempters with high medical damage scores (chi2=9.054, df=1, p=0.0026). The results suggest that the S-allele may predispose for suicidal behavior characterized by high determination.

The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt.

BACKGROUND: Serotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters. METHODS: The involvement of the implicated G-allele of the 5-HTR1A C(-1019)G polymorphism (rs6295) was analyzed with the transmission disequilibrium test (TDT) in a sample of 272 suicide attempter families. RESULTS: No overtransmission of the G-allele was found in the entire sample of suicide attempters (p = 0.1460; n = 272 trios). However, a strong trend for overtransmission of the G-allele was observed in a sub-sample selected for a high level of previous traumatic and/or stressful life events prior to the suicide attempt (p = 0.0630, two-tail; n = 94 trios). CONCLUSION: The current results show that variation at the rs6295 polymorphism of the HTR1A gene is not associated with suicide attempts generally. However, the results indicate a possible role of the G-allele in suicidal behavior in connection with high exposure to traumatic and/or stressful life events, which is in need of future investigation.

Identification of herpes simplex virus RNAs that interact specifically with regulatory protein ICP27 in vivo.

Herpes simplex virus type 1 (HSV-1) protein ICP27 has an essential regulatory role during viral replication, in part by post-transcriptional control of gene expression, and has a counterpart in all herpes viruses sequenced so far. Although much is known about the functions of this signature herpesvirus protein, little is known about its RNA binding capabilities; ICP27 interacts with specificity for a subset of intronless HSV-1 RNAs and poly(G), through its RGG box. We performed an in vivo yeast three-hybrid screen of an HSV-1 genomic library, searching for ICP27 interacting RNAs. Comparable with a yeast genomic screen, 24 of 55 single inserts mapped to antisense strands of HSV-1 transcribed regions or non-transcribed regions. The 31 HSV-1 sense RNAs identified were 35 to 225 nucleotides in length and interacted with preferred specificity for ICP27 as compared with an unrelated RNA-binding protein. They map to 10 monocistronic and 10 polycistronic transcripts of all kinetic classes and represent 28 open reading frames encoding predominantly essential viral proteins with roles in viral DNA replication and virion maturation. Several studies show regulatory effects by ICP27 on the majority of these transcripts, consistent with its regulation of the early-late switch in the HSV-1 life cycle. Deletion of the ICP27 RGG box and the ICP27 M15 mutation, both lethal in virus, abolished or severely reduced the ICP27-RNA interactions, indicating their biological relevance. The study facilitates continued study of gene regulation by ICP27 by further defining its interactions with viral RNAs.

Inhibition of translation by UAUUUAU and UAUUUUUAU motifs of the AU-rich RNA instability element in the HPV-1 late 3' untranslated region.

The human papillomavirus type 1 (HPV-1) late mRNAs contain a 57-nucleotide adenosine- and uridine-rich RNA instability element termed h1ARE in their late 3' untranslated regions. Here we show that five sequence motifs in the h1ARE (named I-V) affect the mRNA half-life in an additive manner. The minimal inhibitory sequence in motifs I and II was mapped to UAUUUAU, and the minimal inhibitory sequence in motifs III-V was mapped to UAUUUUUAU. We also provide evidence that the same motifs in the AU-RNA instability element inhibit mRNA translation, an effect that was entirely dependent on the presence of a poly(A) tail on the mRNA. Additional experiments demonstrated that the h1ARE interacted directly with the poly(A)-binding protein, suggesting that the h1ARE inhibits translation by interfering with the function of the poly(A)-binding protein.