Youths’ involvement in organized crime is worrisome, as it not only disrupts a healthy development, but also aggravates youths’ criminal behavior, and makes it harder to return to living a crime-free life. Social ties play an import role in the way youths get and stay involved in organized crime, that is why interventions are needed that target the youth, but also the youth’s social environment. We examine hotspots and mechanisms underlying organized crime involvement and use the knowledge gained to improve and implement intervention strategies. This way, the proposed project directly contributes to effectively decreasing youths’ involvement in organized crime.

Transcription of protein-coding genes is carried out by RNA polymerase II enzymes (RNAPII), which travel along the DNA to synthesize complementary RNA transcripts. When RNAPII encounters DNA damage in the template strand, this blocks its forward translocation and causes a genome-wide transcriptional arrest. To survive, cells must overcome this arrest by local DNA repair and effective restart of global gene transcription. Once stalled, RNAPII molecules themselves become major obstacles for DNA replication in dividing cells. Collisions between the transcription and replication machineries are emerging as a key source of genome instability. Our understanding of the different molecular mechanisms that repair transcription-blocking DNA lesions, or protect human cells against transcription–replications conflicts, is still far from complete. Transcription-coupled repair (TCR) is a specialized DNA repair pathway that selectively removes DNA lesions encountered while genes are actively transcribed. Through genome-wide CRISPR screens, we recently identified a network of novel TCR genes, centred around the previously uncharacterized ELOF1 gene. Drug-genetic network mapping revealed a defined set of genes that co-operates with ELOF1 in a common molecular pathway with a converging function at the intersection of TCR and DNA replication. In this project, we will combine our complementary expertise in TCR and transcription genomics (LUMC) with that in DNA replication stress pathways and genome-wide CRISPR screening (Amsterdam UMC) to dissect how the ELOF1 network orchestrates DNA repair during transcription and resolves transcription–replication conflicts in human cells. Our three objectives are: (1) to elucidate the mechanism by which ELOF1 directs TCR, (2) to dissect the roles of the ELOF1 network members in TCR, and (3) to define the role of the ELOF1 network in resolving conflicts between transcription and replication machineries. Dissecting these molecular mechanisms will reveal how the ELOF1 network safeguards genomic stability at the crossroads of transcription, repair and replication in human cells, which will provide an advanced, mechanistic understanding of the transcription-coupled DNA damage response.

Some claim that rising rates of referrals to gender clinics are driven by an increasing number of adolescents with adverse childhood experiences ‘mistakenly’ labelling themselves as transgender and seeking medical transition, which is purported to be unlikely to alleviate their psychological distress. The proposed project will therefore examine changes from 2002 to 2022 in proportions of adolescents seeking care who are exposed to adverse childhood experiences, as well as whether exposure to such events in childhood limits the efficacy of gender-affirming care in reducing psychological distress into young adulthood. This work may lead to trauma-informed approaches to care.

Unstructured data, like free text, is guesstimated to account for 80% of all patient data but is severely underused. This project applies natural language processing and machine learning methods responsibly and reliably to use unstructured data to support research, education, and patient care with focus on the Dutch healthcare ecosystem.

More than 180.000 children and adults in the Netherlands are affected by an inborn bleeding disorder. They experience frequent bleeding episodes which cause extreme discomfort, invalidity due to joint and muscle bleeds, and sometimes death. Personalisation of treatment is urgently needed. It will safeguard quality of care while restraining rising costs in these debilitating and expensive diseases. Current treatment strategies are suboptimal and lead to either under treatment with risk of continued bleeding or overtreatment with excessive costs. Novel therapeutic approaches are upcoming and expected to be even more expensive. However, effectiveness, (long term) side effects and therefore, positioning and optimal use of these new treatments is not clear. Better insight into the pathophysiology of these diseases is required in order to develop more precise diagnostic techniques. Moreover, safe therapeutic approaches with minimal complications and their cost-effective patient orchestrated implementation are warranted. In this study proposal, we present a step-wise approach by an interdisciplinary team of experts in collaboration with stakeholders, to achieve 1) precision diagnosis; 2) to develop and implement safe and cost-effective treatment strategies; while 3) integrating yields of translational research. Highlights of the study are the development and systematic measurement of both patient-relevant outcome measures as well as costs of treatment, according to value-based health care methodology. In addition, e-health modules will aid implementation of treatment innovations and measurement of outcomes. Moreover, advanced laboratory techniques will be applied to develop novel diagnostic tests and to perform proteomic profiling to explain the interindividual variation of clinical manifestations in these bleeding disorders. Ultimately, the SYMPHONY consortium aims to identify best treatment choice for each individual with a bleeding disorder. Jointly, composing life-changing innovations with significant clinical and societal impact.