Mutant Nrf2E79Q enhances the promotion and progression of a subset of oncogenic Ras keratinocytes and skin tumors.

Squamous cell carcinomas (SCCs), including lung, head & neck, bladder, and skin SCCs often display constitutive activation of the KEAP1-NRF2 pathway. Constitutive activation is achieved through multiple mechanisms, including activating mutations in NFE2L2 (NRF2). To determine the functional consequences of Nrf2 activation on skin SCC development, we assessed the effects of mutant Nrf2E79Q expression, one of the most common activating mutations in human SCCs, on tumor promotion and progression in the mouse skin multistage carcinogenesis model using a DMBA-initiation/TPA-promotion protocol where the Hras A->T mutation (Q61L) is the canonical driver mutation. Nrf2E79Q expression was temporally and conditionally activated in the epidermis at two stages of tumor development: 1) after DMBA initiation in the epidermis but before cutaneous tumor development and 2) in pre-existing DMBA-initiated/TPA-promoted squamous papillomas. Expression of Nrf2E79Q in the epidermis after DMBA initiation but before tumor occurrence inhibited the development/promotion of 70% of squamous papillomas. However, the remaining papillomas often displayed non-canonical Hras and Kras mutations and enhanced progression to SCCs compared to control mice expressing wildtype Nrf2. Nrf2E79Q expression in pre-existing tumors caused rapid regression of 60% of papillomas. The remaining papillomas displayed the expected canonical Hras A->T mutation (Q61L) and enhanced progression to SCCs. These results demonstrate that mutant Nrf2E79Q enhances the promotion and progression of a subset of skin tumors and alters the frequency and diversity of oncogenic Ras mutations when expressed early after initiation.

Verification of a simplified aneurysm dimensionless flow parameter to predict intracranial aneurysm rupture status.

OBJECTIVES: Aneurysm number (An) is a novel prediction tool utilizing parameters of pulsatility index (PI) and aneurysm geometry. An has been shown to have the potential to differentiate intracranial aneurysm (IA) rupture status. The objective of this study is to investigate the feasibility and accuracy of An for IA rupture status prediction using Australian based clinical data. METHODS: A retrospective study was conducted across three tertiary referral hospitals between November 2017 and November 2020 and all saccular IAs with known rupture status were included. Two sets of An values were calculated based on two sets of PI values previously reported in the literature. RESULTS: Five hundred and four IA cases were included in this study. The results demonstrated no significant difference between ruptured and unruptured status when using An ≥1 as the discriminator. Further analysis showed no strong correlation between An and IA subtypes. The area under the curve (AUC) indicated poor performance in predicting rupture status (AUC1 = 0.55 and AUC2 = 0.56). CONCLUSIONS: This study does not support An ≥1 as a reliable parameter to predict the rupture status of IAs based on a retrospective cohort. Although the concept of An is supported by hemodynamic aneurysm theory, further research is needed before it can be applied in the clinical setting. ADVANCES IN KNOWLEDGE: This study demonstrates that the novel prediction tool, An, proposed in 2020 is not reliable and that further research of this hemodynamic model is needed before it can be incorporated into the prediction of IA rupture status.

Keratometry Changes Between Year One to Seven After Corneal Cross-Linking in Patients With Keratoconus.

PURPOSE: We evaluated the timing at and extent to which midterm to long-term keratometric changes can occur in year 1 to 7 after corneal collagen cross-linking (CXL) in patients with keratoconus. METHODS: We conducted a subgroup analysis of a retrospective cohort study of all consecutive patients who underwent CXL at our cornea center between 2007 and 2011. The inclusion criteria comprised CXL according to the Dresden protocol and a full set of keratometry parameters collected by Scheimpflug tomography preoperatively and at year 1, 3, 5, and 7 after CXL. In addition, best-corrected visual acuity was evaluated. RESULTS: Sixty-three eyes of 47 patients were enrolled. Mean age was 25.46 years ±7.39 years (80.9% male patients). All relevant keratometric parameters showed significant improvement at year 1 after CXL (except for posterior astigmatism). According to mixed-effects model analysis, they all showed further significant change at different points in time between year 1, 3, 5, and 7 (except for K1). In addition, best-corrected visual acuity improved statistically significant between year 1, 3, 5, and 7. Suspected disease progression was noted in 22.2% of patients, mostly between year 1 and 3 after CXL. CONCLUSIONS: After initial improvement 1 year after CXL, keratometric and functional parameters were stable until year 5 after CXL in most cases; further improvement can take place even after up to 7 years post-CXL. By contrast, in case of disease progression, changes seem to occur already between year 1 and 3 after CXL.

Effects of a comprehensive brain computed tomography deep learning model on radiologist detection accuracy.

OBJECTIVES: Non-contrast computed tomography of the brain (NCCTB) is commonly used to detect intracranial pathology but is subject to interpretation errors. Machine learning can augment clinical decision-making and improve NCCTB scan interpretation. This retrospective detection accuracy study assessed the performance of radiologists assisted by a deep learning model and compared the standalone performance of the model with that of unassisted radiologists. METHODS: A deep learning model was trained on 212,484 NCCTB scans drawn from a private radiology group in Australia. Scans from inpatient, outpatient, and emergency settings were included. Scan inclusion criteria were age ≥ 18 years and series slice thickness ≤ 1.5 mm. Thirty-two radiologists reviewed 2848 scans with and without the assistance of the deep learning system and rated their confidence in the presence of each finding using a 7-point scale. Differences in AUC and Matthews correlation coefficient (MCC) were calculated using a ground-truth gold standard. RESULTS: The model demonstrated an average area under the receiver operating characteristic curve (AUC) of 0.93 across 144 NCCTB findings and significantly improved radiologist interpretation performance. Assisted and unassisted radiologists demonstrated an average AUC of 0.79 and 0.73 across 22 grouped parent findings and 0.72 and 0.68 across 189 child findings, respectively. When assisted by the model, radiologist AUC was significantly improved for 91 findings (158 findings were non-inferior), and reading time was significantly reduced. CONCLUSIONS: The assistance of a comprehensive deep learning model significantly improved radiologist detection accuracy across a wide range of clinical findings and demonstrated the potential to improve NCCTB interpretation. CLINICAL RELEVANCE STATEMENT: This study evaluated a comprehensive CT brain deep learning model, which performed strongly, improved the performance of radiologists, and reduced interpretation time. The model may reduce errors, improve efficiency, facilitate triage, and better enable the delivery of timely patient care. KEY POINTS: • This study demonstrated that the use of a comprehensive deep learning system assisted radiologists in the detection of a wide range of abnormalities on non-contrast brain computed tomography scans. • The deep learning model demonstrated an average area under the receiver operating characteristic curve of 0.93 across 144 findings and significantly improved radiologist interpretation performance. • The assistance of the comprehensive deep learning model significantly reduced the time required for radiologists to interpret computed tomography scans of the brain.

Posttraumatic stress moderates return intentions: a factorial survey experiment with internally displaced persons in Nigeria.

Background: Persons displaced by conflict often consider returning to their area of origin. Lack of reliable information about conditions in the area of origin makes this decision more difficult. Displaced persons address this by seeking information from other sources, but must then assess the credibility of these sources.Objective: This study examines the role of symptoms of posttraumatic stress as a moderator of how information from a trustworthy source influences return intentions among displaced persons.Method: We test our hypotheses with a factorial survey experiment, drawing participants (N = 822) from residents of internally displaced person (IDP) camps in northeastern Nigeria.Results: Information from a more trustworthy source led to increased return intentions. However, the more participants reported symptoms of posttraumatic stress, the smaller the effect source trustworthiness had on their return intentions.Conclusions: Findings highlight how traumatic experiences during wartime can undermine the effectiveness of the provision of information from a trustworthy source about good conditions in displaced persons' areas of origin, and suggest that interventions addressing posttraumatic stress could have downstream effects on safe, durable, and dignified return.

Examines the impact of posttraumatic stress on the decision-making process of internally displaced persons in Nigeria.Credible information from trustworthy sources can positively influence return intentions, but this effect is diminished by symptoms of posttraumatic stress.Highlights the importance of addressing both information needs and mental health concerns to support displaced persons in making informed decisions about their future.

Peptide Conjugates of a 2'-O-Methoxyethyl Phosphorothioate Splice-Switching Oligonucleotide Show Increased Entrapment in Endosomes.

Antisense oligonucleotides (ASOs) are short, single-stranded nucleic acid molecules that alter gene expression. However, their transport into appropriate cellular compartments is a limiting factor in their potency. Here, we synthesized splice-switching oligonucleotides (SSOs) previously developed to treat the rare disease erythropoietic protoporphyria. Using chemical ligation-quantitative polymerase chain reaction (CL-qPCR), we quantified the SSOs in cells and subcellular compartments following free uptake. To drive nuclear localization, we covalently conjugated nuclear localization signal (NLS) peptides to a lead 2'-O-methoxyethyl phosphorothioate SSO using thiol-maleimide chemistry. The conjugates and parent SSO displayed similar RNA target-binding affinities. CL-qPCR quantification of the conjugates in cells and subcellular compartments following free uptake revealed one conjugate with better nuclear accumulation relative to the parent SSO. However, compared to the parent SSO, which altered the splicing of the target pre-mRNA, the conjugates were inactive at splice correction under free uptake conditions in vitro. Splice-switching activity could be conferred on the conjugates by delivering them into cells via cationic lipid-mediated transfection or by treating the cells into which the conjugates had been freely taken up with chloroquine, an endosome-disrupting agent. Our results identify the major barrier to the activity of the peptide-oligonucleotide conjugates as endosomal entrapment.

Poor maternal mental health is associated with a low degree of proactive control in refugee children.

This study assesses the development of proactive control strategies in 100 Syrian refugee families (394 individuals) with 6- to 18-year-old children currently living in Turkish communities. The results demonstrate that children's age and their mothers' post-traumatic stress symptoms were associated with the degree of proactive control in their children, with worse mental health being associated with a larger reliance on reactive control and lesser reliance on proactive, future-oriented, control (measured via d' in the AX-CPT task). None of the following factors contributed to children's performance: fathers' experience with post-traumatic stress, parents' exposure to potentially traumatic war-related events, perceived discrimination, a decline in socio-economic status, religious beliefs, parents' proactive control strategies, or the education or gender of the children themselves. The association between mothers' mental health and proactive control strategies in children was large (in terms of effect size), suggesting that supporting mothers' mental health might have clear effects on the development of their children.

An Analysis of Nucleotide-Amyloid Interactions Reveals Selective Binding to Codon-Sized RNA.

Interactions between RNA and proteins are the cornerstone of many important biological processes from transcription and translation to gene regulation, yet little is known about the ancient origin of said interactions. We hypothesized that peptide amyloids played a role in the origin of life and that their repetitive structure lends itself to building interfaces with other polymers through avidity. Here, we report that short RNA with a minimum length of three nucleotides binds in a sequence-dependent manner to peptide amyloids. The 3'-5' linked RNA backbone appears to be well-suited to support these interactions, with the phosphodiester backbone and nucleobases both contributing to the affinity. Sequence-specific RNA-peptide interactions of the kind identified here may provide a path to understanding one of the great mysteries rooted in the origin of life: the origin of the genetic code.

Copper-Mediated Fluoroalkylation of Aryl Bromides and Chlorides Enabled by Directing Groups.

This report describes the reactions between N-heterocyclic carbene copper(I) fluoroalkyl complexes and aryl halides bearing ortho-directing groups. Pyridine, pyrazole, oxazoline, imine, and ester directing groups are shown to dramatically enhance the reactivity of aryl bromides and chlorides with (IPr)CuI-fluoroalkyl complexes (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; fluoroalkyl = difluoromethyl and pentafluoroethyl) to afford aryl-fluoroalkyl coupling products. This approach is leveraged to achieve the Cu-catalyzed directed fluoroalkylation of a series of aryl bromide substrates.

Exposure to organophosphorus compounds: best practice in managing timely, effective emergency responses.

Increasing indications, reports and studies demonstrate that threats from the deliberate use of chemical weapons remain high and are evolving. One of the deadliest classes of chemical weapons are the organophosphorus nerve agents. It is now clear that both state and non-state actors have the ability to deploy and use these types of weapons against individuals and the wider civilian population posing a real and significant threat. The objective of this article is to provide an overview of the issues impacting on a timely critical response to the accidental or deliberate release of Organophosphorus Nerve Agents in order to enhance the understanding of their effects and provide guidance on how first responders might better treat themselves or victims of exposure through a discussion of available evidence and best practices for rapid skin decontamination. The article also examines use of the current nomenclature of 'wet' and 'dry' to describe different forms of decontamination. One of the key conclusions of this article is that adequate preparedness is essential to ensuring that responders are trained to understand the threat posed by Organophosphorus Nerve Agents as well as how to approach a contaminated environment. A key aspect to achieving this will be to ensure that generic medical countermeasures are forward-deployed and available, preferably within minutes of a contamination and that first responders know how to use them.

Multi-proxy evidence for sea level fall at the onset of the Eocene-Oligocene transition.

Continental-scale expansion of the East Antarctic Ice Sheet during the Eocene-Oligocene Transition (EOT) is one of the largest non-linear events in Earth's climate history. Declining atmospheric carbon dioxide concentrations and orbital variability triggered glacial expansion and strong feedbacks in the climate system. Prominent among these feedbacks was the repartitioning of biogeochemical cycles between the continental shelves and the deep ocean with falling sea level. Here we present multiple proxies from a shallow shelf location that identify a marked regression and an elevated flux of continental-derived organic matter at the earliest stage of the EOT, a time of deep ocean carbonate dissolution and the extinction of oligotrophic phytoplankton groups. We link these observations using an Earth System model, whereby this first regression delivers a pulse of organic carbon to the oceans that could drive the observed patterns of deep ocean dissolution and acts as a transient negative feedback to climate cooling.

Supervised versus unsupervised approaches to classification of accelerometry data.

Sophisticated animal-borne sensor systems are increasingly providing novel insight into how animals behave and move. Despite their widespread use in ecology, the diversity and expanding quality and quantity of data they produce have created a need for robust analytical methods for biological interpretation. Machine learning tools are often used to meet this need. However, their relative effectiveness is not well known and, in the case of unsupervised tools, given that they do not use validation data, their accuracy can be difficult to assess. We evaluated the effectiveness of supervised (n = 6), semi-supervised (n = 1), and unsupervised (n = 2) approaches to analyzing accelerometry data collected from critically endangered California condors (Gymnogyps californianus). Unsupervised K-means and EM (expectation-maximization) clustering approaches performed poorly, with adequate classification accuracies of <0.8 but very low values for kappa statistics (range: -0.02 to 0.06). The semi-supervised nearest mean classifier was moderately effective at classification, with an overall classification accuracy of 0.61 but effective classification only of two of the four behavioral classes. Supervised random forest (RF) and k-nearest neighbor (kNN) machine learning models were most effective at classification across all behavior types, with overall accuracies >0.81. Kappa statistics were also highest for RF and kNN, in most cases substantially greater than for other modeling approaches. Unsupervised modeling, which is commonly used for the classification of a priori-defined behaviors in telemetry data, can provide useful information but likely is instead better suited to post hoc definition of generalized behavioral states. This work also shows the potential for substantial variation in classification accuracy among different machine learning approaches and among different metrics of accuracy. As such, when analyzing biotelemetry data, best practices appear to call for the evaluation of several machine learning techniques and several measures of accuracy for each dataset under consideration.

C/EBPß deficiency enhances the keratinocyte innate immune response to direct activators of cytosolic pattern recognition receptors.

The skin is the first line of defense to cutaneous microbes and viruses, and epidermal keratinocytes play a critical role in preventing infection by viruses and pathogens through activation of the type I interferon (IFN) response. Using RNAseq analysis, here we report that the conditional deletion of C/EBPß transcription factor in mouse epidermis (CKOß mice) resulted in the upregulation of IFNß and numerous keratinocyte interferon-stimulated genes (ISGs). The expression of cytosolic pattern recognition receptors (cPRRs), that recognize viral RNA and DNA, were significantly increased, and enriched in the RNAseq data set. cPRRs stimulate a type I IFN response that can trigger cell death to eliminate infected cells. To determine if the observed increases in cPRRs had functional consequences, we transfected CKOß primary keratinocytes with the pathogen and viral mimics poly(I:C) (dsRNA) or poly(dA:dT) (synthetic B-DNA) that directly activate PRRs. Transfected CKOß primary keratinocytes displayed an amplified type I IFN response which was accompanied by increased activation of IRF3, enhanced ISG expression, enhanced activation of caspase-8, caspase-3 and increased apoptosis. Our results identify C/EBPß as a critical repressor of the keratinocyte type I IFN response, and demonstrates that the loss of C/EBPß primes keratinocytes to the activation of cytosolic PRRs by pathogen RNA and DNA to induce cell death mediated by caspase-8 and caspase-3.

Tranexamic acid as a novel adjunct in the management of vessel perforation complicating Endovascular Clot Retrieval.

AIM: To assess the safety and utility of tranexamic acid (TXA) as an adjunct salvage therapy in iatrogenic vessel perforation complicating endovascular clot retrieval. Iatrogenic vessel perforation and extravasation are known and potentially fatal complications of endovascular clot retrieval (ECR). Various methods of establishing haemostasis post perforation have been reported. TXA is widely utilised intraoperatively to reduce bleeding in various surgical specialities. The use of TXA in endovascular procedures has not been previously described in the literature. METHODS: Retrospective case control study of all cases that underwent ECR. Cases where arterial rupture occurred were identified. Details of management and functional status at 3 months were recorded. Modified Rankin score (mRS) 0-2 was considered a good functional outcome. Comparison of proportions analysis was performed. RESULTS: Of 1378 cases of ECR, rupture complicated 36 (2.6%). TXA was administered in addition to standard care in 11 cases (31%). At 3 months, 4 of 11 cases (36%) where TXA was administered had a good functional outcome compared to 3 of 22 (12%) in the standard care group (P=0.09). Mortality at 3 months occurred in 4 of 11 cases (41.7%) where TXA was administered compared to 16 of 25 (64%) where it was not (P=0.13). CONCLUSION: Tranexamic acid administration in iatrogenic vessel rupture was associated with a lower mortality rate and a larger proportion of patients achieving a good functional outcome at 3 months. This effect trended towards but was not statistically significant. TXA administration was not associated with adverse effects.

Future directions for medicinal chemistry in the field of oligonucleotide therapeutics.

In the last decade, the field of oligonucleotide therapeutics has matured, with the regulatory approval of several single-stranded and double-stranded RNA drugs. In this Perspective, I discuss enabling developments and likely future directions in the field from the perspective of oligonucleotide chemistry.

The role of maternal trauma and discipline types in emotional processing among Syrian refugee children.

Stressful experiences in armed conflict incur intergenerational effects through parental behaviors with their children. A recent study reported that among Syrian refugee families, mothers' (but not fathers') post-traumatic stress (PTS) impacted children's emotional processing. In this study, we aim to shed further light on this phenomenon by analyzing how the parenting practices in the context of post-traumatic stress confers protection or risk for children's emotional processing. Participants were 6-18-year-old children (n = 212) and their mothers (n = 94), who fled from Syria and were residing in Turkish communities. We used the computer-based emotional processing task including photos of facial movements typically associated with different emotions to measure children's capacity for emotional processing. Mothers reported their PTS and the discipline types they use, as well as the contextual factors related to their refugee background. Linear mixed effect models were constructed first, to find out the discipline types that are most strongly associated with emotional processing of the child, and second, to examine whether these discipline types moderate the effect of maternal PTS on children's emotional processing. Finally, generalized linear models were constructed to examine which contextual factors are associated with the use of these discipline types by mothers. We found that spanking as a discipline type was associated with poorer child emotional processing, whereas withholding of media access was associated with better emotional processing. Younger and less religious mothers were more prone to use spanking. The study underlines the need for parenting programs alongside with efforts to address mental health issues among mothers living under armed conflict.

Corneal cross-linking in patients with keratoconus: up to 13 years of follow-up.

INTRODUCTION: To evaluate long-term safety and efficacy of corneal collagen cross-linking (CXL) in patients with keratoconus up to 13 years. MATERIALS AND METHODS: In this mono-centre exploratory study, we included all consecutive patients who underwent CXL in our cornea centre from 01/01/2007 to 12/30/2011 and met the inclusion criteria. CXL was performed in all patients according to the Dresden protocol. Evaluation included best-corrected visual acuity (BCVA), topographic keratometry by Scheimpflug corneal tomography and endothelial cell count (ECC). Follow-up measurements were taken up to 13 years after treatment were compared with baseline values. RESULTS: The study enrolled 168 eyes. The mean age of our patients was 26.3 years ± 7.8 years. A complete topographic dataset was available 1 year postoperatively for 142 eyes, 5 years postoperatively for 105 eyes, 10 years postoperatively for 61 eyes and 13 years postoperatively for 9 eyes. BCVA increased statistically significant after 1 year, 5 years and 10 years and non-significantly after 13 years. All keratometric parameters with exception of posterior astigmatism showed a statistically significant decrease after 1 year, 5 years and 10 years. After 13 years, the decrease was statistically significant only in Kmax, K2 and thinnest cornea. No significant changes in ECC were detected. Three eyes received Re-CXL, none of the eyes received penetrating keratoplasty and no infections occurred in this cohort. CONCLUSIONS: CXL can slow down or even stop the progression of keratoconus in the majority of cases. The effect is long-lasting with excellent safety.

Pharmacological inhibition of Lin28 promotes ketogenesis and restores lipid homeostasis in models of non-alcoholic fatty liver disease.

Lin28 RNA-binding proteins are stem-cell factors that play key roles in development. Lin28 suppresses the biogenesis of let-7 microRNAs and regulates mRNA translation. Notably, let-7 inhibits Lin28, establishing a double-negative feedback loop. The Lin28/let-7 axis resides at the interface of metabolic reprogramming and oncogenesis and is therefore a potential target for several diseases. In this study, we use compound-C1632, a drug-like Lin28 inhibitor, and show that the Lin28/let-7 axis regulates the balance between ketogenesis and lipogenesis in liver cells. Hence, Lin28 inhibition activates synthesis and secretion of ketone bodies whilst suppressing lipogenesis. This occurs at least partly via let-7-mediated inhibition of nuclear receptor co-repressor 1, which releases ketogenesis gene expression mediated by peroxisome proliferator-activated receptor-alpha. In this way, small-molecule Lin28 inhibition protects against lipid accumulation in multiple cellular and male mouse models of hepatic steatosis. Overall, this study highlights Lin28 inhibitors as candidates for the treatment of hepatic disorders of abnormal lipid deposition.

A Systematic Review of Neuropsychological Outcomes After Treatment of Intracranial Aneurysms.

BACKGROUND: Aneurysmal subarachnoid hemorrhage is a cause of profound morbidity and mortality. Its effects extend beyond functional neurological status to neurocognitive and psychological functioning. Endovascular treatment is becoming more prevalent after increasing evidence for its safety and efficacy; however, there is a relative paucity of evidence specific to neurocognitive status after treatment. OBJECTIVE: To assess and compare neuropsychological outcomes after the treatment of ruptured and unruptured intracranial aneurysms. METHODS: A systematic review of the literature was conducted searching for articles assessing the neuropsychological and cognitive outcomes after the treatment of ruptured and unruptured intracranial aneurysms. Inclusion criteria were English language, publication between January 2000 and October 2020, and discussion of neuropsychological outcomes in adequate detail. Outcomes were categorized into 8 domains: 5 Neurocognitive (Language, Executive Function, Complex Attention, Memory and Learning, and Perceptual motor function), Intelligence Quotient, Affect, and Quality of Life. RESULTS: Twenty-four articles were included comprising 2236 patients (924 surgical clipping, 1095 endovascular coiling, and 217 controls). These studies reported that most tests revealed no significant difference [n = 356/421 (84.56%)] between treatment modalities. More studies reported significantly superior test scores in the fields of language, executive function, and memory and learning after coiling [n = 53/421 tests (12.59%)] compared with clipping [n = 12/421 tests (2.85%)]. CONCLUSION: The current available data and published studies demonstrate a trend toward improved neurocognitive and psychological outcomes after endovascular treatment. Although these findings should be considered when deciding on the optimal treatment method for each patient, drawing definitive conclusions is difficult because of heterogeneity between patients and studies.

The solution structure of Dead End bound to AU-rich RNA reveals an unusual mode of tandem RRM-RNA recognition required for mRNA regulation.

Dead End (DND1) is an RNA-binding protein essential for germline development through its role in post-transcriptional gene regulation. The molecular mechanisms behind selection and regulation of its targets are unknown. Here, we present the solution structure of DND1's tandem RNA Recognition Motifs (RRMs) bound to AU-rich RNA. The structure reveals how an NYAYUNN element is specifically recognized, reconciling seemingly contradictory sequence motifs discovered in recent genome-wide studies. RRM1 acts as a main binding platform, including atypical extensions to the canonical RRM fold. RRM2 acts cooperatively with RRM1, capping the RNA using an unusual binding pocket, leading to an unusual mode of tandem RRM-RNA recognition. We show that the consensus motif is sufficient to mediate upregulation of a reporter gene in human cells and that this process depends not only on RNA binding by the RRMs, but also on DND1's double-stranded RNA binding domain (dsRBD), which is dispensable for binding of a subset of targets in cellulo. Our results point to a model where DND1 target selection is mediated by a non-canonical mode of AU-rich RNA recognition by the tandem RRMs and a role for the dsRBD in the recruitment of effector complexes responsible for target regulation.