Publikationer från Uppsala Universitet
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How dangerous are the Ukrobanderites? : A study on the securitization of the Ukrainian Kursk military operation and the construction of an enemy image in Belarus’ media discourses
No full textUkraine launched a military operation in Kursk oblast at the beginning of August 2024, which caught both Russia and Belarus by surprise. In reaction to the event, Belarus increased its troops along the border of Ukraine. This study will assess the enemy image, securitization, and frames of existential threat surrounding the Kursk military operation in Belarusian state-runned BelTA and Russian-owned Komsomolskaya Pravda v Belarusi (KP). A multimodal critical discourse analysis is used to analyze the media discourses of the two news outlets. The study has a comparative approach, identifying differences between the news outlets in the discursive construction of an enemy and securitization during armed conflict. Differences were found predominantly in the construction of an enemy where BelTA presented more features of a less dangerous, benign enemy, whilst KP more often presented a less humane, malign enemy. Two strands of securitization were identified in both news outlets: one strand being the securitization of energy structure and the second being the securitization of armed conflict.
Skin regional specification and higher-order HoxC regulation
No full textThe integument plays a critical role in functional adaptation, with macro-regional specification forming structures like beaks, combs, feathers, and scales, while micro-regional specification modifies skin appendage shapes. However, the molecular mechanisms remain largely unknown. Craniofacial integument displays dramatic diversity, exemplified by the Polish chicken (PC) with a homeotic transformation of comb-to-crest feathers, caused by a 195-base pair (bp) duplication in HoxC10 intron. Micro-C analyses show that HoxC-containing topologically associating domain (TAD) is normally closed in the scalp but open in the dorsal and tail regions, allowing multiple long-distance contacts. In the PC scalp, the TAD is open, resulting in high HoxC expression. CRISPR-Cas9 deletion of the 195-bp duplication reduces crest feather formation, and HoxC misexpression alters feather shapes. The 195-bp sequence is found only in Archelosauria (crocodilians and birds) and not in mammals. These findings suggest that higher-order regulation of the HoxC cluster modulates gene expression, driving the evolution of adaptive integumentary appendages in birds
High-Speed Electron Flows in the Earth Magnetotail
No full textHigh-speed electron flows (HSEFs) play a crucial role in the energy dissipation and conversion processes within the terrestrial magnetosphere and can drive various types of plasma waves and instabilities, affecting the electron-scale dynamics. The existence, spatial distribution, and general properties of HSEFs in the Earth magnetotail are still unknown. In this study, we conduct a comprehensive survey of HSEFs in the Earth magnetotail, utilizing NASA's Magnetospheric Multiscale (MMS) mission observations from 2017 to 2021. A total of 642 events characterized by electron bulk speeds exceeding 5,000 km/s are identified. The main statistical properties are: (a) The duration of almost all HSEFs are less than 4 s, and the average duration is 0.74 s. (b) HSEFs exhibit a strong dawn-dusk (30%-70%) asymmetry. (c) 39.6%, 29.0%, and 31.4% of the events are located in the plasma sheet, plasma sheet boundary layer (PSBL), and lobe region, respectively. (d) In the plasma sheet, HSEFs have arbitrary moving directions regarding the ambient magnetic field, and the events near the neutral line predominantly move along the same direction as the ion outflows, indicating outflow electrons generated by magnetic reconnection. (e) HSEFs in the PSBL and lobe mainly move along the ambient magnetic field, and 70% of HSEFs in the PSBL exhibit features of reconnection inflow. The HSEFs in lobe regions may locate near the reconnection electron edges. Our study reveals that the HSEFs in magnetotail are closely associated with magnetic reconnection, and the statistical results deepen the understanding of HSEF fundamental properties in collisionless plasma
YmoA functions as a molecular stress sensor in Yersinia
No full textPathogenic bacteria sense and respond to environmental fluctuations, a capability essential for establishing successful infections. The YmoA/Hha protein family are conserved transcription regulators in Enterobacteriaceae, playing a critical role in these responses. Specifically, YmoA in Yersinia adjusts the expression of virulence-associated traits upon temperature shift. Still, the molecular mechanisms transducing environmental signals through YmoA remain elusive. Our study employs nuclear magnetic resonance spectroscopy, biological assays and RNA-seq analysis to elucidate these mechanisms. We demonstrate that YmoA undergoes structural fluctuations and conformational dynamics in response to temperature and osmolarity changes, correlating with changes in plasmid copy number, bacterial fitness and virulence function. Notably, chemical shift analysis identifies key roles of a few specific residues and of the C-terminus region in sensing both temperature and salt-driven switch. These findings demonstrate that YmoA acts as a central stress sensor in Yersinia, fine-tuning virulence gene expression and balancing metabolic trade-offs
A minimal model of cognition based on oscillatory and current-based reinforcement processes
No full textBuilding mathematical models of brains is difficult because of the sheer complexity of the problem. One potential starting point is basal cognition, which gives an abstract representation of a range of organisms without central nervous systems, including fungi, slime moulds and bacteria. We propose one such model, demonstrating how a combination of oscillatory and current-based reinforcement processes can be used to couple resources in an efficient manner, mimicking the way these organisms function. A key ingredient in our model, not found in previous basal cognition models, is that we explicitly model oscillations in the number of particles (i.e. the nutrients, chemical signals or similar, which make up the biological system) and the flow of these particles within the modelled organisms. Using this approach, our model builds efficient solutions, provided the environmental oscillations are sufficiently out of phase. We further demonstrate that amplitude differences can promote efficient solutions and that the system is robust to frequency differences. In the context of these findings, we discuss connections between our model and basal cognition in biological systems and slime moulds, in particular, how oscillations might contribute to self-organized problem-solving by these organisms
Expanding the motif-based interactome : Insights into the recognition landscape of deubiquitinases
No full textProtein-protein interactions (PPIs) are inherently dynamic and vital for maintaining normal cellular function. Short linear motifs (SLiMs), which are typically 3-10 amino acid long stretches, are present in intrinsically disordered regions (IDRs) and often serve as binding interfaces for PPIs. SLiM-mediated interactions are essential in various biological processes, such as cellular signaling, cell cycle progression and protein degradation. SLiMs play an important role in targeting E3 ligases to their substrates. They may also recruit deubiquitinating enzymes (DUBs) to their substrates, thereby reversing the action of E3 ligases by removing ubiquitin from target proteins. At present, only a fraction of the predicted SLiMs in the human proteome has been identified. Thus, it is important to develop and utilize methods to identify SLiM-based interactions and to gain further insights into the specificity determinants of the interactions. Proteomic peptide-phage display (ProP-PD) is a high-throughput method developed to capture motif-based PPIs. However, sometimes only a limited set of peptide ligands are identified from these experiments, rendering it challenging to define a consensus binding motif. We therefore developed a deep-mutational scanning (DMS) by peptide-phage display approach, which enables comprehensive examination of the effects of substitutions on peptide-protein interactions. Using the DMS protocol, we deciphered the binding determinants of motif-based interactions of two globular domains of the ubiquitin carboxyl-terminal hydrolase 8 (USP8). We uncovered that the MIT domain, which is a previously described motif-binding domain, binds to degenerate motif variants. Furthermore, we revealed a peptide binding capability of the Rhodanese domain and demonstrated that it recognizes more than one type of motif. The information enabled the prediction of potential binding sites in USP8 known interactors. Expanding the analysis to other DUBs, a screening for additional motif-binding auxiliary domains of proteins from the USP family was performed. Fourteen domains were found to bind to peptides, which expanded the previously unexplored landscape of DUB-motif recognition. The zf-UBP and DUSP2 domains of USP20 and USP33 were found to act as peptide-binding domains, recognizing novel consensus motifs. Finally, extending beyond DUBs, a contribution was made towards charting interactions for numerous peptide-binding domains. The research presented in this thesis, sheds light on the previously underexplored area of motif-recognition of DUBs and contributes towards expanding the motif-based map of the human interactome
Machine learning explainability for survival outcome in head and neck squamous cell carcinoma
No full textBackground: Diagnosis and treatment of head and neck squamous cell carcinoma (HNSCC) induces psychological variables and treatment-related toxicity in patients. The evaluation of outcomes is warranted for effective treatment planning and improved disease management. Objectives: This study aimed to build a prognostic system by combining clinicopathological parameters, treatment-related factors, and sociodemographic factors as integrative inputs to build a machine learning (ML) model to estimate the overall survival (OS) of patients with HNSCC. Furthermore, we explored the complementary prognostic potentials of these input parameters. We provide explainability and interpretability using Local Interpretable Model-agnostic Explanations (LIME) and SHapley Additive exPlanations (SHAP) techniques. Methods: A total of 419 patients with HNSCC were recruited from three University Hospitals in Sweden. We compared the performance of TabNet, a state-of-the-art deep learning algorithm for tabular data, with extreme gradient boosting (XGBoost) and voting ensemble to predict OS in patients with HNSCC. Results: Both TabNet and XGBoost showed comparable performance accuracies, with TabNet and XGBoost showing a performance accuracy of 88.1% each and voting ensemble showing an accuracy of 88.7%. The aggregate feature importance showed that p16 (a tumor suppressor protein that plays a crucial role in cell cycle regulation), cancer stage, hemoglobin, age at diagnosis, T class, N class, smoking pack-years, body mass index (BMI), treatment modality, erythrocyte count, and human papillomavirus (HPV) status were the most important parameters for the predictive ability of the model for OS. Furthermore, we found survival trends in this cohort by individually considering parameters such as p16, cancer stage, hemoglobin, age at diagnosis, HPV status, Tumor Nodal Metastasis staging, and socioeconomic factors (marital status, housing, and level of education). In addition, both the LIME and SHAP techniques showed the contribution of each feature to the prediction made by the model. Conclusions: The clinical implementation of an ML model can lead to individualized risk-based therapeutic decision-making. Therefore, validating these models with multiinstitutional datasets and testing them in the context of clinical trials is warranted for safe clinical implementation
The effect and cost-effectiveness of a group-based parenting intervention for parents of preschool children with subclinical neurodevelopmental disorders and mental health problems : protocol for a multiple-baseline single-case experimental design (SCED) with a pre-, post and follow-up
No full textBackgroundYoung children with subclinical neurodevelopmental disorders (NDDs) and concurrent emotional and behavioral problems (EBP) are at significant risk of negative short- and long-term outcomes. Although early parenting support interventions are recommended and requested, there is a lack of interventions specifically designed for this group and adapted to the Swedish context. Based on this gap, a parenting support intervention for parents with children aged 2-6 years with subclinical NDDs and EBP has been co-created with clinicians and parents. The project described in this study protocol aims to evaluate the effectiveness and cost-effectiveness of this new group-based parenting intervention.MethodsThe project uses a multiple-baseline single-case experimental design (SCED) with pre-post measures and a 3-month follow-up. The intervention is provided to families with children who are referred to child health psychologists at the child pediatric outpatient clinic in Uppsala Region, Sweden. Outcomes will include child EBP and parent self-efficacy, stress, well-being, and quality of life, as well as costs for the intervention, health care use, and QALYs.DiscussionThe project could lead to improved mental health in both children and parents through participation in the group-based parenting intervention. The study design, with longitudinal data from both children and/or their parents, will provide valuable insights into the trajectories of mental health and well-being within this group. In addition, the inclusion of young children as informants will provide important information about their experiences. Furthermore, the use of pre-, post- and follow-up questionnaires will allow reliable and clinically significant changes to be assessed and our findings to be compared with randomized trials in similar populations. The results of this project will be relevant to children with subclinical NDDs and their parents, as well as to health care organizations and the scientific community. The intervention is well adapted to the end users and the clinical context, as it has been co-created with clinicians and parents.Trial registrationISRCTN10835479 https://doi.org/10.1186/ISRCTN10835479, date of registration 2024-10-08
RNA Sequencing Reveals the Long Non-Coding RNA Signature in Psoriasis Keratinocytes and Identifies CYDAER as a Long Non-Coding RNA Regulating Epidermal Differentiation
No full textPsoriasis is a common chronic inflammatory skin disease determined by genetic and environmental factors, resulting in the activation of IL-23/IL-17-mediated immune response, epidermal hyperproliferation, and keratinocyte activation. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts > 500 nucleotides with diverse regulatory functions; their role in epidermal dysfunction in psoriasis is poorly understood. To identify epidermal transcripts with potential roles in psoriasis, including lncRNAs, we performed RNA sequencing on keratinocytes from psoriasis and healthy skin. We identified 889 differentially expressed lncRNAs, many of which with yet unknown functions. RP11-295G20.2 was identified as a lncRNA significantly induced in psoriasis keratinocytes, and this was verified by qRT-PCR and by single-molecule in situ hybridisation. Analysis of subcellular fractions of epidermis revealed a cytoplasmic localisation in line with results of single molecule in situ hybridisation. We report that RP11-295G20.2 has a skin-enriched expression, and within skin it is mainly expressed in suprabasal epidermal layers. Moreover, RP11-295G20.2 is induced by the key psoriasis cytokine IL-17A and shows a dynamic regulation during keratinocyte differentiation with upregulation during early differentiation and downregulation in the late stage. Knockdown of RP11-295G20.2 in keratinocytes promotes terminal differentiation. Based on our findings, we named RP11-295G20.2 Cytoplasmic Differentiation-Associated Epidermal RNA, CYDAER. In summary, our study provides a comprehensive characterisation of the non-coding RNA landscape of psoriasis keratinocytes and identifies CYDAER as a skin-enriched lncRNA regulating keratinocyte differentiation. Our data suggest that overexpression of CYDAER may contribute to altered differentiation in psoriatic epidermis