Biology subjects

Koenig, J.

Publications and source records attributed to Koenig, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Emotion Dysregulation Links Interoceptive Accuracy and Vagal Activity to Psychopathology in Male but not Female Adolescents

Background: Emotion dysregulation is common across psychiatric disorders, but the biological mechanisms underlying emotional vulnerability remain poorly understood. Cardiac vagal regulation and interoception, the perception of bodily signals, may jointly contribute to emotion regulation. We examined whether their interaction is associated with emotion dysregulation and psychopathology in adolescents receiving psychiatric inpatient treatment. Methods: We studied 279 adolescent psychiatric inpatients. Cardiac vagal regulation was assessed using heart rate variability and interoceptive accuracy using a measure of bodily signal perception. Structural equation modeling tested associations between cardiac vagal regulation, interoceptive accuracy, emotion dysregulation, depressive symptoms, and personality dysfunction, including sex specific pathways and interactions. Results: Here we show that associations between autonomic regulation, interoception, and psychopathology differ by sex. In male adolescents, lower cardiac vagal regulation is associated with greater emotion dysregulation, which is associated with higher depressive symptoms and greater personality dysfunction. These associations depend on interoceptive accuracy and are most evident at low to intermediate levels of bodily signal perception. Comparable pathways are absent in female adolescents. Conclusions: These findings indicate that interactions between cardiac regulation and bodily signal perception contribute to emotional vulnerability in a sex-dependent manner. Altered body-brain communication may contribute to divergent developmental pathways of psychopathology. Integrating sex specific autonomic and interoceptive processes may improve models of emotion regulation and psychiatric risk during adolescence.

neuroscience↗

bioRxiv2026

Postnatal Autonomic Development Predicts Adolescent Psychosocial Outcome

BackgroundThe maturation of the autonomic nervous system (ANS) has been suggested to play a crucial role in the development of emotion regulation and later psychosocial functioning. However, longitudinal evidence linking early autonomic development to long-term outcomes remains limited. This longitudinal study investigated the interplay between birth-related factors, early autonomic activity, and psychosocial outcomes across development. MethodsThe sample comprised 101 participants followed from two weeks to 14 years of age, with heart rate (HR) and vagally ediated heart rate variability (vmHRV) assessed at 2 weeks, 6 weeks, 3 months, 14 months, and 14 years. Linear models were used to examine associations between birth-related factors and early HR and vmHRV, as well as whether HR and vmHRV trajectories during the first 14 months predicted psychosocial outcomes at 5 and 14 years. ResultsMultiple birth-related factors significantly predicted HR and vmHRV at two weeks after birth. Moreover, flatter age-related increases in vmHRV and weaker decreases in HR during infancy predicted higher maternally reported psychosocial difficulties at 14 years in males only, with no such effects at 5 years or in females. ConclusionsThese findings underscore the importance of early autonomic maturation in shaping later psychosocial functioning, with effects on adolescent outcomes observed in males only. Early ANS trajectories may represent meaningful predictors of neurodevelopmental outcomes, highlighting their potential relevance for early identification of later psychosocial risk in a sex-specific manner.

physiology↗

bioRxiv2026

Cortical Thinning Predicts Resting Vagally Mediated Heart Rate Variability: A Longitudinal Study Across Adolescent Development

IntroductionVagally mediated heart rate variability (vmHRV) reflects parasympathetic cardiac control and serves as a peripheral marker of brain-body interaction. While studies in adults link higher vmHRV to greater cortical thickness regions related autonomic regulatory, little is known about its association with longitudinal cortical maturation during puberty, a period of pronounced cortical thinning. MethodsThis longitudinal study examined whether individual differences in cortical thinning trajectories are associated with vmHRV in two independent cohorts of children and adolescents. Structural MRI were acquired in an accelerated longitudinal design over three time points, each one year apart in two cohorts (n = 44; ages 9 and 12 at baseline). Cortical thickness was estimated using FreeSurfer, and annualized regional thinning slopes were derived for 62 cortical regions. vmHRV was measured one year later at follow-up. Elastic net regression with stability selection identified robust predictors, which were entered into linear models separately for each cohort. ResultsAcross both cohorts, vmHRV was associated with distributed patterns of cortical thinning. Consistent associations emerged in medial and posterior midline regions, including the precuneus, isthmus of the cingulate cortex, and medial prefrontal and orbitofrontal areas. Associations showed heterogeneous directions across regions, contrasting with uniform adult findings. DiscussionvmHRV may be linked to network-level cortical maturation during adolescence, particularly within default mode and fronto-limbic systems. Findings extend adult work by demonstrating that brain-autonomic coupling emerges during development and is characterized by regionally differentiated trajectories of cortical thinning.

neuroscience↗

bioRxiv2026

Thymus Involution across the Human Menstrual Cycle

Structured AbstractO_ST_ABSImportanceC_ST_ABSThymic involution in humans has traditionally been conceptualized as a linear, age-associated process. Animal studies suggest transient hormone-dependent fluctuations in thymus size during reproductive transitions, including across the estrous cycle, but translational evidence in humans remains limited. ObjectiveTo determine whether thymus size changes across the menstrual cycle in healthy women and whether these changes are associated with fluctuations in estradiol and progesterone levels. DesignObservational repeated-measures study using quantitative computed tomography (qCT). Data were collected as part of an imaging study examining menstrual cycle-related physiological variation. Participants underwent assessments during menses and the early luteal phase within the same menstrual cycle. Mixed-effects models with robust variance estimation evaluated associations between cycle phase, hormonal contraception, reproductive hormone levels, and thymus size. Thymus segmentation was independently conducted by 2 blinded raters. SettingSingle-center university-based imaging study conducted at the University of Iowa. ParticipantsThirty-one non-smoking women with regular menstrual cycles were included, of whom n = 16 used oral hormonal birth control and n = 15 did not use hormonal contraception. Exclusion criteria included pregnancy, breastfeeding, postmenopausal status, diabetes, body mass index greater than 30 kg/m2, hysterectomy, or use of long-term noncyclic hormonal contraception. Participants tracked menstrual cycles using temperature monitoring and ovulation kits before completing visits during menses and the early luteal phase. All participants provided informed consent before study participation. Main Outcomes and MeasuresPrimary outcome was thymus size measured in mm3 using ultra-low-dose qCT imaging. Secondary outcomes included serum estradiol and progesterone levels. ResultsEstradiol levels increased from menses to the early luteal phase independent of hormonal contraceptive status. Progesterone levels were significantly lower among women using hormonal birth control. Thymus size differed significantly by hormonal contraceptive group, with larger thymus volumes observed among women not using hormonal birth control. Among women not using hormonal contraception, 66.7% demonstrated thymic involution from menses to the early luteal phase, compared with 37.5% of women using hormonal contraception. Estradiol and progesterone significantly interacted in predicting thymus size. Conclusions and RelevanceThese findings provide first-in-human evidence suggesting that thymus involution demonstrates short-term dynamics across the menstrual cycle and may be influenced by reproductive hormones and hormonal contraception. Key PointsO_ST_ABSQuestionC_ST_ABSDoes thymus size change dynamically across the human menstrual cycle in association with fluctuations in reproductive hormones and hormonal contraception use? FindingsIn this repeated-measures quantitative computed tomography study of n = 31 healthy women, thymus size demonstrated within-person variation across the menstrual cycle. Greater thymic involution was associated with larger increases in estradiol, whereas increases in thymus size were associated with larger increases in progesterone; thymus size also differed significantly by hormonal contraceptive status. MeaningThese findings suggest that thymic involution in humans may demonstrate short-term hormone-dependent dynamics beyond age-related atrophy, with potential implications for sex differences in immune regulation and inflammatory disease.

physiology↗

bioRxiv2026

Urban green space exposure reduces subjective stress and physiological arousal

Stress is a major risk factor for mental disorders, and urban living is a key environmental contributor. Nature exposure may promote stress recovery and mental health, but how physiological arousal and subjective stress change across green versus gray space during naturalistic urban mobility is poorly understood. This preregistered study (https://doi.org/10.17605/OSF.IO/HF4RW) employed geolocation-based ambulatory assessment to examine psychophysiological arousal and subjective stress during transitions between urban green and gray environments. Thirty-six healthy urban residents completed a counterbalanced circular walking route in Cologne, Germany, with continuous GPS, cardiovascular, and electrodermal recording alongside ecological momentary assessment of subjective stress, affect, and exertion. Green compared to gray spaces were associated with lower subjective stress and higher affective well-being, with cardiac indices reflecting reduced autonomic arousal during green space exposure. Autonomic changes surrounding environmental transitions persisted beyond the immediate transition window, suggesting that physiological benefits of green space exposure extend into subsequent gray environments. These findings underscore the public health potential of urban green infrastructure for preventing stress-related mental health conditions.

physiology↗

bioRxiv2026

Cyst-type epithelial heterogeneity shapes therapeutic responsiveness in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) exhibits substantial interpatient variability in disease course and therapeutic response, but the cellular basis for this variability remains poorly understood. Here, we combine single-nucleus RNA sequencing of human cyst epithelia with machine learning-based histological analysis of >1,800 cysts to resolve three epithelial cyst types--proximal tubule-like, collecting duct-like, and mixed. These cyst types display distinct injury states, metabolic programs, and stromal microenvironments, including a mixed-cyst niche enriched for CCL2-associated inflammatory signaling. Expression of key therapeutic targets was highly cell-type specific with CFTR enriched in proximal-like epithelia, whereas AVPR2 expression was confined to AQP2-positive collecting duct-like cells. Cyst-type composition varied widely across patients and in an orthologous mouse model (Pkd1RC/RC) in which the burden of AQP2-positive cysts correlated with responsiveness to tolvaptan. These findings identify cyst-type heterogeneity as a major determinant of molecular pathway activation and predictability of therapeutic response in ADPKD.

molecular biology↗

bioRxiv2026

Linking human brain functional connectivity to underlying neurotransmission

The human brain is organized into interacting functional systems. Their underlying neurobiological mechanisms remain difficult to study in vivo. Here, we adopt a topological framework to quantify the association between neurobiology and brain functional connectivity derived from both resting-state fMRI and MEG. Across six healthy adult cohorts (n = 19-112), regional variation in fMRI connectivity robustly aligns with the distribution of neurotransmitter receptors and transporters. These patterns are present in every single subject, replicate across all cohorts, and are mirrored in MEG. Most prominently, noradrenergic modulation of connectivity in a sensorimotor-insular network is consistently detected across individuals and linked to autonomic arousal. In pharmacological and clinical samples, associations are sensitive to neurotransmitter system manipulation and are altered in early psychosis, aligning with clinical symptomatology. These findings provide biological insight into typical and atypical functional organization of the human brain using a framework linking underlying neurobiology to the functional connectome (NEOFC).

neuroscience↗

bioRxiv2026

iCLIP3: A streamlined, non-radioactive protocol for mapping protein-RNA interactions in cellular transcripts at single-nucleotide resolution

UV-C crosslinking and immunoprecipitation (CLIP)-based methods are the gold standard for identifying direct RNA binding protein (RBP) interaction sites on cellular RNA in vivo. Here, we describe individual-nucleotide resolution CLIP version 3 (iCLIP3), an optimized protocol for generating transcriptome-wide maps of RBP-RNA interaction sites at single-nucleotide resolution from low-input material. iCLIP3 introduces several key improvements over previous iCLIP variants, including rapid and safe infrared-based visualization of RBP-RNA complexes, silica column-based RNA isolation, and the incorporation of TruSeq adapter sequences with unique dual indexing. These modifications streamline library preparation, facilitate multiplexing, and enable concurrent sequencing of iCLIP3 libraries alongside unrelated RNA-seq libraries. In addition, we provide a detailed bioinformatics workflow for identifying crosslinking events and defining RBP binding sites. The complete protocol can be performed within 4-5 days, offering a robust and efficient approach for high-resolution mapping of RBP-RNA interactions. HighlightsO_LI3' RNA labeling with pCp-IR750 enables rapid infrared visualization of RBP-RNA complexes C_LIO_LISilica column-based RNA isolation improves efficiency and reproducibility C_LIO_LITruSeq adapters with unique dual indexing enable flexible and scalable multiplexing C_LIO_LIiCLIP3 generates high-quality libraries from ultra-low amounts of cellular material C_LI

genomics↗

bioRxiv2026

RNA G-quadruplexes mediate cooperativity in HNRNPH binding and splicing regulation

Alternative splicing, regulated by RNA-binding proteins (RBPs), enables the generation of diverse transcript isoforms critical for cellular function. However, how RNA secondary structure impacts RBP binding and function remains poorly understood. Here, we unravel how RNA G-quadruplexes (rG4s) facilitate cooperativity in splicing regulation by the RBP heterogeneous nuclear ribonucleoprotein H (HNRNPH). Through high-throughput in vivo and in vitro studies combined with theoretical modeling, we dissect how rG4s mediate cooperative HNRNPH binding to RNA, ultimately modulating the splicing of hundreds of exons. rG4 unfolding by HNRNPH exposes multiple G-rich binding sites, thereby establishing indirect cooperativity, which is further amplified to achieve switch-like splicing regulation. HNRNPH-mediated regulation is evident in breast cancer patients, with tumors showing rG4-disrupting variants and global HNRNPH alterations, driving distinct splicing patterns that distinguish tumor subtypes. Overall, our findings offer valuable insights into the mechanistic role of RNA secondary structures in cooperative RBP binding and splicing regulation and highlight the clinical relevance of HNRNPH-dependent splicing in cancer. HighlightsO_LIHundreds of cassette exons are cooperatively regulated by HNRNPH. C_LIO_LIUnfolding of RNA G-quadruplexes (rG4s) at HNRNPH binding sites facilitates indirect cooperativity in RNA binding. C_LIO_LIMulti-step splicing amplifies the response into highly switch-like regulation. C_LIO_LIrG4-disrupting variants and changing HNRNPH expression are associated with breast cancer phenotypes. C_LI

molecular biology↗

bioRxiv2026

SLBP-independent control of maternal histone mRNA

Replication-dependent (RD) histones are crucial for packaging newly replicated DNA into chromatin, ensuring genome stability. In metazoans, the mRNA of RD histones is uniquely regulated through a conserved 3' stem-loop bound by stem-loop binding protein (SLBP). This allows cell cycle-coupled regulation of these important transcripts. However, oocytes must stabilise histone mRNAs independently of the cell cycle to ensure maternal loading to support the first embryonic divisions. Using Caenorhabditis elegans as a model system, we discovered an SLBP-independent mechanism that ensures RD histone transcript stability during oogenesis. This is mediated by the protein complex PETISCO, bound to the effector protein TOST-1, which directly binds the histone stem-loop region and maintains maternal histone mRNA levels during oogenesis and early embryogenesis. Loss of this mechanism disrupts histone homeostasis, leading to premature genome activation, mitotic defects, and embryonic lethality. Interestingly, the same complex, PETISCO, acts in piRNA biogenesis when bound to the effector PID-1, revealing an intriguing co-option of this histone mRNA homeostasis mechanism by the piRNA pathway. Our findings reveal a unique SLBP-independent mechanism of histone mRNA regulation, that served as a basis for the evolution of a novel piRNA biogenesis mechanism.

molecular biology↗

bioRxiv2025

Ghrelin and risky decision-making: No credible evidence for homeostatic state modulation of neural or behavioural effects

Risk-taking is often thought to depend on homeostatic systems. However, evidence remains mixed, and the underlying mechanisms remain debated. One candidate that might drive changes in risky decision-making due to changes in homeostatic systems may be the hunger hormone ghrelin, which interacts with the dopaminergic system. In two studies, we examined the effects of experimental interventions known to affect ghrelin levels on human risky choice in healthy male participants, either after a brief fasting period (study 1, N = 37; N = 26 for fMRI analyses) or a single night of total sleep deprivation (study 2, N = 40; N = 36 for fMRI analyses). We found no credible effects of the experimental manipulations on the proportion of risky choices. In addition, computational modelling indicated that the standard prospect theory, without accounting for choice repetition, best described the observed behaviour. However, it did not reveal consistent effects of state manipulations on model parameters, and the inclusion of manipulation-induced changes in ghrelin levels in the model likewise revealed no robust associations. FMRI analyses did not reveal effects of state manipulation on neural signatures of subjective value or choice in a priori defined regions of interest (bilateral ventromedial prefrontal cortex, ventral striatum, posterior cingulate cortex, and anterior cingulate cortex for subjective value; bilateral anterior insula, ventral striatum, and right medial prefrontal cortex for choice). Our results suggest that state-dependent influences on risky decision-making may be weaker than previously thought.

neuroscience↗

bioRxiv2025

Replating induces mTOR-dependent rescue of protein synthesis in Charcot-Marie-Tooth diseased neurons

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy characterized by sensory dysfunction and muscle weakness, manifesting in the most distal limbs first and progressing more proximal. Over a hundred genes are currently linked to CMT with enrichment for activities in myelination, axon transport, and protein synthesis. Mutations in tRNA synthetases cause dominantly inherited forms of CMT and animal models with CMT-linked mutations in these enzymes display defects in neuronal protein synthesis. Rescuing protein synthesis in CMT mutant neurons could offer exciting therapeutic options beyond symptom management. To address this need, we expressed CMT-linked variants in tyrosyl tRNA synthetase (YARS-CMT) in primary sensory neurons and evaluated impacts on protein synthesis and cell viability. YARS-CMT expression reduced protein synthesis in these neurons prior to the onset of caspase-dependent axon degeneration and cell death. To determine how YARS-CMT expression affects axon outgrowth, we dissociated and replated these neurons to stimulate axon regeneration. To our surprise, axonal regrowth occurred normally in replated YARS-CMT neurons. Moreover, replating YARS-CMT neurons rescued protein synthesis. Inhibiting mTOR suppressed rescue of protein synthesis after replating, consistent with its significant role in protein synthesis during axon regeneration. These discoveries identify new avenues for augmenting protein synthesis in diseased neurons and restoring protein synthesis in CMT or other neurological disorders.

neuroscience↗

bioRxiv2025

Context-dependent effects of mutations on complex splicing decisions

Alternative pre-mRNA splicing is an essential step in human gene regulation, and mutation-induced aberrant splicing is frequently found in diseases and therapy resistance. Splicing regulation is highly dependent on sequence and cellular context, posing a challenge to predict outcomes of splicing-related disease mutations. Here, we use kinetic modeling to derive the underlying quantitative principles, describing splice site competition and downstream effects on a wide spectrum of splice isoforms. Employing statistical learning on a large-scale mutagenesis dataset for CD19 mRNA splicing, our model quantitatively describes the generation of 93 RNA isoforms. It takes into account various splicing events such as cassette exon skipping, intron retention, and extensive alternative 3 and 5 splice site usage, which are implicated in CART therapy resistance in leukemia. Beyond CD19, by analyzing genome-wide RNA sequencing data and large-scale screening of synthetic splicing decisions, we find that splice site distance is an important parameter controlling the switch from canonical to alternative/cryptic splice site usage, as mutations located in between two nearby splice sites show a pronounced directionality, regulating up- and downstream effectors in opposite direction. Taken together, our work demonstrates that a quantitative description of splice site competition provides insights into context-dependent, complex isoform changes and cryptic splice site activation in health and disease.

systems biology↗

bioRxiv2025

Dissecting the RNA binding capacity of the multi-RRM protein Rrm4 essential for endosomal mRNA transport

RNA-binding proteins (RBPs) utilize multiple RNA-binding domains (RBDs) to engage with extensive mRNA networks. Understanding the intricate interplay of modular RBDs is essential for uncovering RBP function. Yet, how individual RBDs shape transcriptome-wide interactions remains poorly understood. Here, we dissect the roles of the three RNA recognition motifs (RRMs) in the endosomal mRNA transporter Rrm4 during polar growth of Ustilago maydis. Using a comparative mutant-based iCLIP2 approach, we disclose an extensive inventory of RRM-specific binding sites. Most binding sites are prominently governed by RRM3, however, they are not critical for function. Conversely, functionally essential binding sites are recognized by a more complex RBD interplay, involving RRM1 and/or RRM2 with partial support from RRM3. By integrating transcriptome-wide RNA binding data with transcriptomics, we pinpoint their function as regulatory RNA elements affecting mRNA abundance, linking endosomal transport to stability. The modular RNA binding of Rrm4 defines distinct RNA regulons controlling mitochondrial activity, polarity factors, and cell wall remodeling - processes critical for polar growth. These findings disclose the intricate binding modes of an RBP in vivo, emphasizing how multiple RBDs differentiate functional binding sites from accessory ones to determine mRNA fate. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/636894v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1af77b6org.highwire.dtl.DTLVardef@dc7178org.highwire.dtl.DTLVardef@9d7ebforg.highwire.dtl.DTLVardef@1ec5a05_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO C_FIG

molecular biology↗

bioRxiv2024

Coordinated alternative splicing decisions via stepwise exon definition

Alternative splicing of pre-mRNA is a fundamental step in human gene regulation and aberrant slic-ing is tightly linked to diseases including cancer. Various splicing events, such as alternative exon (AE) choice and intron retention (IR), are controlled by a common molecular machinery, the spliceo-some. However, it remains elusive how the regulation of spliceosome activity coordinately affects these splicing decisions. Here, we analyze a large-scale mutagenesis screen and genome-wide RNA sequencing data to show that IR and AE choice are tightly coupled, as IR products primarily accu-mulate in alternative exons showing intermediate inclusion levels. Using data-driven mathematical modeling, we reveal that multistep exon recognition by the spliceosome explains the observed AE-IR dependency for cis-acting sequence mutations and upon knockdown of trans-acting RNA-binding proteins. Furthermore, we show that multistep exon definition is frequently perturbed in cancer cells, which leads to the coordinated deregulation of intron retention and AE choice. In conclusion, we showed that the spliceosome coordinates complex splicing decisions via stepwise exon definition, which potentially facilitates the search for common molecular mechanisms for mis-splicing in cancer.

systems biology↗

bioRxiv2024

Microbial iCLIP2: Enhanced mapping of RNA-Protein interaction by promoting protein and RNA stability

The entire RNA lifecycle, spanning from transcription to decay, is intricately regulated by RNA-binding proteins (RBPs). To understand their precise functions, it is crucial to identify direct targets, pinpoint their exact binding sites, and unravel the underlying specificity in vivo. Individual-nucleotide resolution UV crosslinking and immunoprecipitation 2 (iCLIP2) is a state-of-the-art technique that enables the identification of RBP binding sites at single-nucleotide resolution. However, in the field of microbiology, optimized iCLIP protocols compared to mammalian systems are lacking. Here, we present the first microbial iCLIP2 approach using the multi-RRM domain protein Rrm4 from the fungus Ustilago maydis as an example. Key challenges such as inherently high RNase and protease activity in fungi were addressed by improving mechanical cell disruption and lysis buffer composition. Our modifications increased the yield of crosslink events and improved the identification of Rrm4 binding sites. Thus, we were able to pinpoint that Rrm4 binds the stop codons of nuclear-encoded mRNAs of mitochondrial respiratory complex I, III and V - revealing an intimate link between endosomal mRNA transport and mitochondrial physiology. Thus, our study serves as a paradigm for optimizing iCLIP2 procedures in challenging organisms or tissues under high RNase/ protease conditions.

molecular biology↗

bioRxiv2024

An atlas of RNA-dependent proteins in cell division reveals the riboregulation of mitotic protein-protein interactions

Ribonucleoprotein complexes are dynamic assemblies of RNA with RNA-binding proteins (RBPs), which can modulate the fate of the RNA molecules from transcription to degradation. Vice versa, RNA can regulate the interactions and functions of the associated proteins. Dysregulation of RBPs is linked to diseases such as cancer and neurological disorders. RNA and RBPs are present in mitotic structures like the centrosomes and spindle microtubules, but their influence on mitotic spindle integrity remains unknown. Thus, we applied the R-DeeP strategy for the proteome-wide identification of RNA-dependent proteins and complexes to cells synchronized in mitosis versus interphase. The resulting atlas of RNA-dependent proteins in cell division can be accessed through the R-DeeP 3.0 database (R-DeeP3.dkfz.de). It revealed key mitotic factors as RNA-dependent such as AURKA, KIFC1 and TPX2 that were linked to RNA despite their lack of canonical RNA-binding domains. KIFC1 was identified as a new interaction partner and phosphorylation substrate of AURKA at S349 and T359. In addition, KIFC1 interacted with both, AURKA and TPX2, in an RNA-dependent manner. Our data suggest a riboregulation of mitotic protein-protein interactions during spindle assembly, offering new perspectives on the control of cell division processes by RNA-protein complexes. HighlightsO_LIDifferential R-DeeP screens in mitosis and interphase are provided as a resource in a user-friendly database at R-DeeP3.dkfz.de C_LIO_LIAn atlas of RNA-dependent proteins in cell division identifies a substantial number of unconventional RNA-binding proteins among mitotic factors C_LIO_LIInvestigation of protein-protein interactions reveals KIFC1 as a new AURKA and TPX2 interaction partner during spindle assembly C_LIO_LIKIFC1, AURKA and TPX2 interact with each other in an RNA-dependent manner and directly bind to RNA C_LIO_LIAURKA phosphorylates KIFC1 at residues S349 and T359 C_LI

cell biology↗

bioRxiv2024

T-cell development and activation in humanized mice lacking mouse major histocompatibility complexes

Humanized mice transplanted with CD34+ hematopoietic progenitor cells (HPCs) are used to study human immune responses in vivo. However, the mismatch between the mouse major histocompatibility complexes (MHCs) and the human leukocyte antigens (HLAs) is not optimal for T-cell development and can trigger xenograft reactivity. We evaluated human T-cell development in NOD.Scid.Gamma mice lacking expression of MHC class I and II (NSG-DKO). Human leukocyte engraftment was detectable at 8 weeks post-transplantation. Human CD4+ and CD8+ T-cells were detectable in blood, thymus, bone marrow and spleen of humanized NSG-DKO mice for up to 20 weeks post-transplantation. Further, we evaluated the effects of lentiviral vector (LV) systemic delivery of HLA-A*02:01, HLA-DRB1*04:01, human GM-CSF/IFN- and the human cytomegalovirus gB antigen. LV delivery promoted development and activation of human central memory, {beta} and {gamma}{delta} T-cells with amplifications of the T-cell repertoire. LV administration unleashed multiple reactome pathways such as type-I interferon responses, cell cycle and metabolic processes. In summary, development of human T-cells in humanized mice does not rely on mouse MHCs and can be boosted systemically via LV administration.

immunology↗