iScience

Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions. HighlightsO_LISex chromosome aneuploidy induces cell-type specific changes in gene expression C_LIO_LIDampening of the inactive X chromosome in XXY alleviate X overexpression C_LIO_LIHigh Y-linked gene expression in XXY neuronal precursor cells but not cardiomyocytes C_LIO_LISex chromosome aneuploidy disrupts sex biases in autosomal gene expression C_LI

Planarian flatworms represent one of the most evolutionarily informative nervous systems for an account of ancient bilaterian brains. Likewise, the unparalleled regenerative ability of planarians makes possible certain investigations of neural development, memory, and behavior that are simply impossible with other model organisms. Despite these facts, learning and memory are today underexplored in planarians, likely due in part to the shadow of controversial 20th-century experiments on the transfer of memories between individual flatworms. Here, we attempted to replicate and extend the classical conditioning experiments in planarians that were the basis of the later memory transfer work. We failed to find evidence for classical conditioning in any of our procedural variations and obtained similar results using computer vision methods to avoid subjectivity in manual video annotation. Our results cast doubt on the suitability of planarian flatworms for studying primitive learning processes and the molecular basis of memory using classical conditioning.

The central role of microglia in CNS function in health and disease has resulted in large interest in targeting microglial as treatments for neurodegenerative disease; understanding the factors that regulate microglial gene expression will be crucial to this goal. microRNAs (miRNAs) are among the most abundant post transcriptional regulators of gene expression. miRNAs suggests miRNA were likely key to significant evolutionary events as regulators of gene expression. The miRNAome of microglia is critical to their correct functioning but the miRNA that define microglia identity and regulate key functions have not been fully defined. In this study we performed a detailed analysis of the microglial miRNAome to identify miRNA enriched in microglia that are conserved across species (human, mouse, and xenopus). We further characterised the expression of these conserved miRNAs during demyelination and remyelination and identified conserved function of a microglial-enriched miRNA across species. These findings reveal evolutionary conservation of specific miRNAs, suggesting an important role in establishing and maintaining microglial identity. They also highlight miRNAs that may be critical for microglial function in the central nervous system in both health and disease. Overall, this work advances our understanding of the factors that regulate microglial gene expression.

Zebrafish have been used a prominent model for high-throughput phenotypic screens of candidate risk gene mutations for several disorders. This also includes models for attention deficit/hyperactivity disorder (ADHD). Traditional behavioural tests, such as the forced light/dark assay, concentrate on basic locomotion measures. However, recently developed visually-driven locomotion assays, for example closed-loop systems using virtual reality, have allowed extraction of richer data on animal locomotion and decision-making under different sensory stimuli. Here, we have used such a system to assess the behaviour in adgrl3.1 mutant fish, an established model for ADHD. Our results show that mutants exhibit a higher baseline excitability and a lower threshold for initiating motor events, demonstrating that collecting behavioural responses in an interactive environment enables a more precise characterisation of ADHD-relevant phenotypes associated with adgrl3.1 disruption. More generally, we establish a scalable translational platform to screen gene-function relationships and possible therapeutic interventions, not only for ADHD but multiple neurodevelopmental disorders.

Cancer cells exposed to nutrient deprivation activate adaptive programs to survive metabolic stress, often acquiring enhanced plasticity and motility. We have previously reported that colon cancer cell lines that survived nutrient depletion underwent partial epithelial-mesenchymal transition (pEMT), which was further exacerbated when these cells also underwent lysosomal alkalinization. Here, we have attempted to dissect the molecular mechanisms that drive the motility and shape change from cobblestone to elongated in subpopulations of cells. Using RNA-seq-based bioinformatic analyses integrated with pathway scoring, protein-protein interaction networks, probabilistic modeling and confirmatory experimental data, we have identified the coordinated activation of sublethal apoptotic signaling, fatty acid oxidation, mitochondrial ROS generation, and Ca{superscript 2}-dependent lysosomal exocytosis in the nutrient-depleted cells. Among these phenotypes, the cells undergoing starvation and lysosomal alkalinization exclusively mediated lysosomal exocytosis and cell motility. Probabilistic modeling further revealed non-linear relationships between metabolic stress signals and cell fate transitions, highlighting heterogeneous lysosomal functions as a key determinant of the altered phenotype of cells under nutrient depletion. Overall, our study has identified that aberrant lysosomal functioning in cells under nutrient depletion can specifically select for a subpopulation of cells that are highly viable, metabolically plastic and capable of motility.

O_LICardiac rate and rhythm reveal how animals adapt physiologically to day-to-day challenges, with consequences for health and fitness. However, these data remain difficult to collect in wild animals, despite their relevance for individual health and fitness. C_LIO_LIHere, we present a system for collecting and transmitting long-term, fine-scaled physiological data in wild animals. We implanted Bluetooth-enabled cardiac and physiological monitor devices in three wild adult female baboons in the Amboseli ecosystem in Kenya and paired these devices with collars that enabled remote data downloads over long-range wide area network (LoRaWAN). C_LIO_LIThe system performed well over >10 months, providing the first long-term cardiac data in wild primates. The baboons showed strong circadian patterns in heart rate, heart rate variability, and activity. We also present data on one female who left her social group for unknown reasons; while alone she exhibited higher heart rate variability, lower activity, and evidence of disrupted sleep. C_LIO_LIIn sum, physiologgers paired with low-energy methods of remote data retrieval are powerful tools for investigating physiology in wild animals on timescales that extend over many months, with minimal disruption to their behavior. C_LI

Breast cancer is globally the most common cancer among women. Although the five-year survival rate exceeds 80% for patients with localized disease, it drops to approximately 30% once metastasis occurs, underscoring the urgent need to define mechanisms that drive metastatic progression. Breast is a highly innervated organ and most of its innervation is sensory. However, whether sensory neurons can directly impact breast cancer cells remains an understudied topic. Here, we show that mammary tumors have increased CGRP sensory innervation. Using our novel microfluidic Device for Cancer cell-Axon Interaction Testing (DACIT), we demonstrate that the presence of axons strongly inhibits ECM-degrading ability of cancer cells. The sensory neuron secretome suppresses assembly and function of invadopodia, which are cancer cell protrusions controlling ECM degradation, and essential for intravasation and metastasis. We identify calcitonin gene-related peptide (CGRP) as the key component of the sensory neuron secretome responsible for the inhibitory effect. CGRP signaling occurs through the CRLR/RAMP1 receptor complex expressed by breast cancer cells, inducing a rapid increase in intracellular cAMP levels in breast cancer cells, followed by an increase in RhoC activity and suppression of invadopodia and ECM degradation. Loss of RAMP1 function enhances 3D spheroid invasion, cancer cell motility in vivo and significantly increases the number and the size of lung metastatic foci. Consistently, in silico analyses of both mouse and human RNASeq data point to a link between increasingly invasive subtypes with a gradual decrease in expression of RAMP1 and CRLR. To validate in silico findings, we compare RAMP1 expression in the patient breast tumors with adjacent normal tissues, confirming the invasive breast tumors have reduced levels of RAMP1. Together, our findings identify a protective role for the paracrine CGRP signaling in limiting breast cancer invasion and metastasis. We also demonstrate how cancer cells circumvent CGRP inhibition by suppressing RAMP1 expression, highlighting CGRP-RAMP1-cAMP axis as a potential therapeutic target in breast cancer.

Neural circuit assembly relies on different neuronal subtypes coming together to form a functional circuit. The question of how the appropriate number of each subtype is integrated into an emerging circuit remains relatively unknown. To answer this question, we used the mouse retina to uncover the molecular mechanisms responsible for neuron subtype integration in a developing circuit. In the mammalian retina, bipolar neurons are a class of interneurons that relay visual information from photoreceptors to ganglion cells. Extensive studies have shown there are 15 distinct bipolar subtypes: 6 types of OFF cone bipolars, 8 types of ON cone bipolars, and 1 type of rod bipolar. During retinal development, bipolar neurons are born in excess and through programmed cell death, a precise number of each subtype remains to give rise to the retinal circuit. Although this process has been well-described, little is known about the key molecules responsible for bipolar subtype integration in the developing retina. Our work uncovered a new role for the autism-associated risk gene, Protocadherin 9 (Pcdh9) in bipolar subtype integration. Deletion of Pcdh9 using a floxed allele leads to loss of OFF and ON cone bipolars; however, disruption in the extracellular binding of Pcdh9 leads to selective loss of ON cone bipolars but not rod bipolars. Moreover, we found this later function of Pcdh9 is mediated by homophilic interactions between ON cone bipolars and their known synaptic partners. Taken together, our work revealed a new role for Pcdh9 in bipolar subtype integration during retinal development. SUMMARY STATEMENTNeural circuits are comprised of multiple neuronal subtypes where a specific number need to come together to give rise to a functional circuit. Although this is a critical process during neurodevelopment, little is known about the molecular mechanisms that determines the precise number of each subtype during circuit development. In the present study, we identified the autism risk gene, Protocadherin 9 as a critical molecule in subtype integration of bipolar neurons within the developing mouse retina. Using newly generated mouse lines, we found distinct requirements of Pcdh9 to promote survival in different bipolar subtypes during retinal circuit assembly. The significance of this work is that it shed lights into how different neuronal subtypes are integrated in nascent neural circuits.

A distinctive feature of bodily experience is its transparency. During skilled action, our limbs recede from awareness and function as the medium of interaction rather than perceptual objects1. This is reflected in systematic perceptual biases: humans reliably underestimate the weight of their own hands2, potentially reflecting predictive motor processes that modulate self-generated sensory signals. Wearable technologies may test the limits of this perceptual transparency. Exoskeletons and other augmentative devices attach directly to the body, adding mass that must be integrated into sensorimotor control3; yet little is known about how such devices are experienced as they become integrated into the sensorimotor system. Here, we tested whether training with finger-extending exoskeletons alters their perceived weight and whether such changes depend on active use. We developed a Bayesian analytic framework combining individual psychometric modelling with a regression-based decomposition of perceived weight, to partition contributions of the biological hand and attached exoskeletal device. Thirty-four right-handed adults completed a weight-perception task before and after 20 minutes of training with either finger-extending or non-augmenting control devices. Participants compared the perceived weight of their right hand, with or without the exoskeleton, to reference weights suspended from the opposite wrist. Before training, the weight of both the biological hand and the exoskeleton were underestimated to a similar degree ([~]25- 30%), suggesting rapid perceptual integration following attachment. Training selectively increased attenuation of the perceived weight of the finger-extending exoskeleton, with no corresponding change for the biological hand and little evidence for a general training effect. These findings support a two-stage embodiment process in which passive attachment initiates perceptual updating, while sensorimotor training consolidates integration through functional interaction with the device. Perceived weight thus provides a behavioral marker of embodiment, offering insight into how the sensorimotor system integrates wearable augmentative technologies.

A long-standing hypothesis in sensory neuroscience suggests that the evolutionary expansion of cortex in mammals may contribute to sensory-dependent adaptation by acting on subcortical pathways that drive innate behavior. However, direct experimental evidence is lacking. Taking the visual system as a model, it is known that there is significant interaction between the evolutionarily conserved Superior Colliculus (SC) and the comparatively modern Visual Cortex (VC), key structures in the mammalian visual system. In the SC, local alignment is established between a retinotopic map of the visual field and a map of orienting movement vectors during development and drives accurate visually guided orienting behavior throughout an organisms lifespan. Interestingly mammals, like humans and non-human primates, readily adapt to altered visual experiences, while evolutionarily older vertebrates, like amphibians, lack this behavioral plasticity. To address this outstanding question, we have developed a novel behavioral paradigm for inducing visuomotor adaptation in freely moving mice that is analogous to paradigms utilized in primates. Our paradigm combines a visually guided orienting task and a novel mouse prism goggle system to shift the visual field. Using this paradigm, we demonstrate for the first time that mice gradually adapt to a chronic shift of their full visual field, suggesting this type of behavioral plasticity is conserved across mammalian species. Furthermore, we show that lesioning primary visual cortex (V1) prior to shifting the visual field disrupts normal visuomotor adaptation, suggesting that VC may play a generative role in the plasticity of fundamental visually guided behaviors. These findings lend support to the hypothesis that a particular evolutionary benefit of sensory cortex is the allowance for experience-dependent behavioral plasticity.

Staphylococcus aureus (S. aureus) is an opportunistic pathogen that is a global health concern for its ability to cause a wide spectrum of clinical infections. Due to the emergence of resistance to commonly used antibiotics, there has been interest in exploring the use of antimicrobial peptides to treat S. aureus infections. However, changes in the lipid composition of the lipid bilayer membrane can alter the activity of peptides, and S. aureus is able to induce variations in lipid composition in response to environmental stress. Here, we explore how the main lipid components in S. aureus are altered when exposed to LL-37, a human cathelicidin involved in primary immune response, and ATRA-1, a short antimicrobial peptide derived from the snake Naja atra venom. A lipidomic study is conducted through HPLC-MS-MS (LC-ESI-MS/MS) to quantify phosphatidylglycerol, cardiolipin, lysyl-phosphatidylglycerol, monogalacto- and digalacto-diacylglycerol, and carotenoids. In addition, menaquinones, responsible for electron transport during oxidative phosphorylation, were also quantified. Biophysical properties such as membrane electric surface potential and lipid packing were assessed. We find that lipid adaptation is specific to the type of antimicrobial peptide, where ATRA-1 mainly induces changes in the electric surface potential through variations in Lysyl-PG, while exposure to LL-37 changes carotenoid levels, inducing an increase in membrane rigidity as measured by FTIR. In addition, both peptides induce a reduction in menaquinone and DGDG levels. These findings highlight the role of membrane lipid remodeling as a peptide-specific response mechanism in S. aureus, with implications for the development of AMP-based therapies. HighlightsO_LIStaphylococcus aureus responds through shifts in lipid composition and membrane biophysical properties to exposure to the antimicrobial peptides LL-37 and ATRA-1. C_LIO_LIBoth LL-37 and ATRA-1 lead to shifts in the glycolipids MGDG and DGDG; two lipids involved in regulating negative membrane curvature stress and responsible for shifting resistance to antimicrobial peptide activity in Staphylococcus aureus. C_LIO_LILL-37 treatment leads to an overall reduction in carotenoid content in Staphylococcus aureus, including the carotenoid end-product staphyloxanthin and the precursor 4,4-diaponeurosporenoic acid. Both lipids regulate membrane biophysical properties and protect Staphylococcus aureus from oxidative stress. C_LIO_LIBoth LL-37 and ATRA-1 lead to a reduction in menaquinone levels, which are involved in the electron transport chain during oxidative phosphorylation. Reduction in these menaquinones have been associated to the formation of small colony variants that are often observed in chronic Staphylococcus aureus infections. C_LI

Aging reshapes the cellular and molecular landscape of mammalian tissues. These changes can be progressive, preceding linearly with age, or occur as abrupt transitions of the course of lifespan. To investigate the age-dependent cellular and molecular shifts we profiled matched proteomes and transcriptomes from male and female murine spleens across eight time points, from stable adults through late life. The spleen was chosen to integrate understanding of age-dependent changes associated with immune surveillance, inflammaging, and immune-related proteostasis. Male and female mice follow distinct aging trajectories particularly in protein-RNA correlation in late life, reflecting both compositional shifts and failure of post-transcriptional buffering. To investigate whether these changes could be attributed to specific cell-types within the spleen, we developed Celestial, a machine-learning framework to identify cell-type-specific changes in bulk tissue samples. We found that age-related bulk molecular changes could be attributed in part to compositional remodeling of cell-types--expansion of GZMK+ CD8+ T cells and C1Q+ macrophages alongside naive T cell and global B cell loss. These results demonstrate that cell-type-aware interpretation can inform bulk multi-omic data for accurate mechanistic inference in heterogeneous tissues undergoing complex molecular remodeling.

Stratified epithelial tissues such as the skin epidermis maintain barrier integrity during development and homeostasis through the coordinated action of cell proliferation, differentiation, delamination, and tissue-scale mechanical forces. During development, the orientation of cell division within the basal layer plays a pivotal role in tissue stratification; however, the mechanical principles linking the orientation of the division plane to these processes across developmental stages remain poorly understood. Here, we expand a recently developed three-dimensional vertex model for stratified epithelia, composed of the basement membrane, basal, and suprabasal layers, to study the mechanical and structural impact of cell divisions with a wider range of orientations. The model integrates developmental stage via specific changes in heterotypic interfacial tensions (arising from actomyosin cortical contractility and adhesion molecules at the basal-suprabasal interface) and tissue stiffness that have been quantified previously in experiments. By systematically varying background mechanical parameters, we investigate how heterotypic tension, division orientation, and tissue fluidity collectively influence the outcome of cell division. Our goal is to uncover the strategies that the embryo may employ to generate stratified phenotypes at different developmental stages, recognizing that these strategies might evolve over time. Although our focus is on the embryonic developmental stages of the epidermis, this framework may also be extended to investigate transformed cells, such as in cancer, to explore how altered division orientation contributes to precancerous or transformed phenotypes.

The human auditory system decomposes complex sounds into distinct components via a collection of processing steps. Knowing whether Spiral Ganglion Cells (SGCs) play an active role in the decoding of complex sounds can facilitate the development of Cochlear Implant (CI) coding strategies and clinical assessment tools. Early animal studies reported SGCs being similar across different characteristic frequencies (CFs). In this study, human electrically evoked compound action potentials (eCAPs) were analysed to probe the relationship between the reciprocal of CF and the duration of the eCAP. A significant relationship could indicate that SGCs may not simply be passive cables. eCAP datasets from 6 published studies (175 CI users, 1243 recordings) were analysed and their peaks were automatically labelled. The n1p2 latency was derived for each recording as a proxy of the action potential duration. The CF of each recording was estimated by mapping the average insertion angle of the electrode to the human SGC map. A weak but statistically significant relationship was observed between the n1p2 latency and the reciprocal of CF (random-effects model with random intercepts for subject, r = 0.09, p = 0.024, n= 450) supporting the hypothesis that lower CF is associated with slower repolarisation (longer n1p2 latency) in human spiral ganglion cells.

Both splicing and kinase signaling are biochemical processes that fundamentally determine and shape cell physiology. Although there has been some indication that there is an interaction between the two - splicing can alter the availability of exons encoding kinase targets and kinases can phosphorylate splicing factors - it has yet to be established the extent to which altering splicing factor expression impacts kinase signaling networks. In this work, we implemented a data-driven analysis using ENCODE RNA-sequencing data and prior work mapping post-translational modifications onto splice events to identify candidate splice factor perturbations that show extensive alterations to phosphorylation-encoding protein products. We then replicated the ENCODE knockdown experiments and performed global phosphoproteomics for two candidates, U2AF1 and SRSF3, complementing the transcription-level data. Both knockdowns showed extensive changes in phosphorylation and kinase activities, both basally and upon receptor tyrosine kinase stimulation. U2AF1 knockdown drove decreased JNK-associated cell death signaling but elevated chromosome regulation through CSNK2A1, PLK, and EIF2AK4 activity. SRSF3 knockdown, on the other hand, led to decreased cell cycle signaling through CDK and HIPK2 but increased cytoskeletal signaling through various PAKs. In addition, we found a striking enrichment of phosphorylated splicing regulators in both knockdowns that were linked to their splicing activity, such as HNRNPC, suggesting potential feedback and crosstalk between splice factors through signaling pathway activation. Importantly, comparison of differential phosphorylation measurements from this study to mRNA expression and splicing measurements from ENCODE revealed significant knockdown-dependent protein regulation, not captured by transcriptomic measurements alone, underscoring the value of phosphoproteomic profiling after splice factor perturbations. Combined, the transcriptomics and phosphoproteomics reveal deep interconnection between the two processes that are relevant to understanding cell signaling in health and disease.

The tumor microenvironment (TME) is a complex ecosystem composed of tumor cells, cancer-associated fibroblasts (CAFs), immune suppressive cells, and the extracellular matrix (ECM), playing a crucial role in tumor development and CAR-T cell therapy efficacy. CAR-T therapy has shown promise in hematological malignancies but faces challenges in solid tumors due to the TMEs ability to suppress CAR-T cell infiltration, proliferation, and cytotoxicity. Traditional drug evaluation models, such as 2D cell cultures and animal models, have significant limitations due to oversimplification of the in vivo environment or physiological differences between species. Organoid models offer a more biomimetic approach but often fail to fully recapitulate the TMEs complexity and heterogeneity. Our research developed a tumor organoid and CAF co-culture model using the IBAC co-culture chip, demonstrating that CAFs significantly impact CAR-T cell therapy efficacy by forming physical (e.g., fibronectin) and chemical (e.g., IL-10) barriers that prevent CAR-T cell infiltration and cytotoxicity. This model provides a high-biomimetic platform for investigating the TMEs effects on CAR-T therapy and highlights the importance of incorporating a comprehensive stromal component into in vitro models to enhance their predictive power for cancer treatment.

An increasing number of studies highlight the role of saccadic remodulation in compensatory mechanisms following vestibular injury, and the reappearance of SHIMP saccades correlates with symptom improvement measured by the Dizziness Handicap Inventory (DHI). To investigate the influence of attentional processes and working memory on visuo-vestibular interaction, three independent but interrelated experiments were conducted. In the first two experiments, healthy subjects and patients with unilateral or bilateral vestibular deficits underwent vHIT in SHIMP mode and the Functional Head Impulse Test (fHIT), performed first separately and subsequently simultaneously. Mean latency and clustering of SHIMP saccades, together with Landolt C recognition rates, were analyzed. Differences between separate and combined protocols were assessed, and, in patients, correlated with symptom severity measured by the DHI, to determine whether the near-simultaneous execution of tasks mediated by shared parietal cortical substrates influenced performance. In the third experiment, vHIT in HIMP mode and fHIT were performed using separate and combined protocols to evaluate whether recognition-related cognitive load affected recovery saccade latency and clustering. Results suggest that visual recognition modulates visuo-vestibular interaction, supporting integrated dual-task protocols for ecological balance assessment and helping explain clinical discrepancies.

Bimodal gene expression systems have played a major role in uncovering the function of genes, cells and organ systems during and after development. Employed initially in model systems such as flies and mice, advances in gene technology have vastly expanded the number of species in which these systems can be deployed. One of their limitations is the challenge of imposing temporal expression control. Here, we report the incorporation of temperature-sensitive intein modules with different temperature profiles into QF2, the transcription factor anchoring the Q-system widely used in Drosophila and introduced recently into several insect species and the zebrafish D. rerio. Intein removal from temperature-sensitive QF2_INTts activators in Drosophila larvae and adult flies raised under permissive conditions (18{degrees}C to 25{degrees}C) renders QF2 active and drives strong expression of QUAS reporters. In contrast, raising Drosophila at restrictive temperatures (23{degrees}C to 30{degrees}C) keeps QF2_INTts in a non-functional state unable to bind DNA and therefore, keeping QUAS reporters inactive. We further show that reporter expression can be turned on and off both during development and in flies by changing temperature conditions between restrictive to permissive. Finally, QF2_INTts animals carrying QUAS-Kir2.1 encoding the inward rectifying potassium channel raised under restrictive conditions are fully viable, while raised at or moved as adults to permissive temperature results in embryonic lethality or leads to paralysis. Thus, the intein-based Q-system renders the difficult to employ drug-dependent suppressor QS unnecessary, greatly facilitating temporal regulation of gene expression. Having several advantages over the GAL4 system, the Q system has gained broad acceptance in other insect species and the zebrafish D. rerio, and thus QF2_INTts drivers can be implemented in many other organisms, including disease-transmitting mosquitoes and poikilotherm vertebrate animals much more closely related to humans, to study gene and cell function at any time during or after development.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and continues to face low treatment-trial participation, fragmented evidence workflows, and labor-intensive ab- straction of unstructured clinical text. Existing oncology-focused language models show promise, but many depend on private institutional corpora, limiting reproducibility and practical reuse across centers. We present Onca, an open 9B dense model designed for four PDAC-relevant tasks: trial eligibility screening, case-specific clinical reasoning, structured pathology report extraction, and molecular variant evidence reasoning. Onca is fine-tuned from Qwopus3.5-9B-v3 with a single Un- sloth BF16 LoRA adapter on 37,364 training rows drawn from openly available sources. The evalu- ation spans 11 panels and compares Onca against Woollie-7B, CancerLLM-7B, OpenBioLLM-8B, and the unmodified Qwopus base. Onca achieves the strongest overall results on Trial Screening (81.6 F1), Clinical Reasoning (14.1 composite), Pathology Extraction (30.5 field exact-match), Pub- MedQA Cancer (68.3 macro-F1), and PubMedQA (66.5 macro-F1). The strongest gains appear in tasks closest to routine oncology workflow, especially trial review and pathology structuring. These findings suggest that clinically targeted pancreatic-cancer language models can be built from open data with competitive performance while remaining practical to train on a single workstation-scale GPU setup.

Kaposis Sarcoma Herpesvirus (KSHV), an enveloped double-stranded DNA virus, is the etiological agent of Kaposis sarcoma (KS), an endothelial cell-based tumor. KSHV is a leading cause of infection-related cancers in sub-Saharan Africa and immunocompromised individuals worldwide. Therefore, it is vital to identify the underlying mechanisms of viral infection and transmission to effectively identify specific therapeutic strategies and combat the disease. Here, we demonstrate that KSHV rewires the host cell lipidome during lytic infection. Bulk lipidomic analysis shows significant changes in the abundance of neutral lipids and phospholipids during lytic infection. We further investigated fatty acid-binding proteins (FABPs) to understand the underlying mechanisms that support KSHV pathogenesis. Using the doxycyclin-inducible iSLK.BAC16 cell line, we find that FABP genes are differentially regulated by lytic KSHV infection compared to latent infection. We report that FABP4 is significantly upregulated during lytic infection. Loss of FABP4 during lytic infection does not impact viral gene transcription however, lytic protein translation is reduced. Moreover, our intracellular and extracellular viral titers indicate that FABP4 affects maximal infectious virion production. This study highlights the role of FABP4 and its therapeutic potential as a target that facilitates KSHV infection and pathogenesis.