Biology subjects

Hassan, S.

Publications and source records attributed to Hassan, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Jade1S SUMOylates tau and targets oligomers for degradation

The accumulation of insoluble tau aggregates is a pathological hallmark of tauopathies, including Alzheimer's disease. While molecular chaperones and clearance pathways regulate tau homeostasis, the mechanisms governing tau oligomerization and degradation remain incompletely defined. Recent genome-wide association studies (GWAS) have linked the JADE1 locus to tauopathy, and the PHD zinc finger protein Jade1S has been identified in complexes with tau in post-mortem brain tissue, prompting investigation into their biochemical relationship. Here, we characterize the reciprocal interactions between Jade1S and 0N4R tau stability and turnover. Covalent labeling mass spectrometry and co-immunoprecipitation mappings reveal that Jade1S binds wild-type 0N4R tau through redundant sites within its N-terminal and plant homeodomain (PHD) zinc finger domains. In vitro assays demonstrate that Jade1S functions as a SUMO E3 ligase, utilizing its PHD domains to mediate tau SUMOylation. Cell-based cycloheximide chase assays reveal a reciprocal stabilization dynamic: tau co-expression extends the overall physiological half-life of Jade1S from less than an hour to ~17 hours, arresting its turnover specifically within sarkosyl-insoluble fractions. Conversely, Jade1S selectively accelerates the degradation of sarkosyl-insoluble tau without altering the turnover of the soluble monomeric pool over chased time. Mechanistically, Jade1S redirects the clearance of SUMO2/3-modified tau oligomers away from basal autophagic-lysosomal pathways and toward proteasome-dependent degradation. Furthermore, Jade1S exhibits intrinsic molecular chaperone activity, inhibiting arachidonic acid-induced tau oligomerization in vitro. Together, these data characterize Jade1S as a dual-function SUMO ligase and chaperone that regulates tau stability, prevents oligomer assembly, and promotes the targeted proteasomal clearance of aggregated tau.

biochemistry↗

bioRxiv2026

Targeting ribosome biogenesis sensitizes PARPi-resistant triple-negative breast cancer

Poly (ADP-ribose) polymerase inhibitors (PARPi) are the only targeted treatment available for early triple-negative breast cancer (TNBC), an aggressive subtype with limited treatment options. While PARPi are effective in patients with BRCA mutations, resistance to these inhibitors can arise. We previously developed BRCA-mutant cell lines, HCC1395, with acquired resistance to talazoparib and olaparib, and have now developed PARPi-resistant MX1 cell lines in an analogous manner. Ribosomal pathways were upregulated in 3/4 cell lines with acquired PARPi resistance. The resistant cell lines showed high and low basal nucleolar stress based on nucleolar morphology and nucleophosmin delocalization from nucleolus to nucleoplasm. Treatment of these cell lines with the combination of olaparib and a ribosome biogenesis inhibitor, BMH-21, demonstrated synergy in the PARPi-resistant cell lines, but not in the parental cells. Interestingly, HCC1395 cells, which had lower baseline nucleolar stress, showed greater nucleophosmin delocalization with combination treatment than MX1 cells, which had higher baseline nucleolar stress. All four cell lines demonstrated sustained DNA damage with the combination. We extended our investigation to 3 BRCA wild-type TNBC cell lines, BT549, Hs578T, and MDAMB231 and identified synergy in the context of intrinsic PARPi resistance. In MDAMB231 cells, combining olaparib with BMH-21 induced a senescence-like phenotype, increasing gH2AX-positive cells by up to 7.3-fold, senescence-associated B-galactosidase (SA-B-gal) staining by 5.6-fold, and p21 by 3.6-fold. These results were mirrored with a second ribosome biogenesis inhibitor, CX-5461. Finally, we identified distinct patterns of ribosomal pathway activity in a cohort of patients with treatment-resistant TNBC, and found correlations between ribosomal pathways with MYC, proliferation, DNA damage, and senescence. Together, these data identify ribosome biogenesis as a potential therapeutic vulnerability in PARPi-resistant TNBC and support its targeting in combination with PARPi, while demonstrating a broader for ribosome biogenesis in treatment-resistant TNBC.

cancer biology↗

bioRxiv2026

Computational Designing of a Multi-Epitope Vaccine Against Streptococcus pyogenes

Group A Streptococcus (GAS), or Streptococcus pyogenes is almost exclusive and greatly adapted human pathogen. It causes a wide array of clinical symptoms, ranging from minor infections of the skin and soft tissues to pharyngitis, meningitis, pneumonia, bacteraemia, cellulitis, puerperal sepsis, and necrotising fasciitis. The risk of S. pyogenes infection is known to be influenced by several host characteristics, including age, underlying diseases like diabetes, varicella, or skin lesions, both chronic and acute, and certain risk behaviours such as use of drugs. Household size and overcrowding are two environmental factors that significantly affect the transmission of S. pyogenes. The majority of cases occur spontaneously in the community, and preventative opportunities are still limited. A large portion of GAS-related mortality is found in low-income areas and communities. Based on aforementioned public health risk, the creation of effective therapeutic vaccines would be an excellent addition to current control measures. The purpose of this work is to address the need for new instruments to aid in the elimination of S. pyogenes infections. The discovery of high antigenic regions in several highly conserved proteins brings us one step closer to developing peptide vaccines capable of influencing the different phases of S. pyogenes infection, providing more effective defence and greater serotype coverage. This study used various techniques of immunoinformatics to design an effective multi-epitope vaccine that produced neutralising antibodies against multiple strains of S. pyogenes.

bioinformatics↗

bioRxiv2026

FEATMAP: Targeted Correction of Acquisition Signatures Harmonizes Medical Foundation Model Embeddings and Enables Robust Task Generalization

AO_SCPLOWBSTRACTC_SCPLOWMedical foundation models compress biomedical data into embeddings that support diverse downstream clinical tasks. However, successful model deployment is hampered by performance degradation on external data. It is recognized that embeddings capture acquisition signatures, such as hardware and technical differences, in addition to biology. Effective harmonization must remove the acquisition signature while preserving biological signals, a trade-off that current methods fail to balance adequately. Input-level normalization fails to eliminate acquisition signatures from embeddings, whereas embedding-level methods adjust features in an untargeted manner. We present FEATMAP, a harmonization approach that models acquisition signatures as geometric distortions between manifolds of similarly arranged embeddings. Using paired data that isolate the effect of acquisition signatures, FEATMAP fits a single global affine transformation per foundation model to correct acquisition signatures directly in the embedding space. This targeted, reusable correction aims to preserve biological and demographic variation while harmonizing across acquisition signatures. Across scanner and foundation-model harmonization in digital pathology and field-strength harmonization in brain MRI, FEATMAP improves cross-condition embedding similarity, reduces performance gaps without retraining, and suggests potential for the alignment of disparate embedding spaces.

bioinformatics↗

bioRxiv2026

CORe Designer: a CRISPR design tool for proteome engineering

Precision proteome engineering requires tools that leverage CRISPR technologies, yet most current design platforms remain gene-centric. To bridge this gap, we introduce CORe Designer. Featuring an intuitive graphical user interface, CORe Designer enables researchers to design guide RNAs and homology-directed repair templates in a protein-centric manner. By automating these workflows, CORe Designer enables the design of targeted mutagenesis experiments for precision proteome engineering to be completed in minutes.

bioengineering↗

bioRxiv2026

Paraventricular thalamus gates hippocampal coding of salient experiences.

Adaptive behavior requires neural circuits that encode salient stimuli to guide approach and avoidance. The hippocampal ventral subiculum (vSub) encodes information related to avoidance and reward seeking, yet how upstream inputs shape its representations of salient appetitive and aversive events remains unclear. Here, we show that a projection from the anterior paraventricular thalamus (PVT) to vSub carries an aversive-state signal that biases vSub representations toward threat-related information. In anxiety-provoking environments, anterior PVT to vSub activity is associated with avoidance behavior and enhanced vSub discrimination of threat and safety. During associative learning, this circuit preferentially promotes vSub responses to threat-predictive cues and aversive outcomes while constraining representations of rewarding stimuli. These findings refine canonical limbic circuit models by identifying a direct thalamic influence over hippocampal coding of rewarding versus aversive stimuli and the approach-avoidance behaviors they guide.

neuroscience↗

bioRxiv2026

Gene function and expression profiling in yeast spores, killifish diapause embryos, and their post-dormant offspring cells

Dormancy is a reversible cellular state characterised by suspended proliferation and increased stress resilience, enabling long-term viability under adverse conditions. Although dormant cells are critical for the life cycle of diverse organisms, from microbes to humans, they are understudied compared to proliferating cells. We present a comparative investigation of dormant cells in two divergent species: spores of fission yeast and diapause embryos of turquoise killifish. A genome-wide screen for genes affecting the lifespan and heat-shock resilience of spores uncovered a trade-off between longevity and heat resistance, and considerable differences in the genetic basis for lifespan between spores and chronologically aging yeast cells. RNA-seq and mass-spectrometry analyses revealed substantial transcriptomic and proteomic changes in spores and diapause embryos, with ribosomal proteins induced as transcripts but repressed as proteins. Transcriptomic regulation of biological processes, but less so of specific genes, is broadly conserved across yeast spores, killifish diapause, and human dormant cancer cells, including the induction of autophagy- and translation-related processes and the repression of cell cycle-related processes. Spores and diapause embryos modulate their transcriptomes and proteomes in response to heat stress and prolonged time. These RNA and protein expression changes are uncoupled and differ from aging-related expression signatures in yeast cells and adult fish. Cells derived from older or stressed spores retain phenotypic differences for several cell divisions, reflected in altered expression signatures, lifespan and stress resilience. Similarly, diapause duration and heat exposure are associated with long-term expression signatures in post-diapause embryos before hatching. This study highlights core biological processes and principles that are remarkably conserved in distinct types of dormant cells.

genetics↗

bioRxiv2026

Molecularly defined subpopulations of leptin receptor neurons dissociate the control of food intake from blood pressure

While previous studies have suggested that leptin regulates cardiovascular function independently of body weight, the specific leptin receptor (Lepr)-expressing neurons that mediate these distinct effects remain unknown. We found that genes located in blood pressure (BP)-associated genome-wide association study loci were regulated by leptin in Lepr and glucagon-like peptide-1 receptor (Glp1r)-expressing (LeprGlp1r) neurons. Ablating Lepr from these cells decreased BP despite causing hyperphagic obesity. Single-cell and spatial transcriptomics revealed that LeprGlp1r neurons segregate into two distinct subpopulations of cells located in the arcuate nucleus (ARC) and dorsomedial hypothalamic nucleus (DMH). Activating ARC LeprGlp1r neurons suppressed food intake without impacting energy expenditure or cardiovascular function. Conversely, DMH LeprGlp1r neurons increased energy utilization and BP without altering food intake. Our results identify distinct LeprGlp1r neuron subpopulations that dissociate the control of food intake from outputs related to sympathetic tone, including BP, suggesting the potential therapeutic utility of targeting of these subpopulations independently.

physiology↗

bioRxiv2025

ODDB: Ocular Disease Database for integrated analysis of ocular disease gene drug relationships

Ocular diseases such as age-related macular degeneration, glaucoma, diabetic retinopathy, and inherited retinal dystrophies are leading causes of vision loss worldwide, yet existing databases often address only limited aspects of these disorders. To fill this gap, we developed the Ocular Disease Database (ODDB), a web-based resource that integrates genes, biomarkers, variants, and drugs associated to ocular diseases. Data were systematically collected through literature mining of PubMed-indexed journals, the NCBI Gene Expression Omnibus (GEO), and drug regulatory agency datasets. Multi-omics, experimental, and clinical information were harmonized using standardized integration workflows. The database is organized according to two complementary ontologies: one based on the anatomical site of pathology (cornea, retina, optic nerve) and another on gene inheritance pattern. ODDB currently covers over 170 ocular diseases, more than 1190 genes, 2400+ variants, and 386 drugs, including both approved and investigational compounds. Each record includes detailed annotations of associated genes, variants, therapeutic targets, and mechanisms of action. The platform supports interactive querying and network-based visualization of disease-gene-drug relationships. All data was internally validated for accuracy and are compliant with FAIR principles, ensuring accessibility and interoperability. ODDB (https://www.oculardiseases.fi/) provides a comprehensive and standardized reference for exploring molecular mechanisms and therapeutic opportunities in ocular diseases.

bioinformatics↗

bioRxiv2025

The absence of collagen VI reduces systolic function but paradoxically increases Ca2+ release in the rat heart

Collagen VI has recently been strongly linked to poor outcomes in heart failure with preserved ejection fraction through increased endotrophin, a collagen VI-derived signalling molecule linked to fibrotic remodelling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to critical function in muscle physiology. However, the role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodelled T-tubules, suggesting a possible role in tubular structure and Ca2+ dynamics. To test this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1-/-) was generated in the rat. T-tubule structure and ryanodine receptor cluster organisation were unchanged, but echocardiography demonstrated reduced systolic function. Paradoxically, isolated cardiomyocytes from the Col6a1-/- rat had increased Ca2+ transient amplitude and increased sarcoplasmic reticulum Ca2+ load. {beta}-adrenergic stimulation further increased Ca2+ transient amplitude and was associated with diastolic Ca2+ release events in Col6a1-/- cardiomyocytes. The disturbed Ca2+ dynamics are remarkedly similar to defects found in cardiac myocytes of the MDX mouse that has non-functional dystrophin protein. Together, these data suggest that collagen VI contributes to regulation of Ca2+ signalling in the heart through its linkage to the dystrophin-glycoprotein complex.

physiology↗

bioRxiv2025

Regulation of Female Reproductive Aging by the Spag17 Gene

Reproductive aging in females is characterized by a decline in oocyte quantity and quality, as well as uterine and cervical dysfunction that contributes to infertility and pregnancy complications. To investigate mechanisms underlying reproductive aging, we explored the contribution of Spag17, a cilia-related gene associated with tissue homeostasis and fibrosis. Spag17 was expressed throughout the female reproductive tract; however, its expression declined with age in ovarian tissue, while high expression levels were observed in the cervix of young females during cervical tissue remodeling in the pre- and post-parturition periods. Loss of Spag17 in mice resulted in impaired fertility, obstructed labor, and maternal death. This phenotype was associated with accelerated ovarian aging, increased fibrosis, and cervical stiffness, further complicating parturition. At the molecular level, Spag17 loss activated key aging-associated pathways, including proinflammatory, profibrotic, and senescence signaling, suggesting that SPAG17 may be a critical player in female reproductive aging. TEASERSpag17 is a key modulator of female reproductive aging.

cell biology↗

bioRxiv2025

Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium

Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis1 and provide a niche that supports adjacent epithelial stem cells. Here we report that Pdgfra-expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra+ fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoids ex vivo. Genetic reduction of Cdx2 in the {beta}-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue in vivo. These results demonstrate that Pdgfra+ fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.

cancer biology↗

bioRxiv2025

A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists

GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and that mediate the physiologic control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem Glp1r neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Hence, we defined roles for AP and NTS Glp1r-expressing neurons (APGlp1r and NTSGlp1r neurons, respectively) in the physiologic control of body weight, the GLP1RA-dependent suppression of food intake, and the GLP1RA-mediated stimulation of aversive responses. While silencing non-aversive NTSGlp1r neurons interfered with the physiologic restraint of feeding and body weight, restoring NTSGlp1r neuron Glp1r expression on an otherwise Glp1r-null background failed to enable long-term body weight suppression by GLP1RAs. In contrast, selective Glp1r expression in APGlp1r neurons restored both aversive responses and long-term body weight suppression by GLP1RAs. Thus, while non-aversive NTSGlp1r neurons control physiologic feeding, aversive APGlp1r neurons mediate both the anorectic and weight loss effects of GLP1RAs, dictating the functional inseparability of these pharmacologic GLP1RA responses at a circuit level.

neuroscience↗

bioRxiv2025

A Cross-Species Atlas of the Dorsal Vagal Complex Reveals Neural Mediators of Cagrilintide's Effects on Energy Balance

Amylin analogs, including potential anti-obesity therapies like cagrilintide, act on neurons in the brainstem dorsal vagal complex (DVC) that express calcitonin receptors (CALCR). These receptors, often combined with receptor activity-modifying proteins (RAMPs), mediate the suppression of food intake and body weight. To understand the molecular and neural mechanisms of cagrilintide action, we used single-nucleus RNA sequencing to define 89 cell populations across the rat, mouse, and non-human primate caudal brainstem. We then integrated spatial profiling to reveal neuron distribution in the rat DVC. Furthermore, we compared the acute and long-term transcriptional responses to cagrilintide across DVC neurons of rats, which exhibit strong cagrilintide responsiveness, and mice, which respond poorly to cagrilintide over the long term. We found that cagrilintide promoted long-term transcriptional changes, including increased prolactin releasing hormone (Prlh) expression, in the nucleus of the solitary tract (NTS) Calcr/Prlh cells in rats, but not in mice, suggesting the importance of NTS Calcr/Prlh cells for sustained weight loss. Indeed, activating rat area postrema Calcr cells briefly reduced food intake but failed to decrease food intake or body weight over the long term. Overall, these results not only provide a cross-species and spatial atlas of DVC cell populations but also define the molecular and neural mediators of acute and long-term cagrilintide action.

bioinformatics↗

bioRxiv2024

PinkyCaMP a mScarlet-based calcium sensor with exceptional brightness, photostability, and multiplexing capabilities

Genetically encoded calcium (Ca2+) indicators (GECIs) are widely used for imaging neuronal activity, yet current limitations of existing red fluorescent GECIs have constrained their applicability. The inherently dim fluorescence and low signal-to-noise ratio of red-shifted GECIs have posed significant challenges. More critically, several red-fluorescent GECIs exhibit photoswitching when exposed to blue light, thereby limiting their applicability in all-optical experimental approaches. Here, we present the development of PinkyCaMP, the first mScarlet-based Ca2+ sensor that outperforms current red fluorescent sensors in brightness, photostability, signal-to-noise ratio, and compatibility with optogenetics and neurotransmitter imaging. PinkyCaMP is well-tolerated by neurons, showing no toxicity or aggregation, both in vitro and in vivo. All imaging approaches, including single-photon excitation methods such as fiber photometry, widefield imaging, miniscope imaging, as well as two-photon imaging in awake mice, are fully compatible with PinkyCaMP.

neuroscience↗

bioRxiv2024

Volumetric imaging and computation to explore contractile function in zebrafish hearts

Despite advancements in cardiovascular engineering, heart diseases remain a leading cause of mortality. The limited understanding of the underlying mechanisms of cardiac dysfunction at the cellular level restricts the development of effective screening and therapeutic methods. To address this, we have developed a framework that incorporates light field detection and individual cell tracking to capture real-time volumetric data in zebrafish hearts, which share structural and electrical similarities with the human heart and generate 120 to 180 beats per minute. Our results indicate that the in-house system achieves an acquisition speed of 200 volumes per second, with resolutions of up to 5.02 {+/-} 0.54 {micro}m laterally and 9.02 {+/-} 1.11 {micro}m axially across the entire depth, using the estimated-maximized-smoothed deconvolution method. The subsequent deep learning-based cell trackers enable further investigation of contractile dynamics, including cellular displacement and velocity, followed by volumetric tracking of specific cells of interest from end-systole to end-diastole in an interactive environment. Collectively, our strategy facilitates real-time volumetric imaging and assessment of contractile dynamics across the entire ventricle at the cellular resolution over multiple cycles, providing significant potential for exploring intercellular interactions in both health and disease.

bioengineering↗

bioRxiv2024

Representations of stimulus meaning in the hippocampus

The ability to discriminate and categorize the meaning of environmental stimuli and respond accordingly is essential for survival. The ventral hippocampus (vHPC) controls emotional and motivated behaviors in response to environmental cues and is hypothesized to do so in part by deciphering the positive or negative quality of these cues. Yet, what features of the environment are represented in the activity patterns of vCA1 neurons, and whether the positive or negative meaning of a stimulus is present at this stage, remains unclear. Here, using 2-photon calcium imaging across six different experimental paradigms, we consistently found that vCA1 ensembles encode the identity, sensory features, and intensity of learned and innately salient stimuli, but not their overall valence. These results offer a reappraisal of vCA1 function, wherein information corresponding to individual stimulus features and their behavioral saliency predominates, while valence-related information is attached elsewhere.

neuroscience↗

bioRxiv2024

Targeting FEN1 to enhance efficacy of PARP inhibition in triple-negative breast cancer

Patients with triple-negative breast cancer (TNBC) have limited targeted therapeutic options. PARP inhibitors (PARPi) have demonstrated an important role for BRCA-mutant patients with early TNBC. Combination approaches with PARPi can broaden the use of PARPi to a larger cohort of TNBC patients. We selected six genes from our previously identified 63-gene signature that was associated with PARPi response. siFEN1 increased cells in G2/M arrest, DNA damage and particularly apoptosis. Targeting FEN1 with a chemical inhibitor enhanced the efficacy of PARPi in 7/10 cell lines, and synergy was demonstrated mainly in PARPi-resistant TNBC cell lines. A BRCA2-mutant cell line with acquired resistance to olaparib (HCC1395-OlaR) was strongly synergistic, with a combination index value of 0.20. The combination of PARPi and FEN1 inhibition also showed synergy in a PARPi-resistant xenograft-derived organoid model. Two mechanisms which explain the underlying efficacy are rapid progression in DNA replication fork speed and enhancement of DNA damage. The combination induced the highest fork speed (47% difference in comparison to control, P<0.0001) when FEN1 inhibition and PARPi equally increased fork speed individually in a cell line with a pre-existing increase in replication stress. The combination also increased DNA damage at lower drug concentrations, driving response in most of the synergistic cell lines. Gene expression analysis suggested that the sensitizing role of FEN1 inhibition in PARPi-resistant cell lines may be due to downregulation of pathways including mismatch repair. Therefore, targeting FEN1 shows great therapeutic potential as a targeted combination approach, particularly in the context of PARPi-resistant TNBC.

cancer biology↗