Biology subjects

Manzl, C.

Publications and source records attributed to Manzl, C..

5 recordsLinked to original sources

bioRxiv2025

Ultrasensitive saliva-based detection of early Alzheimer's disease biomarkers via nanoparticle-enhanced evanescent scattering microscopy

Alzheimers disease (AD) is the most common neurodegenerative disease, yet early diagnosis remains a major challenge. Current cerebrospinal fluid (CSF) assays are invasive and unsuitable for large-scale or repeated screening. Blood-based biomarkers have achieved sensitivities above 90%, but still face challenges of standardization, cost, technical complexity, and the need for sophisticated instrumentation. Saliva offers an attractive, non-invasive solution; however, the low concentrations of AD biomarkers have thus far hindered its clinical applicability. Here, we introduce a saliva-based diagnostic platform that combines Total Internal Reflection Scattering (TIRS) microscopy with antibody-functionalized metallic nanoparticles (NPs), for ultrasensitive, real-time quantification of salivary amyloid-{beta} (A{beta}) proteins. Using two established AD mouse models (APPsl and 5xFAD), we found that salivary A{beta}2 levels robustly distinguish transgenic from wild-type animals and correlate with brain amyloid deposition. Pooled and stratified analyses suggest these associations are primarily driven by the transgenic-wild-type contrast rather than linear changes within groups. Predictive modeling further confirmed diagnostic utility: in APPsl, Logistic Regression and Support Vector Machine (SVM) classifiers both achieved 92% accuracy with balanced sensitivity and specificity, while in 5xFAD, SVM reached 88% accuracy with perfect specificity. These results establish the NPs-enhanced TIRS sensor as a rapid, accurate and non-invasive tool for AD detection via saliva. By addressing a critical unmet need in neurodegenerative disease screening, this platform has strong potential to transform early diagnosis, enable timely interventions, and support biomarker-guided clinical trials. Its simplicity, speed, and scalability, make it well-suited for point-of-care diagnostics and large-scale screening initiatives. One Sentence SummaryUltrasensitive saliva test detects early Alzheimers biomarkers using nanoparticle-enhanced scattering microscopy

biochemistry↗

bioRxiv2025

IBDome: An integrated molecular, histopathological, and clinical atlas of inflammatory bowel diseases

Multi-omic and multimodal datasets with detailed clinical annotations offer significant potential to advance our understanding of inflammatory bowel diseases (IBD), refine diagnostics, and enable personalized therapeutic strategies. In this multi-cohort study, we performed an extensive multi-omic and multimodal analysis of 1,002 clinically annotated patients with IBD and non-IBD controls, incorporating whole-exome and RNA sequencing of normal and inflamed gut tissues, serum proteomics, and histopathological assessments from images of H&E-stained tissue sections. Transcriptomic profiles of normal and inflamed tissues revealed distinct site-specific inflammatory signatures in Crohns disease (CD) and ulcerative colitis (UC). Leveraging serum proteomics, we developed an inflammatory protein severity signature that reflects underlying intestinal molecular inflammation. Furthermore, foundation model-based deep learning accurately predicted histologic disease activity scores from images of H&E-stained intestinal tissue sections, offering a robust tool for clinical evaluation. Our integrative analysis highlights the potential of combining multi-omics and advanced computational approaches to improve our understanding and management of IBD.

molecular biology↗

bioRxiv2024

TXNIP mediates LAT1/SLC7A5 endocytosis to reduce amino acid uptake in cells entering quiescence

Entry and exit from cellular quiescence require dynamic adjustments in nutrient acquisition, yet the mechanisms by which quiescent cells downregulate amino acid (AA) transport remain poorly understood. Here, we demonstrate that cells entering quiescence select plasma membrane-resident AA transporters for endocytosis and lysosomal degradation, to match AA uptake with reduced translation. We identify the -arrestin TXNIP as a key regulator of AA uptake during quiescence, since it mediates the endocytosis of the SLC7A5-SLC3A2 (LAT1-4F2hc) transporter complex in response to reduced AKT signaling. Mechanistically, TXNIP interacts with HECT-type ubiquitin ligases to facilitate transporter ubiquitination. Loss of TXNIP disrupts this regulation, resulting in dysregulated AA uptake, sustained mTORC1 signaling, and accelerated quiescence exit. A novel TXNIP loss-of-function mutation in a patient with severe metabolic disease further supports its role in nutrient homeostasis and human health. These findings highlight TXNIPs role in controlling SLC7A5-SLC3A2 mediated AA acquisition with implications for quiescence biology and disease.

cell biology↗

bioRxiv2024

The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development

The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and ploidy can help developing new heart regenerative therapies. Here, we uncover that the PIDDosome, a multi-protein complex activating the endopeptidase Caspase-2, helps to implement a CM-specific differentiation program that limits ploidy during postnatal heart development. DNA content analyses show that PIDDosome-loss causes a cell-autonomous increase in nuclear and cellular CM ploidy. Remarkably, increased ploidy does not affect cardiac structure nor function. PIDDosome-imposed ploidy restriction commences at postnatal day 7 (P7), reaching a plateau on P14. PIDDosome activation requires ANKRD26, targeting PIDD1 to mother centrioles. Opposite to prior observations in liver development, the PIDDosome limits CM polyploidization in a p53-independent manner but reliant on p21/Cdkn1a, a notion supported by nuclear RNA sequencing and genetic deletion experiments. Our results provide new insights how proliferation of polyploid CMs is restricted during postnatal heart development.

developmental biology↗

bioRxiv2018

Checkpoint kinase 1 is essential for fetal haematopoiesis and hematopoietic stem cell survival

Checkpoint kinase 1 is critical for S-phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumour cells have developed a strong dependence on CHK1 for survival and hence this kinase has developed into a popular drug-target. Chk1-deficiency in mice results in blastocyst death due to G2/M checkpoint-failure showing that it is an essential gene and may be difficult to target therapeutically without side-effects. Here, we show that chemical inhibition of CHK1 kills murine hematopoietic stem and progenitor cells (HSPCs) as well as human CD34+ HSPCs by the induction of BCL2-regulated but p53-independent apoptosis. Moreover, Chk1 is essential for stem cell survival and definite hematopoiesis in the mouse embryo. Remarkably though, cell death inhibition in hematopoietic stem cells (HSC) cannot restore blood cell formation in utero as Chk1 loss causes severe DNA damage that ultimately prevents HSC expansion. Our findings establish a previously unrecognized role for CHK1 in establishing hematopoiesis; they also suggest adverse effects of therapeutic CHK1-inhibtion, particularly under conditions forcing stem cells out of dormancy, such as chemotherapy-induced myelosuppression.

developmental biology↗