Biology subjects

Huber, N.

Publications and source records attributed to Huber, N..

8 recordsLinked to original sources

bioRxiv2026

Orally available designed miniproteins inhibit enterotoxigenic Bacteroides fragilis pathology by blocking toxin receptor binding

Toxigenic bacterial infections in the gut are a significant contributor to the global burden of disease. Advanced tools for protein and live biotherapeutic engineering offer potentially transformative strategies for treating such diseases, while avoiding the collateral effects of traditional antibacterials. Here we used de novo protein design to identify inhibitors of the metzincin family protease Bacteroides fragilis toxin (BFT). These inhibitors, which bind distal to the active site, interfere with toxin-mediated E-cadherin cleavage and downstream proinflammatory signaling by blocking claudin-4 receptor binding. We tested the inhibitors as disulfide-stabilized variants administered directly to the cecum or in drinking water, as well as through in situ secretion by an engineered live biotherapeutic. Across these delivery modalities, the inhibitors successfully neutralized the toxin and effectively prevented BFT-associated gut pathology, including tumor formation. These results highlight the potential of de novo designed proteins as precise, non-antibiotic interventions to mitigate bacterial toxin-driven disease in the gut.

microbiology↗

bioRxiv2026

Loss of competitive strength in European conifer species under climate change

Climate change is expected to alter species assemblages by affecting the outcome of competition between species. Investigating processes of competition remains challenging particularly in tree communities, as they unfold over extensive spatio-temporal scales. Here, we developed a deep-learning approach to leverage a novel database of 135 million simulated local-scale tree responses to climate across continental Europe to investigate changes in the competitiveness of nine major tree species under different scenarios of climate change. Specifically, we trained a Deep Neural Network on local process model projections to investigate climate change effects on indicators of competitive strength and species dominance. We found decreasing competitive strength for all investigated evergreen coniferous species across their distribution, while major deciduous broadleaved species such as Quercus robur and Fagus sylvatica increased in competitiveness. Changes in tree species competition with climate differed locally, but most investigated species lost competitive strength at their warm range edges. As a consequence of these changes, up to 19% of Europes forests could experience a change in the dominant tree species until the end of the 21st century. Our results suggest a profound climate-induced reassembly of Europes forests and identify areas that may require specific attention in forest policy and management.

ecology↗

bioRxiv2024

C9orf72 repeat expansion-carrying iPSC-microglia from FTD patients show increased phagocytic activity concomitantly with decreased number of autophagosomal-lysosomal vesicles

C9orf72 hexanucleotide repeat expansion (HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The role of microglia in these C9orf72 HRE-associated diseases is understudied. To elucidate effects of C9orf72 HRE on microglia, we have characterized human induced pluripotent stem cell-derived microglia (iMG) from behavioral variant frontotemporal dementia (bvFTD) patients carrying the C9orf72 HRE. C9orf72 HRE iMG were compared to iMG from healthy controls and sporadic bvFTD patients. The phenotypes of iMG were analyzed using bulk RNA sequencing, biochemical and immunofluorescence analyses, and live cell imaging. C9orf72 HRE-carrying iMG showed nuclear RNA foci and poly-GP dipeptide repeat proteins but no decreased C9orf72 mRNA or protein expression. TDP-43 pathology was absent from all bvFTD iMG. As compared to healthy control iMG, quantitative immunofluorescence analyses indicated that all bvFTD iMG had reduced number, size, and intensity of LAMP2-A-positive vesicles. C9orf72 HRE-carrying iMG additionally showed decreased number, size, and intensity of p62/SQSTM1-positive vesicles. These changes were accompanied by increased phagocytic activity of the C9orf72 HRE-carrying iMG. Serum starvation increased phagocytic activity also in the iMG of sporadic bvFTD patients. RNA sequencing revealed that iMG of C9orf72 HRE-carrying bvFTD patients as compared to the iMG of sporadic bvFTD patients showed differential gene expression in pathways related to RNA and protein regulation and mitochondrial metabolism. Our data suggest potential alterations in the autophagosomal/lysosomal pathways in bvFTD patient iMG, which are further reinforced by the C9orf72 HRE and functionally manifest as increased phagocytic activity.

neuroscience↗

bioRxiv2024

Fibroblasts carrying intermediate C9orf72 hexanucleotide repeat expansions from iNPH patients show impaired energy metabolism but no cell pathologies

Long C9orf72 hexanucleotide repeat expansions (C9-HRE) are the most common genetic cause of frontotemporal dementia (FTD), a group of neurodegenerative syndromes leading to cognitive dysfunction and frontal and temporal atrophy. FTD is a potential comorbidity of idiopathic normal pressure hydrocephalus (iNPH) and carrying the C9-HRE can modify the age-of-onset in iNPH patients. While intermediate-length C9-HRE (<30 repeats) are often considered non-pathogenic, the exact pathological cutoff is unclear. In this study, we assessed whether fibroblasts from iNPH patients carrying intermediate C9-HRE display C9-HRE-associated pathological hallmarks and changes in cellular function. C9-HRE-associated RNA foci were not detected in the intermediate carriers. The number of p62-positive puncta was significantly increased only in long C9-HRE carrier fibroblasts, in line with p62-positive intracellular inclusions observed in a brain biopsy from the patient. Specific parameters of mitochondrial respiration were significantly reduced in both the long and intermediate C9-HRE carrier fibroblasts. Fibroblasts from the intermediate C9-HRE carriers showed upregulated glycolytic activity, possibly to counteract the reduced mitochondrial respiration, which could not be observed in the long C9-HRE carriers. In conclusion, these data suggest that while the long C9-HRE leads to more severe cellular pathologies than intermediate C9-HRE, the latter might predispose cells to pathological changes.

neuroscience↗

bioRxiv2024

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Frontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased TDP-43 nucleus-to-cytosolic shuttling and p62/SQSTM1 accumulation, and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.

neuroscience↗

bioRxiv2023

Controlled expression of avian migratory fattening influences innate immune responses

While immunity is frequently suppressed when birds engage in strenuous migratory flights, whether and how immunity changes during the rapid accumulation of energy stores in preparation for migration remains largely unknown. Here, we induced pre-migratory fattening through controlled changes of daylight in common quails Coturnix coturnix and regularly assessed changes in a marker of constitutive innate immunity (Leukocyte Coping Capacity or LCC) and measures of body composition (lean and fat mass). LCC responses were highest in the mid-fattening phase and lowest when fattening was completed. At mid-fattening, we also found that the birds that kept a higher proportion of lean mass (i.e. accumulated less fat) had the highest LCC peaks. Our results indicate that migratory birds undergo rapid immunological changes as they accumulate energy stores for migration and propose that this could be due to competing or trade-off processes between metabolic remodelling and innate immune system function. Summary statementImmunity is vital when migrating to new environments. It is costly and competivite to other physiological processes. Here we bring new evidence on this process in migratory birds.

physiology↗

bioRxiv2021

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

Loss-of-function of the mRNA export protein GANP (MCM3AP gene) cause early-onset sensorimotor neuropathy, characterised by axonal degeneration in long peripheral nerves. GANP functions as a scaffold at nuclear pore complexes, contributing to selective nuclear export of mRNAs. Here, we aimed to identify motor neuron specific transcripts that are regulated by GANP and may be limiting for local protein synthesis in motor neuron axons. We compared motor neurons with a gene edited mutation in the Sac3 mRNA binding domain of GANP to isogenic controls. We also examined patient-derived motor neurons. RNA sequencing of motor neurons as well as nuclear and axonal subcompartments showed that mutant GANP had a profound effect on motor neuron transcriptomes, with alterations in nearly 40 percent of all expressed genes and broad changes in splicing. Expression changes in multiple genes critical for neuronal functions, combined with compensatory upregulation of protein synthesis and early-stage metabolic stress genes, indicated that RNA metabolism was abnormal in GANP-deficient motor neurons. Surprisingly, limited evidence was found for large-scale nuclear retention of mRNA. This first study of neuropathy-linked GANP defects in human motor neurons shows that GANP has a wide gene regulatory role in a disease-relevant cell type that requires long-distance mRNA transport.

neuroscience↗

bioRxiv2020

"The stressed bird in the hand": Influence of sampling design on the physiological stress response in a free-living songbird

Despite the widely used application of standardized capture-handling protocols to collect blood and assess the physiological stress response, the effect of the actual sampling design (e.g. timing and the number of blood samples) often differs between studies, and the potential implications for the measured physiological endpoints remain understudied. We, therefore, experimentally tested the effects of repeated handling and multiple blood sampling on the stress response in wintering free-living great tits (Parus major). We modified a well-established sampling protocol of avian studies by adding either an additional blood sample or a "sham-manipulation" (i.e. handling associated with the blood sampling procedure without venepuncture), to disentangle the effects of handling stress and blood loss. We combined three different stress metrics along the endocrine-immune interface to investigate the acute short-term stress response: total corticosterone levels (CORT), the heterophil/lymphocyte ratio (H:L), and the Leukocyte Coping Capacity (LCC). Our study provided three key results: i) no relationship between CORT-levels, LCC and H:L, confirming that these three parameters represent different physiological endpoints within the stress response; ii) contrasting dynamics in response to stress by the measured parameters and iii) no difference in stress levels 30 minutes after capture due to one additional blood sampling or handling event. By optimising the sampling design, our results provide implications for animal welfare and planning experimental procedures on stress physiology in passerine species. Summary StatementWhen testing the short-term stress response in free living passerines, both - the scientist and the bird may be better off with a 15-minute stress protocol.

physiology↗