Biology subjects

Hoffmann, G.

Publications and source records attributed to Hoffmann, G..

13 recordsLinked to original sources

bioRxiv2025

AGO5 restricts virus vertical transmission in plant gametophytes

The propagation of a viral infection from a host parent to its progeny is known as vertical transmission, or seed transmission in plants. It allows viral infections to rapidly spread locally via pollen and worldwide through seeds. To be vertically transmitted to each progeny, a virus must pass through the tight bottleneck of at least one cell per parent - the gametes. Therefore, stopping infection during sexual reproduction is of vital importance to generate healthy offspring. Accordingly, vertical transmission of plant viruses often occurs at very low rates, if at all, suggesting the existence of highly effective - yet unknown - antiviral defenses in pre-meiotic cells, gametes and/or embryos. In this study, we show that AGO5, an RNA interference factor expressed specifically in shoot apical meristem stem cells and the germline of Arabidopsis thaliana, drastically reduces the vertical transmission of Turnip yellow mosaic virus (TYMV). Through a series of controlled pollination experiments leveraging different zygosity of ago5 knock-out, cell type-specific rescue of ago5 and TYMV detection in whole-mount reproductive tissues, we provide evidence that AGO5 acts in pollen and sperm cells to restrict virus transmission to progeny. We further show that triggering antiviral RNA interference specifically in sperm cells leads to a significant reduction in TYMV vertical transmission. In summary, this study provides the first description of a gamete-specific antiviral defense mechanism restricting virus vertical transmission, paving the way for new strategies to prevent the spread of pollen- and seed-borne viral epidemics.

plant biology↗

bioRxiv2025

Cerebrospinal fluid flow and clearance driven by lateral ventricle volume oscillations

In the human brain, substance clearance is intimately connected to the cerebrospinal fluid (CSF) and its flow. CSF extends from the lateral ventricles (LVs) to the parenchymas perivascular spaces. Macroscopic undulating CSF flow is present during both wakefulness and sleep and can be experimentally induced. However, the mechanisms generating this flow and its contribution to brain clearance remain unclear. Using fMRI and PET across various conditions, we demonstrate that LV-volume oscillations drive undulating CSF flow in the ventricles and subarachnoid basal cisternae. LV oscillations are driven by cortical blood-volume changes induced by neuronal activity, heartbeat and respiration. LV oscillations amplitudes determine PET-tracer clearance from the LVs. Conclusively, induced by extra- and intracranial physiological drivers and mediated by cortical blood-volume changes, LV-volume oscillations drive macroscopic CSF flow and clearance.

neuroscience↗

bioRxiv2025

Spectral disruption of inter-hemispheric resting-state BOLD coherence at vasomotor frequency (~0.1 Hz) links vascular dysfunction to functional connectivity loss in carotid artery stenosis

In the brain, vasomotor dynamics at infra-slow frequencies ([~]0.1 Hz), driven by synchronized oscillations of smooth muscle cells in vessel walls, are thought to play a crucial role in regulating cerebral perfusion and underlie resting-state functional connectivity (FC), typically measured by correlated time courses of functional signals. In particular, rodent studies have demonstrated that vasomotor activity contributes to the coherence of blood oxygenation level dependent (BOLD) signal fluctuations. However, in humans, detecting this contribution non-invasively remains challenging due to the limited spatiotemporal sensitivity of functional magnetic resonance imaging (fMRI) to vasomotion. Given that prior studies have identified internal carotid artery stenosis (ICAS) as an informative conditional lesion model of vasomotor and hemodynamic impairments in humans, we investigated whether ICAS affects interhemispheric BOLD coherence at [~]0.1 Hz. Using a multi-modal fMRI framework integrating resting-state fMRI with quantitative mapping of cerebral blood volume, blood flow, oxygen metabolism, and BOLD time lag, we compared BOLD coherence between patients with asymptomatic unilateral ICAS and healthy controls. Frequency-specific analysis revealed significantly diminished interhemispheric BOLD coherence at [~]0.1 Hz across canonical resting-state networks in ICAS patients, while ultra-slow (<0.05 Hz) coherence remained largely preserved. This reduction was spatially widespread and particularly pronounced in watershed areas, i.e., border zones between major vascular territories, associated with significantly increased lateralization of cerebral blood volume (p < 0.01). Notably, coherence-based FC patterns at [~]0.1 Hz were heterogeneous within watershed areas but homogeneous outside, suggesting an interplay between compensatory mechanisms and cerebrovascular impairment. Taken together, our findings demonstrate that ICAS induces subtle, frequency-and region-specific alterations in interhemispheric FC, consistent with a model in which impaired vasomotor activity impacts on resting-state FC in the human brain.

neuroscience↗

bioRxiv2025

Efficient Design of Affilin(R) Protein Binders for HER3

Engineered scaffold-based proteins that bind to concrete targets with high affinity offer significant advantages over traditional antibodies in theranostic applications. Their development often relies on display methods, where large libraries of variants are physically contacted with the desired target protein and pools of binding variants can be selected. Herein, we use a combined artificial intelligence/physics-based computational framework and phage display approach to obtain ubiquitin based Affilin(R) proteins targeting the HER3 extracellular domain, a relevant tumor target. We demonstrate that the developed in silico pipeline can generate de novo Affilin(R) proteins with high experimental success rate using a small training set of sequences (<1000 sequences). The classical phage display yielded primary candidates with low nanomolar affinities. These binders could be further optimized by phage display and computational maturation alike. These combined efforts resulted in four HER3 ligands with high affinity, cell binding, and serum stability that have theranostic potential.

biochemistry↗

bioRxiv2023

Early root architectural traits and their relationship with yield in Ipomoea batatas L.

Root system architecture in storage root crops are an important component of plant growth and yield performance that has received little attention by researchers because of the inherent difficulties posed by in-situ root observation. Sweetpotato (Ipomoea batatas L.) is an important climate-resilient storage root crop of worldwide importance for both tropical and temperate regions, and identifying genotypes with advantageous root phenotypes and improved root architecture to facilitate breeding for improved storage root yield and quality characteristics in both high and low input scenarios would be beneficial. We evaluated 38 diverse sweetpotato genotypes for early root architectural traits and correlated a subset of these with storage root yield. Early root architectural traits were scanned and digitized using the RhizoVision Explorer software system. Significant genotypic variation was detected for all early root traits including root mass, total root length, root volume, root area and root length by diameter classes. Based on the values of total root length, we separated the 38 genotypes into three root sizes (small, medium, and large). Principal component analysis identified four clusters, primarily defined by shoot mass, root volume, root area, root mass, total root length and root length by diameter class. Average total and marketable yield and number of storage roots, was assessed on a subset of eight genotypes in the field. Several early root traits were positively correlated with total yield, marketable yield, and number of storage roots. These results suggest that root traits, particularly total root length and root mass could improve yield potential and should be incorporated into sweetpotato ideotypes. To help increase sweetpotato performance in challenging environments, breeding efforts may benefit through the incorporation of early root phenotyping using the idea of integrated root phenotypes.

plant biology↗

bioRxiv2023

Lysosomal acid lipase-activity as a novel target to efficiently address triple-negative breast cancer high malignancy

Increased metabolism of neutral lipids, e.g. triglycerides and cholesterol esters, is a hallmark of malignant cancers such as triple-negative breast cancer (TNBC). Predominantly, cancer cells with a high epigenetic stem cell-associated signature increasingly utilize neutral lipids to maintain their high degree of tumor stemness, linking metabolic aberrations to epigenetically dysregulated differentiation processes. Lysosomal acid lipase (LIPA) is a central enzyme in the cellular utilization of exogenous and endogenous neutral lipids; however, the role of LIPA-activity in TNBC remains unexplored. We here show for the first time that pharmacological inhibition of LIPA, highly expressed in TNBC, reduces the expression markers of breast cancer stemness in cell culture models of TNBC. A role of LIPA in maintaining TNBC high cellular stemness was stressed by specific siRNA knock-down. Furthermore, inhibition of LIPA sensitized TNBC cells to therapy with Paclitaxel and Doxorubicin, two important chemotherapeutics in current TNBC treatment. When LIPA-activity was inhibited in a three-dinensional (3D) patient derived organoid model, we observed a significant reduction in TNBC cellular viability. Importantly, LIPA inhibition prevented tumor metastasis in a TNBC-zebrafish xenograft model in vivo. These findings introduce LIPA-activity as a novel pharmacological target in TNBC therapy to specifically address its high cancer malignancy with a potential for implementation of LIPA inhibitors into personalized treatment in the future.

cancer biology↗

bioRxiv2023

Global neuronal activity drives cerebrospinal fluid motion mediated by brain blood volume changes in humans

In the mammalian brain, the directed motion of cerebrospinal fluid (CSF-flux) is instrumental in the distribution and removal of solutes. Changes in total cerebral blood volume (CBV) have been hypothesized to drive CSF-flux. We tested this hypothesis in two multi-modal brain imaging experiments in healthy humans, in which we drove large changes in total CBV by neuronal burst-suppression under anesthesia, or by transient global vasodilation in a hypercapnic challenge. We developed a technique to monitor CBV changes based on associated changes in total brain volume by functional MRI (fMRI) and measured cerebral blood flow by arterial spin-labeling. Relating CBV-sensitive signals to fMRI-derived measures of macroscopic CSF flow across the basal cisternae, we demonstrate that increasing total CBV extrudes CSF from the skull and decreasing CBV allows its influx. Moreover, CSF largely stagnates when CBV is stable. Together, our results establish the direct coupling between total CBV changes and CSF-flux.

neuroscience↗

bioRxiv2022

Cauliflower mosaic virus disease spectrum uncovers novel susceptibility factor NCED9 in Arabidopsis thaliana

Viruses are intimately linked with their hosts and especially dependent on gene-for-gene interactions to establish successful infections. The genotype of their hosts thus has a strong influence on the outcome virus disease. On the host side, defence mechanisms like tolerance and resistance can occur within the same species leading to differing virus accumulation in relation to symptomology and plant fitness. The identification of novel resistance genes and susceptibility factors against viruses is an important part in understanding viral pathogenesis and securing food production. The model plant Arabidopsis thaliana displays a wide symptom spectrum in response to RNA virus infections and unbiased genome-wide association studies have proven a powerful tool to identify novel disease-genes. In this study we infected natural accessions of Arabidopsis thaliana with the pararetrovirus Cauliflower mosaic virus to study the phenotypic variations between accessions and their correlation with virus accumulation. Through genome-wide association mapping of viral accumulation differences, we identified several susceptibility factors for CaMV, the strongest of which was the abscisic acid synthesis gene NCED9. Further experiments confirmed the importance of abscisic acid homeostasis and its disruption for CaMV disease.

plant biology↗

bioRxiv2022

Cauliflower mosaic virus protein P6 forms a microenvironment for RNA granule proteins and interferes with stress granule responses

Biomolecular condensation is a multipurpose cellular process that viruses use ubiquitously in their multiplication. CaMV replication complexes are condensates that differ from most viruses in being non-membranous assemblies and consist of RNA and protein, mainly viral protein P6. Despite description of these viral factories already half a century ago with many observations that followed since, functional details of the condensation process, their properties and relevance has remained enigmatic. Our main findings include a large dynamic mobility range of host proteins within viral factories, while the viral matrix protein P6 is immobile in accordance with representing the central node of these condensates. As novel components of VFs we identify stress granule (SG) nucleating factors G3BP7 and the UBP1 family. Similarly, as SG components localize in VFs during infection, ectopic P6 localizes to SGs and reduces their assembly after stress. Intriguingly, it appears that soluble rather than condensed P6 suppresses SGs and mediates also other essential P6 functions, suggesting that the increased condensation over the infection time-course may accompany a progressive shift in selected P6 functions. Together, this study highlights VFs as dynamic condensates and P6 as a complex modulator of SG responses.

plant biology↗

bioRxiv2021

Cauliflower Mosaic Virus Utilizes Processing Bodies to Escape Translational Repression in Arabidopsis

Viral infections impose extraordinary RNA stress on a cell, triggering cellular RNA surveillance pathways like RNA decapping, nonsense-mediated decay and RNA silencing. Viruses need to maneuver between these pathways to establish infection and succeed in producing high amounts of viral proteins. Processing bodies (PBs) are integral to RNA triage in eukaryotic cells with several distinct RNA quality control pathways converging for selective RNA regulation. In this study, we investigate the role of Arabidopsis thaliana PBs during Cauliflower Mosaic Virus (CaMV) infection. We find that several PB components are co-opted into viral replication factories and support virus multiplication. This pro-viral role was not associated with RNA decay pathways but instead, we could establish PB components as essential helpers in viral RNA translation. While CaMV is normally resilient to RNA silencing, PB dysfunctions expose the virus to this pathway, similar to previous observations on transgenes. Transgenes, however, undergo RNA Quality Control dependent RNA degradation, whereas CaMV RNA remains stable but becomes translationally repressed through decreased ribosome association, revealing a unique dependence between PBs, RNA silencing and translational repression. Together, our study shows that PB components are co-opted by the virus to maintain efficient translation, a mechanism not associated with canonical PB functions.

plant biology↗

bioRxiv2021

Turnip crinkle virus targets host ATG8 proteins to attenuate antiviral autophagy

Autophagy has emerged as a central player in plant virus disease and resistance. In this study we have addressed the potential roles of autophagy in Turnip crinkle virus (TCV) infection. We found that autophagy attenuates disease severity and contributes to resistance against TCV by limiting virus accumulation. These autophagy-dependent disease phenotypes intensify further when combined with defects in RNA silencing, suggesting that these two major defence pathways are largely uncoupled in TCV disease. Intriguingly, as a counterdefence, TCV employs the viral silencing suppressor protein P38 to suppress antiviral autophagy, likely by directly sequestering ATG8 proteins. This strategy appears to be novel for plant viruses, yet resembles mechanisms described for other pathogen classes. Together, these results broaden our understanding of autophagy in plant virus disease, and strengthens our view of virus-specific adaptation to the autophagy pathway.

plant biology↗

bioRxiv2020

Autophagic degradation of the Cucumber mosaic virus virulence factor 2b balances antiviral RNA silencing with proviral plant fitness and virus seed transmission

Autophagy is a conserved intracellular degradation pathway that has recently emerged as an integral part of plant responses to virus infection. The elucidated mechanisms of autophagy range from the selective degradation of viral components to a more general attenuation of disease symptoms. In addition, several viruses are able to manipulate the autophagy machinery and counteract autophagy-dependent resistance. Despite these findings, the complex interplay of autophagy activities, viral pathogenicity factors, and host defence pathways in disease development remains poorly understood. In the current study, we analysed the interaction between autophagy and Cucumber mosaic virus (CMV) in Arabidopsis thaliana. We show that autophagy is induced during CMV infection and promotes the turnover of the major CMV virulence protein and RNA silencing suppressor 2b. Intriguingly, 2b itself dampens plant autophagy. In accordance with 2b degradation, we found that autophagy provides resistance against CMV by reducing viral RNA accumulation in an RNA silencing-dependent manner. Moreover, autophagy and RNA silencing pathways contribute to plant longevity and fecundity of CMV infected plants in an additive manner, uncoupling it from resistance. In addition to reduced fecundity, autophagy-deficient plants also failed to support seed transmission of the virus. We propose that autophagy attenuates CMV virulence via 2b degradation and thereby increases both plant and virus fitness with a trade-off penalty arising from increased RNA silencing-mediated resistance. Author summaryThe capacity of plants to fight pathogenic viruses in order to survive and minimize damage relies on profound cellular reprogramming events. These include the synthesis of new as well as the degradation of pre-existing cellular components, together shifting cellular homeostasis towards a better tolerance of disease and fortification of antiviral defence mechanisms. Autophagy is a prominent and highly conserved cellular degradation pathway that supports plant stress resilience. Autophagy functions vary broadly and range from rather unspecific renewal of cytoplasm to highly selective degradation of a wide collection of specific substrates. Autophagy is well established to be involved during virus infections in animals, and its importance has also recently emerged in virus diseases of plants. However, we are still far from a comprehensive understanding of the complexity of autophagy activities in host-virus interactions and how autophagy pathway engineering could be applied against viruses. Here, we have analyzed one of the traditional model plant viruses, Cucumber mosaic virus (CMV), and its interactions with autophagy. Our study revealed that autophagy is tightly integrated into CMV disease, influencing processes from plant health to CMV epidemiology.

plant biology↗

bioRxiv2019

Arabidopsis thaliana natural variation in temperature-modulated immunity uncovers transcription factor UNE12 as a thermoresponsive regulator

Temperature impacts plant immunity and growth but how temperature intersects with endogenous pathways remains unclear. Here we uncover variation between Arabidopsis thaliana natural accessions in response to two non-stress temperatures (22{degrees}C and 16{degrees}C) affecting accumulation of the thermoresponsive stress hormone salicylic acid (SA) and plant growth. Analysis of differentially responding A. thaliana accessions shows that pre-existing SA provides a benefit in limiting bacterial pathogen infection at both temperatures. Several A. thaliana genotypes display a capacity to mitigate negative effects of high SA on growth, indicating within-species plasticity in SA - growth tradeoffs. An association study of temperature x SA variation, followed by physiological and immunity phenotyping of mutant and over-expression lines, identifies the transcription factor unfertilized embryo sac 12 (UNE12) as a temperature-responsive SA immunity regulator. Here we reveal previously untapped diversity in plant responses to temperature and a way forward in understanding the genetic architecture of plant adaptation to changing environments.

plant biology↗