Biology subjects

Kaiser, M.

Publications and source records attributed to Kaiser, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Transcranial focused ultrasound stimulation of the anterior temporal lobe enhances semantic memory by modulating brain morphology, neurochemistry and neural dynamics

AbstractsUnderstanding neural functioning and plasticity of the brain is a fundamental goal of neuroscience. The ventromedial anterior temporal lobe (ATL) has been suggested as the centre-point of a core transmodal hub for semantic memory, playing a crucial role in the representation of coherent conceptual knowledge. However, non-invasive direct modulation of the ventromedial ATL has remained challenging. Transcranial ultrasound stimulation (TUS) is an emerging neuromodulatory technique that delivers acoustic energy with high spatial precision, making it uniquely suited for targeting deep brain structures non-invasively. In this study, we investigated whether theta-burst TUS (tbTUS) to the ventromedial ATL could enhance semantic memory performance in the adult brain. Using a multimodal neuroimaging approach-- magnetic resonance spectroscopy (MRS), functional MRI (fMRI), and voxel-based morphometry (VBM)--we assessed tbTUS-induced changes in neurochemical concentrations, functional network connectivity, structural plasticity, and semantic memory performance. Compared to control stimulation (ventricle), tbTUS at the ventromedial ATL significantly improved semantic task performance in healthy individuals. MRS analysis revealed that tbTUS decreased GABA and increased Glx levels, reflecting shifts in excitation-inhibition balance. Additionally, tbTUS increased neurometabolites in the ATL, including NAA, creatine and choline, suggesting enhanced neuronal function and metabolism. fMRI analysis demonstrated that tbTUS reduced task-induced regional activity in the ATL and functionally connected semantic regions, while also enhancing intrinsic and effective connectivity across the semantic network. Structural analysis revealed increased grey matter volume in the ATL following tbTUS compared to control stimulation. These findings provide the first convergent evidence that tbTUS can modulate neurochemistry, functional dynamics, and brain morphology to enhance semantic memory function. Our results highlight TUS as a powerful neuromodulatory tool with potential applications in cognitive enhancement and neurorehabilitation, offering a promising intervention for dementia and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Bacterial pathogen deploys iminosugar galactosyrin to manipulate plant glycobiology

The extracellular space (apoplast) of plants is an important molecular battleground during infection by many pathogens. We previously found that a plant-secreted {beta}-galactosidase BGAL1 acts in immunity by facilitating the release of immunogenic peptides from bacterial flagellin and that Pseudomonas syringae suppresses this enzyme by producing a small molecule inhibitor called galactosyrin. Here, we elucidated the structure and biosynthesis of galactosyrin and uncovered its multifunctional roles during infection. Structural elucidation by cryo-EM and chemical synthesis revealed that galactosyrin is an iminosugar featuring a unique geminal diol attached to the pyrrolidine moiety that mimics galactose binding to the {beta}-galactosidase active site. Galactosyrin biosynthesis branches off from purine biosynthesis and involves three enzymes of which the first is a reductase that is unique in iminosugar biosynthesis. Besides inhibiting BGAL1 to avoid detection, galactosyrin also changes the glycoproteome and metabolome of the apoplast. The manipulation of host glycobiology may be common to plant-associated bacteria that carry putative iminosugar biosynthesis clusters.

plant biology↗

bioRxiv2025

Lack of AtMC1 catalytic activity triggers autoimmunity dependent on NLR stability

Plants utilize cell surface-localized pattern recognition receptors (PRRs) and intracellular nucleotide-binding leucine-rich repeat (NLR) receptors to detect non-self and elicit robust immune responses. Fine-tuning the homeostasis of these receptors is critical to prevent their hyperactivation. Here, we show that Arabidopsis plants lacking metacaspase 1 (AtMC1) display autoimmunity dependent on immune signalling components downstream of NLR and PRR activation. Overexpression of a catalytically inactive AtMC1 in an atmc1 background triggers severe autoimmunity partially dependent on the same immune signalling components. Overexpression of the E3 ligase SNIPER1, a master regulator of NLR homeostasis, fully reverts the AtMC1-dependent autoimmunity phenotype, inferring that a broad defect in NLR turnover may underlie the severe phenotype observed. Catalytically inactive AtMC1 localizes to punctate structures that are degraded through autophagy. Altogether and considering previous evidence on the proteostatic functions of AtMC1, we speculate that Wt AtMC1 may either directly or indirectly control NLR protein levels, thereby preventing autoimmunity.

plant biology↗

bioRxiv2025

Understanding the high-order network plasticity mechanisms of ultrasound neuromodulation

Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique, offering a potential alternative to pharmacological treatments for psychiatric and neurological disorders. While functional analysis has been instrumental in characterizing TUS effects, understanding the underlying mechanisms remains a challenge. Here, we developed a whole-brain model to represent functional changes as measured by fMRI, enabling us to investigate how TUS-induced effects propagate throughout the brain with increasing stimulus intensity. We implemented two mechanisms: one based on anatomical distance and another on broadcasting dynamics, to explore plasticity-driven changes in specific brain regions. Finally, we highlighted the role of higher-order functional interactions in localizing spatial effects of off-line TUS at two target areas--the right thalamus and inferior frontal cortex--revealing distinct patterns of functional reorganization. This work lays the foundation for mechanistic insights and predictive models of TUS, advancing its potential clinical applications. Significance StatementTranscranial ultrasound stimulation (TUS) offers a non-invasive approach to modulating brain activity, holding promise for treating psychiatric and neurological disorders. Despite its potential, the mechanisms underlying its effects remain poorly understood. By integrating human fMRI data with whole-brain computational models, we identified how high-order functional interactions localize and propagate TUS-induced effects from local to global brain scales. This work introduces two mechanisms--distance-based propagation and diffusion-like broadcasting--that predict functional plasticity changes, providing a foundation for understanding and optimizing the biological and cognitive outcomes of TUS. Our findings offer critical insights into the dynamics of neuromodulation, bridging experimental results and clinical applications.

neuroscience↗

bioRxiv2024

Pleiotropic function of Dlx5/6 in coordinating the development of mammalian vocal and auditory organs

Acoustic communication, essential for mammalian social interactions, involves both effector (vocal) and receptor (auditory) organs that present a wide variety of morphologies between species. The molecular mechanisms supporting the harmonious diversification of effector and receptor systems along with the evolution of species-specific acoustic communication are still poorly understood. It is conceivable that common genetic pathways determine the parallel morphogenesis of vocal and auditory systems. Here, we investigated this question by generating mutant mice with targeted invalidation of Dlx5/6 genes in the otic placode and cephalic neural crest cells, contributing to the formation of the ear and vocal tract components. We show that Dlx5/6 inactivation provokes simultaneous defects of the outer, middle and inner ear and of the jaw, pharynx and larynx musculoskeletal systems. Our findings support the notion that Dlx5/6 genes played a pleiotropic role in the co-adaptation of vocal and auditory systems in mammals.

developmental biology↗

bioRxiv2024

A non-autonomous protein quality control mechanism targeting tau aggregate propagation

Tauopathies such as Alzheimers disease, frontotemporal dementia with Parkinsonism, and other neurodegenerative disorders are characterized by the spread of tau pathology from an initial brain region to neuroanatomically connected areas. At the molecular level, spreading involves aggregation of tau in a donor cell, externalization of transmissible fragments of amyloid fibrils, internalization by an acceptor cell, followed by seeded aggregation of endogenous tau. However, the protein quality control mechanisms that counteract tau aggregation, and in particular its spreading process, are not well understood. In this context, a co-migrating factor performing location-independent interference of fibril formation and transmission would be an appropriate conceptual solution. Here, we show that the cell-to-cell transfer of the widely conserved serine protease HTRA1 impedes tau pathology by targeting multiple steps within the spreading process. Our results suggest a defense mechanism against the intercellular spread of pathogenic protein conformations.

biochemistry↗

bioRxiv2024

Induced degradation of SNAP-fusion proteins

Self-labeling protein tags are an efficient means to visualize, manipulate, and isolate engineered fusion proteins with suitable chemical probes. The SNAP-tag, which covalently conjugates to benzyl-guanine and -chloropyrimidine derivatives is used extensively in fluorescence microscopy, given the availability of suitable SNAP-ligand-based probes. Here, we extend the applicability of the SNAP-tag to targeted protein degradation. We developed a set of SNAP PROteolysis TArgeting Chimeras (SNAP-PROTACs), which recruit the VHL or CRBN-ubiquitin E3 ligases to induce the degradation of SNAP-fusion proteins. Endogenous tagging enabled the visualization and the selective depletion of a SNAP-clathrin light chain fusion protein using SNAP-PROTACs. The addition of PROTACs to the SNAP-tag reagent toolbox facilitates the comprehensive analysis of protein function with a single gene tagging event.

cell biology↗

bioRxiv2024

Local genetic adaptation to habitat in wild chimpanzees

How populations adapt to their environment is a fundamental question in biology. Yet we know surprisingly little about this process, especially for endangered species such as non-human great apes. Chimpanzees, our closest living relatives, are particularly interesting because they inhabit diverse habitats, from rainforest to woodland-savannah. Whether genetic adaptation facilitates such habitat diversity remains unknown, despite having wide implications for evolutionary biology and conservation. Using 828 newly generated exomes from wild chimpanzees, we find evidence of fine-scale genetic adaptation to habitat. Notably, adaptation to malaria in forest chimpanzees is mediated by the same genes underlying adaptation to malaria in humans. This work demonstrates the power of non-invasive samples to reveal genetic adaptations in endangered populations and highlights the importance of adaptive genetic diversity for chimpanzees. One-Sentence SummaryChimpanzees show evidence of local genetic adaptation to habitat, particularly to pathogens, such as malaria, in forests.

evolutionary biology↗

bioRxiv2024

De novo synthesis of fatty acids in Archaea via an archaeal fatty acid synthase complex

Archaea synthesize membranes using isoprenoid-based ether lipids, whereas Bacteria and Eukarya use fatty acid-based ester lipids. While the factors responsible for this "lipid divide" remain unclear, this has important implications for understanding the evolutionary history of eukaryotes, which likely originated from within the Archaea and therefore changed membrane composition from isoprenoid-based to fatty acid-based lipids. Here, using 13C labelling studies, we demonstrate that the archaeal model organisms Sulfolobus acidocaldarius and Haloferax volcanii are capable of de novo fatty acid synthesis. Biochemical characterization and in vitro pathway reconstitution identify the key enzymes of a newly proposed fatty acid synthesis pathway in S. acidocaldarius and show that ketothiolase, ketoacyl-CoA reductase, and hydroxyacyl-CoA dehydratase form a stable assembly mediated by a DUF35 domain protein, which represents the first characterization of an archaeal fatty acid synthase complex. The final step is catalysed by an NADPH-dependent enoyl-CoA reductase. Deletion of the enoyl-CoA reductase demonstrate that this pathway operates in vivo in S. acidocaldarius. The presented results including phylogenetic analysis reveal that the potential to synthesize fatty acids is widespread across archaeal lineages. Collectively, our findings demonstrate that archaea are capable of synthesizing fatty acids, elucidate the molecular mechanisms involved in this process and provide additional insights into the evolutionary histories of fatty acid synthesis in archaea.

microbiology↗

bioRxiv2024

Extracellular plant subtilases dampen cold shock peptide elicitor levels

Recognizing pathogen-associated molecular patterns (PAMPs) on the cell surface is crucial for plant immunity. The proteinaceous nature of many of these patterns suggests that secreted proteases play important roles in their formation and stability. Here, we demonstrate that the apoplastic subtilase SBT5.2a inactivates the immunogenicity of cold-shock proteins of the bacterial plant pathogen Pseudomonas syringae by cleaving within the immunogenic csp22 epitope. Consequently, mutant plants lacking SBT5.2a activity retain higher levels of csp22, leading to enhanced immune responses and reduced pathogen growth. SBT5.2 sensitivity is influenced by sequence variation surrounding the cleavage site and likely extends to CSPs from other bacterial species. These findings suggest that variations in csp22 stability among bacterial pathogens are a crucial factor in plant-bacteria interactions and that pathogens might exploit plant proteases to avoid pattern recognition.

plant biology↗

bioRxiv2024

Ventricle stimulation as a potential gold-standard control stimulation site for transcranial focused ultrasound stimulation

This research investigates whether ventricular-focused ultrasound stimulation (ventricle-FUS) can serve as an effective control in studies using transcranial FUS, a non-invasive technology for brain modulation. FUS has notable potential for therapeutic applications but requires a robust control to accurately assess its effects. We evaluated the effectiveness of ventricle-FUS, as an active, non-cerebrum control for FUS research, comparing it to sham stimulation. We conducted a comprehensive assessment of ventricle-FUS, employing both questionnaires and multiple neuroimaging metrics such as grey matter and white matter volumes, and functional connectivity. Ventricle-FUS did not alter any of these metrics, thereby successfully retaining the auditory, somatosensory, and experiential elements of FUS without affecting brain structure or function. Importantly, participants were unable to distinguish whether they received ventricle-FUS or sham FUS. Our findings confirm that ventricle-FUS establishes it as a reliable control approach in FUS research, crucial for advancing its therapeutic applications.

neuroscience↗

bioRxiv2024

Subtilase SBT5.2 counterbalances flagellin immunogenicity in the plant apoplast

Most angiosperm plants recognise the flg22 epitope in bacterial flagellin via homologs of cell surface receptor FLS2 and mount pattern-triggered immune responses. However, flg22 is buried within the flagellin protein indicating that proteases might be required for flg22 release. Here, we demonstrate the extracellular subtilase SBT5.2 not only releases flg22, but also inactivates the immunogenicity of flagellin and flg22 by cleaving within the flg22 epitope, consistent with previous reports that flg22 is unstable in the apoplast. The prolonged lifetime of flg22 in sbt5.2 mutant plants results in increased bacterial immunity in priming assays, indicating that SBT5.2 counterbalances flagellin immunogenicity to provide spatial-temporal control and restrict costly immune responses and that bacteria take advantage of the host proteolytic machinery to avoid detection by flagellin having a protease-sensitive flg22 epitope.

plant biology↗

bioRxiv2024

α-Aminooxyacetic acid derivatives acting as pro-drugs against Mycobacterium tuberculosis

Tuberculosis (TB), a significant cause of mortality globally, continues to claim 1.5 million lives each year. Despite recent advances in TB management, the emergence of multidrug-resistant strains of TB is exacerbating the treatment of TB. Therefore, there is an immediate necessity to uncover new anti-TB compounds with unprecedented targets. This study introduces novel antimycobacterial molecules that are based on -aminooxyacetic acid core structures. The lead compounds KSK-104 and KSK-106 displayed potent sub-micromolar antibacterial activity against Mycobacterium tuberculosis H37Rv and XDR clinical isolates, while exhibiting virtually no cytotoxicity against various human cells. Complementation experiments following whole genome sequencing of spontaneously resistant mutants generated against these bactericidal compounds suggested that they are pro-drugs that are intracellularly hydrolyzed by one or both of two specific amidohydrolases, Rv0552 and AmiC. Furthermore, proteomic and transcriptomic analyses of stressed cells and genetic interaction mapping employing transposon insertion sequencing suggest a "dirty drug" mechanism that involves the simultaneous attack of the various drug cleavage products on multiple intracellular targets. Our results suggest a primary role of the pyridoxal 5-phosphate (PLP) synthesis and salvage pathway and/or PLP-dependent enzymes, the oxidative stress network, and the largely uncharacterized Rv3092c-Rv3095 gene cluster in the mode of action.

microbiology↗

bioRxiv2024

Discovery of active mouse, plant and fungal cytochrome P450s in endogenous proteomes and upon expression in planta.

Eukaryotes produce a large number of cytochrome P450s that mediate the synthesis and degradation of diverse endogenous and exogenous metabolites. Yet, most of these P450s are uncharacterized and global tools to study these challenging, membrane-resident enzymes remain to be exploited. Here, we applied activity profiling of plant, mouse and fungal P450s with chemical probes that become reactive when oxidized by P450 enzymes. Identification by mass spectrometry revealed labeling of a wide range of active P450s, including six plant P450s, 40 mouse P450s and 13 P450s of the fungal wheat pathogen Zymoseptoria tritici. We next used transient expression of GFP-tagged P450s by agroinfiltration to show ER-targeting and NADPH-dependent, activity-based labeling of plant, mouse and fungal P450s. Both global profiling and transient expression can be used to detect a broad range of active P450s to study e.g. their regulation and discover selective inhibitors.

plant biology↗

bioRxiv2024

Glycerol degradation in the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius involves an unusual glycerol-3-phosphate dehydrogenase

Glycerol is highly abundant in nature and serve as carbon source for many organisms. Also, several Archaea have the genetic capacity to grow on glycerol but its degradation has so far only been studied Haloferax volcanii. Herein, the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius was shown to grow with glycerol as sole carbon and energy source. After uptake likely involving facilitated diffusion, glycerol is degraded via phosphorylation to glycerol-3-phosphate followed by oxidation to dihydroxyacetone phosphate (DHAP) catalyzed by glycerol kinase (GK) by an unusual quinone reducing FAD-dependent glycerol-3-phosphate dehydrogenase (G3PDH), respectively. The S. acidocaldarius genome harbors two paralogous copies of each GK and G3PDH. However, only one of these GK-G3PDH couples (Saci_2031-2033) is highly upregulated on glycerol. Deletion of the saci_2033 gene encoding GK abolished growth on glycerol and GK activity in crude extracts. In contrast, deletion of the second GK gene (saci_1117) had only minor effects indicating that only one of the two GK-G3PDH couples is essential. Biochemical characterization revealed that both isoenzymes of each, GK and G3PDH, were functionally similar. Whereas the GKs showed high similarity to known enzymes from Bacteria and Eukaryotes, the G3PDHs represent unusual homologues of the bacterial GlpA subunit of the GlpABC complex with remarkable C-terminal sequence differences and a novel type of membrane anchoring via a CoxG-like protein (Saci_2031). Further sequence analyzes discovered a higher versatility of G3PDHs in Archaea with respect to interacting proteins, electron transfer, and membrane anchoring likely reflecting tailored evolutionary solutions to meet different requirements caused by life styles and electron acceptors.

microbiology↗

bioRxiv2024

Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.

The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms ( and {beta}). In chronic hyperglycemia and glucolipotoxicity, ChREBP-mediated ChREBP{beta} expression surges, leading to insulin-secreting {beta}-cell dedifferentiation and death. 14-3-3 binding to ChREBP results in cytoplasmic retention and suppression of transcriptional activity. Thus, small molecule-mediated stabilization of this protein-protein interaction (PPI) may be of therapeutic value. Here, we show that structure-based optimizations of a molecular glue compound led to potent ChREBP/14-3-3 PPI stabilizers with cellular activity. In primary human {beta}-cells, the most active compound retained ChREBP in the cytoplasm, and efficiently protected {beta}-cells from glucolipotoxicity while maintaining {beta}-cell identity. This study may thus not only provide the basis for the development of a unique class of compounds for the treatment of Type 2 Diabetes but also showcases an alternative molecular glue approach for achieving small molecule control of notoriously difficult to target TFs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/580675v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@18a17c8org.highwire.dtl.DTLVardef@11f6c0forg.highwire.dtl.DTLVardef@1ef4e63org.highwire.dtl.DTLVardef@34799_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Conformational plasticity of a BiP-GRP94 chaperone complex

Hsp70/Hsp90-chaperones and their regulatory co-chaperones are critical for maintaining protein homeostasis. GRP94, the sole Hsp90-chaperone in the secretory pathway of mammalian cells, is essential for the maturation of important secretory and transmembrane proteins. Without the requirement of co-chaperones, the Hsp70-protein BiP controls regulatory conformational changes of GRP94 - the structural basis of which has remained elusive. Here, we biochemically and structurally characterize the formation of a BiP-GRP94 chaperone complex and its transition to a conformation expected to support the loading of substrate proteins from BiP onto GRP94. BiP initially binds to the open GRP94 dimer via an interaction interface that is conserved among Hsp70/90 paralogs. Subsequently, binding of a second BiP protein stabilizes a semi-closed GRP94 dimer, thereby advancing the chaperone cycle. Our findings highlight a fundamental mechanism of direct Hsp70/90 cooperation, independent of co-chaperones.

biochemistry↗

bioRxiv2024

Venturicidin A affects the mitochondrial membrane potential and induces kDNA loss in Trypanosoma brucei

Neglected tropical diseases caused by trypanosomatid parasites have devastating health and economic consequences, especially in tropical areas. New drugs or new combination therapies to fight these parasites are urgently needed. Venturicidin A, a macrolide extracted from Streptomyces, inhibits the ATP synthase complex of fungi and bacteria. However, its effect on trypanosomatids is not fully understood. In this study, we tested venturicidin A on a panel of trypanosomatid parasites using Alamar Blue assays and found it to be highly active against Trypanosoma brucei and Leishmania donovani, but much less so against Trypanosoma evansi. Using fluorescence microscopy we observed a rapid loss of the mitochondrial membrane potential in T. brucei bloodstream forms upon venturicidin A treatment. Additionally, we report the loss of the mitochondrial DNA in approximately 40 to 50% of the treated parasites. We conclude that venturicidin A targets the ATP synthase of T. brucei, and we suggest that this macrolide could be a candidate for antitrypanosomatid drug repurposing, drug combinations, or medicinal chemistry programs.

microbiology↗