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Hoffmann, M.

Publications and source records attributed to Hoffmann, M..

At least 37 records · Page 2Linked to original sources
bioRxiv2024

Shaping the developing homunculus: the roles of deprivation and compensatory behaviour in sensory remapping

Some of the most dramatic examples of neuroplasticity in the human brain follow congenital sensory deprivation, though we have limited understanding of the plasticity mechanisms driving such large-scale remapping. Hand loss due to congenital limb differences (CLD) offers a unique temporal dissociation of developmental neuroplasticity mechanisms: While sensory deprivation is congenital, compensatory motor behaviours develop progressively across childhood. Using paediatric neuroimaging and semi-ecological behavioural analysis in children (5-7 years old) and adults (>25 years old) with unilateral upper-limb CLD, we studied deprivation- and use-dependent plasticity in the deprived primary somatosensory cortex and beyond. We reveal that global remapping, encompassing the entire sensory homunculus, is established early and maintained in adulthood. We demonstrate that deprivation-driven homeostatic plasticity can drive this global remapping, with Hebbian-based compensatory learning further contributing to inter-individual differences both in childhood and adulthood. Our findings emphasise the early establishment and stability of cortical maps, despite extensive daily-life behavioural adaptation.

neuroscience↗
bioRxiv2024

Disproportionate regulation of wildlife trade

An increasing number of countries in the Global North have enacted, or are considering, import bans on hunting trophies with the aim of protecting wildlife. We interrogate key arguments used to characterize trophy hunting and associated trade by proponents of such bans, using data from the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) over 25 years (2000-2024), the International Union for Conservation of Nature (IUCN) Red List of Threatened Species, and empirical research. Contrary to claims by proponents of bans, we show that trophy hunting is not a major threat to any CITES-listed species traded as a hunting trophy in 2000-2024. Arguments used to support bans often mischaracterize trophy hunting and its impacts and fail to recognize the benefits it can, and does, have for wildlife and people. Countries that have enacted or are considering import bans account for 64% of global trade in hunting trophies of CITES-listed species taken from the wild. Combined, these policies would restrict approximately one-fifth of this trade, likely with significant implications for conservation. We question whether these legislative actions are proportionate and discuss policy solutions. Wildlife trade solutions may appear simple, but evidence-based, just policies are needed to conserve biodiversity and avoid harming people.

ecology↗
bioRxiv2024

Impact of JN.1 booster vaccination on neutralisation of SARS-CoV-2 variants KP.3.1.1 and XEC

The SARS-CoV-2 KP.3.1.1 lineage is currently the dominating lineage on several continents. In parallel, the XEC lineage, a recombinant of KS.1.1 and KP.3.3, is on track of becoming the next dominant lineage in Europe and North America. Here we performed a rapid virological characterisation of the XEC lineage and studied the impact of JN.1 mRNA booster vaccination on KP.3.1.1 and XEC neutralisation.

molecular biology↗
bioRxiv2024

Single laboratory evaluation of the (Q20+) nanopore sequencing kit for bacterial outbreak investigations

This study aimed to evaluate the potential of Oxford Nanopore Technologies (ONT) GridION with Q20+ chemistry as a rapid and accurate method for identifying and clustering foodborne pathogens. The study focuses on assessing whether ONT Q20+ technology could offer near real-time pathogen identification, including SNP differences, serotypes, and antimicrobial resistance genes, to overcome the drawbacks of existing methodologies. This pilot study evaluated different combinations of two DNA extraction methods (Maxwell RSC Cultured Cell DNA kit, and Monarch high molecular weight extraction kits) and two ONT library preparation protocols (ligation and the rapid barcoding sequencing kit) using five well-characterized strains representing diverse foodborne pathogens. The results showed that any combination of extraction and sequencing kits produced high-quality closed bacterial genomes. However, there were variations in assembly length and genome completeness based on different combinations of methods, indicating the need for further optimization. in silico analyses demonstrated that the Q20+ nanopore sequencing chemistry accurately identified species, genotyped, and detected virulence factors comparable to Illumina sequencing. Phylogenomic clustering methods showed that ONT assemblies clustered with reference genomes, although some indels and SNP differences were observed. There were also differences on SNP accuracy among the different species. The observed SNP differences were likely due to sequencing and analysis processes rather than genetic variations in the sampled bacteria. The study also compared a change in the basecaller model with the previous model (SUP 4Khz 260 bps) and found no significant difference in accuracy (SUP 5Khz 400 bps). In conclusion, the evaluation of ONT Q20+ nanopore sequencing chemistry demonstrated its potential as an alternative for rapid and comprehensive bacterial genome analysis in outbreak investigations. However, further research, verification studies, and optimization efforts are needed to address the observed limitations to adopt and fully realize the impact of nanopore sequencing on public health outcomes and more efficient responses to foodborne disease threats.

genomics↗
bioRxiv2024

Prioritising Functionally Distinct and Globally Endangered (FuDGE) sharks for conservation action

Robust species-level methods for quantifying ecological differences have yet to be incorporated into conservation strategies. Here, we present a conservation prioritisation approach that integrates species trait data and extinction risk to quantify the contribution of individual species to overall functional diversity. The Functionally Irreplaceable with Risk of Extinction (FIRE) metric directs conservation action to species whose extinction is expected to result in significant losses of functional diversity. We applied our framework to sets of species at the global scale. First we assessed the worlds birds, highlighting congruent and divergent priorities identified by trait-based and phylogenetic approaches. Second, we applied FIRE to the worlds sharks, exploring the impact of imputed traits on prioritisation robustness. For birds and sharks, we show that prioritising by functional irreplaceability is an effective strategy to conserve exploited species. The FIRE metric provides a robust tool to facilitate the incorporation of functional diversity into conservation policy and practice, revealing species that may be overlooked by existing approaches.

ecology↗
bioRxiv2024

Immunoglobulin A Carries Sulfated N-glycans Primarily at the Tailpiece Site -- An Oxonium-Ion-Guided Approach for Site-Specific N-glycan Identification

Sulfated N-glycans from human immunoglobulin A (IgA) were recently discovered via glycomic approaches. However, their site-specific description is still pending. Certain N-glycan structures at specific N-glycosylation sites in IgA are crucial for microbial neutralization and effector functions. For instance, sialylated N-glycans on the C-terminal tailpiece mediate anti-viral activity by interfering with sialic-acid-binding viruses. Sulfated N-glycan epitopes can be ligands for viral proteins and thus play a role in the immune response. In this study, we performed a site-specific screening for sulfated N-glycans in two commercially available human serum IgA samples employing an in-depth N-glycoproteomic approach, previously developed by us. We found evidence of complex-type and hybrid-type N-glycans containing sulfated N-acetylhexosamine (sulfated HexNAc) attached to the N-glycosylation sites in the tailpiece and the CH2 domain of both IgA subclasses. A detailed comparison of the N-glycosylation profiles of human serum IgA samples from two suppliers showed such N-glycans with sulfated HexNAc consistently in higher abundance in the tailpiece region. Surprisingly, also complex-type N-glycan compositions bearing O-acetylated sialic acid were identified in the tailpiece. These findings have not been described before for a site-specific glycopeptide analysis. Overall, our work provides a methodology for performing a dedicated site-specific search for sulfated and O-acetylated N-glycans that can be easily transferred, e.g. to human IgA derived from mucosal tissues, milk, or saliva. Our future aim is to include sulfated N-glycans into longitudinal studies of IgA N-glycosylation and to investigate their role as a biomarker and a treatment option. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/597690v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@3d0214org.highwire.dtl.DTLVardef@1537f95org.highwire.dtl.DTLVardef@dd11eeorg.highwire.dtl.DTLVardef@1c43744_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗
bioRxiv2024

Multiscale Detrended Cross-Correlation Coefficient: Estimating Coupling in Nonstationary Neurophysiological Signals

The brain consists of a vastly interconnected network of regions, the connectome. By estimating the statistical interdependence of neurophysiological time series, we can measure the functional connectivity (FC) of this connectome. Pearsons correlation (rP) is a common metric of coupling in FC studies. Yet rP does not account properly for the non-stationarity of the signals recorded in neuroimaging. In this study, we introduced a novel estimator of coupled dynamics termed multiscale detrended cross-correlation coefficient (MDC3). Firstly, we showed that MDC3 had higher accuracy compared to rP using simulated time series with known coupling, as well as simulated functional magnetic resonance imaging (fMRI) signals with known underlying structural connectivity. Next, we computed functional brain networks based on empirical magnetoencephalography (MEG) and fMRI. We found that by using MDC3 we could construct networks of healthy populations with significantly different properties compared to rP networks. Based on our results, we believe that MDC3 is a valid alternative to rP that should be incorporated in future FC studies. Author SummaryThe brain consists of a vastly interconnected network of regions. To estimate the connection strength of such networks the coupling between different brain regions should be calculated. This can be achieved by using a series of statistical methods that capture the connection strength between signals originating across the brain, one of them being Pearsons correlation (rP). Despite its benefits, rP is not suitable for realistic estimation of brain network architecture. In this study, we introduced a novel estimator called multiscale detrended cross-correlation coefficient (MDC3). Firstly, we showed that MDC3 was more accurate than rP using simulated signals with known connection strength, as well as simulated brain activity emerging from realistic brain simulations. Next, we constructed brain networks based on real-life brain activity, recorded using two different methodologies. We found that by using MDC3 we could construct networks of healthy populations with significantly different properties compared to rP networks. Based on our results, we believe that MDC3 is a valid alternative to rP that should be incorporated in future studies of brain networks.

neuroscience↗
bioRxiv2024

ACE2-independent sarbecovirus cell entry is supported by TMPRSS2-related enzymes and reduces sensitivity to antibody-mediated neutralization

The COVID-19 pandemic, caused by SARS-CoV-2, demonstrated that zoonotic transmission of animal sarbecoviruses threatens human health but the determinants of transmission are incompletely understood. Here, we show that most spike (S) proteins of horseshoe bat and Malayan pangolin sarbecoviruses employ ACE2 for entry, with human and raccoon dog ACE2 exhibiting broad receptor activity. The insertion of a multibasic cleavage site into the S proteins increased entry into human lung cells driven by most S proteins tested, suggesting that acquisition of a multibasic cleavage site might increase infectivity of diverse animal sarbecoviruses for the human respiratory tract. In contrast, two bat sarbecovirus S proteins drove cell entry in an ACE2-independent, trypsin-dependent fashion and several ACE2-dependent S proteins could switch to the ACE2-independent entry pathway when exposed to trypsin. Several TMPRSS2-related cellular proteases but not the insertion of a multibasic cleavage site into the S protein allowed for ACE2-independent entry in the absence of trypsin and may support viral spread in the respiratory tract. Finally, the pan-sarbecovirus antibody S2H97 enhanced cell entry driven by two S proteins and this effect was reversed by trypsin. Similarly, plasma from quadruple vaccinated individuals neutralized entry driven by all S proteins studied, and use of the ACE2-independent, trypsin-dependent pathway reduced neutralization sensitivity. In sum, our study reports a pathway for entry into human cells that is ACE2-independent, supported by TMPRSS2-related proteases and associated with antibody evasion.

molecular biology↗
bioRxiv2024

Virological traits of the SARS-CoV-2 BA.2.87.1 lineage

The highly mutated SARS-CoV-2 BA.2.87.1 lineage was recently detected in South Africa, but its transmissibility is unknown. Here, we report that BA.2.87.1 efficiently enters human cells but is more sensitive to antibody-mediated neutralization than the currently dominating JN.1 variant. Acquisition of adaptive mutations might thus be needed for high transmissibility.

molecular biology↗
bioRxiv2024

The NAPstar family of NADP redox state sensors highlights glutathione as the primary mediator of anti-oxidative electron flux

The NADPH/NADP+ redox couple is central to metabolism and redox signalling. NADP redox state is differentially regulated by distinct enzymatic machineries at the subcellular compartment level. Nonetheless, a detailed understanding of subcellular NADP redox dynamics is limited by the availability of appropriate tools. Here, we introduce NAPstars, a family of genetically encoded, fluorescent protein-based NADP redox state biosensors. NAPstars offer real-time, specific, pH-resistant measurements, across a broad-range of NADP redox states, with subcellular resolution. We establish NAPstar measurements in yeast, plants and mammalian cell models, revealing a conserved robustness of cytosolic NADP redox homeostasis. NAPstars uncovered NADP redox oscillations linked to the cell cycle in yeast and illumination- and hypoxia-dependent NADP redox changes in plant leaves. By selectively impairing the glutathione and thioredoxin anti-oxidative pathways under acute oxidative challenge, NAPstars demonstrated an unexpected role for the glutathione system as the primary mediator of anti-oxidative electron flux that is conserved across eukaryotic kingdoms.

biochemistry↗
bioRxiv2023

Blood transcriptomics analysis offers insights into variant-specific immune response to SARS-CoV-2

Bulk RNA sequencing (RNA-seq) of blood is typically used for gene expression analysis in biomedical research but is still rarely used in clinical practice. In this study, we argue that RNA-seq should be considered a routine diagnostic tool, as it offers not only insights into aberrant gene expression and splicing but also delivers additional readouts on immune cell type composition as well as B-cell and T-cell receptor (BCR/TCR) repertoires. We demonstrate that RNA-seq offers vital insights into a patients immune status via integrative analysis of RNA-seq data from patients infected with various SARS-CoV-2 variants (in total 240 samples with up to 200 million reads sequencing depth). We compare the results of computational cell-type deconvolution methods (e.g., MCP-counter, xCell, EPIC, quanTIseq) to complete blood count data, the current gold standard in clinical practice. We observe varying levels of lymphocyte depletion and significant differences in neutrophil levels between SARS-CoV-2 variants. Additionally, we identify B and T cell receptor (BCR/TCR) sequences using the tools MiXCR and TRUST4 to show that - combined with sequence alignments and pBLAST - they could be used to classify a patients disease. Finally, we investigated the sequencing depth required for such analyses and concluded that 10 million reads per sample is sufficient. In conclusion, our study reveals that computational cell-type deconvolution and BCR/TCR methods using bulk RNA-seq analyses can supplement missing CBC data and offer insights into immune responses, disease severity, and pathogen-specific immunity, all achievable with a sequencing depth of 10 million reads per sample. Key PointsO_LIComputational deconvolution of transcriptomes can estimate immune cell abundances in SARS-CoV-2 patients, supplementing missing CBC data. C_LIO_LI10 million RNA sequencing reads per sample suffice for analyzing immune responses and disease severity, including BCR/TCR identification. C_LI

bioinformatics↗
bioRxiv2023

New avenues for human blood plasma biomarker discovery via improved in-depth analysis of the low-abundant N-glycoproteome

To understand implications of protein glycosylation for clinical diagnostic and biopharmaceuticals, innovative glycoproteomic technologies are required. Recently, significant advances were made, particularly toward structure-focused N-glyco-proteomic analyses. The mass spectrometric analysis of intact N-glycopeptides using stepped collision fragmentation along with glycan oxonium ion profiling now enables to reliably discriminate between different N-glycan structures. Still, there are weaknesses that current N-glycoproteomic approaches must overcome: 1) handling of incorrect identifications, 2) identification of rare and modified N-glycans, and 3) insufficient glycoproteomic coverage, especially in complex samples. To address these shortcomings, we have developed an innovative N-glycoproteomic workflow that aims at providing comprehensive site-specific and structural N-glycoproteomic data on human blood plasma glycoproteins. The workflow features protein depletion plus various fractionation strategies and the use of high-resolution mass spectrometry with stepped collision fragmentation. Furthermore, by including a decision tree procedure established for data validation, we could significantly improve the description of the N-glycan micro-heterogeneity. Our data analysis workflow allows the reliable differentiation of ambiguous N-glycan structures like antenna-versus core-fucosylation plus the modified and rare N-glycans such as sulfated and glucuronidated ones. With this workflow, we were able to advance in the analysis of human blood plasma glycoproteins to concentrations as low as 10 pg/mL. A total of 1,929 N-glycopeptides and 942 N-glycosites derived from 805 human middle-to low-abundant glycoproteins were identified. Overall, the presented workflow holds great potential to improve our understanding of protein glycosylation and to foster the discovery of blood plasma biomarkers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/562384v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1548a6eorg.highwire.dtl.DTLVardef@14c74dcorg.highwire.dtl.DTLVardef@8c2377org.highwire.dtl.DTLVardef@6c6845_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗
bioRxiv2023

Mycobacterium tuberculosis infection associated immune perturbations correlate with antiretroviral immunity

Infection with Mycobacterium tuberculosis (MTB) remains one of the most important opportunistic infections in people with HIV-1 (PWH). While active Tuberculosis (TB) leads to rapid progression of immunodeficiency in PWH, the interaction between MTB and HIV-1 during the asymptomatic phase of both infections remains poorly understood. In a cohort of individuals with HIV (PWH) with and without suppressed HIV-1 viral load, the transcriptomic profiles of peripheral blood mononuclear cells (PBMC) clustered in individuals infected with Mycobacterium tuberculosis (MTB) compared to carefully matched controls. Subsequent functional annotation analysis disclosed alterations in the IL-6, TNF, and KRAS pathways. Notably, MTB-associated genes demonstrated an inverse correlation with HIV-1 viremia, evident at both on individual gene level and when employed as a gene score. In sum, our data show that MTB infection in PWH is associated with a shift in the activation state of the immune system, displaying an inverse relationship with HIV-1 viral load. These results could provide an explanation for the observed increased antiretroviral control associated with MTB infection in PWH.

immunology↗
bioRxiv2023

Serine ubiquitination of p62 regulates Nrf2 dependent redox homeostasis

The KEAP1-Nrf2 axis is essential for the cellular response against metabolic and oxidative stress. KEAP1 is an adaptor protein of Cullin-3 ubiquitin ligase that controls the cellular levels of Nrf2, a critical transcription factor of several cytoprotective genes. Oxidative stress, defective autophagy and pathogenic infections activate Nrf2 signaling through phosphorylation of the adaptor protein p62, which competes with Nrf2 for binding to KEAP1. Here we show that phosphoribosyl-linked serine ubiquitination of p62 catalyzed by SidE effectors of Legionella pneumophila controls Nrf2 signaling and cell metabolism upon Legionella infection. Serine ubiquitination of p62 sterically blocks its binding to KEAP1, resulting in Nrf2 ubiquitination and degradation. This reduces Nrf2-dependent antioxidant synthesis in the early phase of infection. Levels of serine ubiquitinated p62 diminish in the later stage of infection allowing the expression of Nrf2-target genes; resulting in a differential regulation of the host metabolome and proteome in a Nrf2 dependent manner.

cell biology↗
bioRxiv2023

Evaluating key evidence and formulating regulatory alternatives regarding the UK Hunting Trophies (Import Prohibition) Bill

Public policy addressing biodiversity loss is most likely to be effective when it is informed by appropriate evidence and considers potential unintended consequences. We evaluate key evidence relating to the Hunting Trophies (Import Prohibition) Bill that was discussed in the UK Parliament between 2022 and 2024. We characterize the UKs role in international hunting trophy trade by analyzing CITES trade data for 2000-2021 and 2015-2021. For CITES-listed species imported to/exported from the UK as hunting trophies in these periods we use data from the International Union for Conservation of Nature Red List of Threatened Species to determine whether hunting designated as "trophy hunting" is i) likely a major threat contributing to species being of elevated conservation concern, ii) likely or possibly causing localized declines, or iii) not a threat. We then use the Red List to determine whether such hunting provides, or potentially provides, benefits for species and/or people. Finally, we evaluate the UK Governments impact assessment of the bill. In 2000-2021 an estimated 3494 hunting trophies from 73 CITES-listed species and subspecies were exported to the UK involving an estimated 2549 whole organism equivalents (WOEs), i.e. individual animals. Imports involved 158.86 {+/-} 66.53 (mean {+/-} SD) trophies/year (115.83 {+/-} 32.27 WOEs/year). In 2015-2021, 79% of imports were from countries where populations of the hunted species are stable, increasing, or abundant. Legal hunting for trophies is not a major threat to any of the species or subspecies imported to the UK, but likely or possibly represents a local threat to some populations of nine species. This hunting does, or could potentially, benefit 20 species and subspecies, and people. Among other concerns, the impact assessment failed to adequately consider the costs and benefits to local communities in countries where such hunting occurs. Informed by these analyses we discuss alternative regulatory options.

ecology↗
bioRxiv2023

Energetic driving force for LHCII clustering in plant membranes

Plants protect themselves against photodamage from excess energy using a process known as non-photochemical quenching (NPQ). A significant fraction of NPQ is induced by a {Delta}pH across the membrane, which changes the conformation, composition, and organization of the antenna complexes. In particular, clustering of the major light-harvesting complex (LHCII) has been observed, yet the thermodynamic driving force behind this reorganization has not been determined, largely because measurements of membrane protein interaction energies have not been possible. Here, we introduce a method to quantify membrane protein interaction energies and its application to the thermodynamics of LHCII clusters. By combining single-molecule measurements of LHCII-proteoliposomes at different protein densities and a rigorous analysis of LHCII clusters and photophysics, we quantified the LHCII-LHCII interaction energy to be approximately -5 kBT at neutral pH and at least -7 kBT at acidic pH. From these values, we found the thermodynamic driving force for LHCII clustering was dominated by these enthalpic contributions. Collectively, this work captures the membrane protein-protein interactions responsible for LHCII clustering from the perspective of equilibrium statistical thermodynamics, which has a long and rich tradition in biology.

biophysics↗
bioRxiv2023

Rheological behavior of Pluronic/Pluronic diacrylate hydrogels used for bacteria encapsulation in living materials

Pluronic (Plu) hydrogels containing Pluronic diacrylate (PluDA) have become popular matrices to encapsulate bacteria in engineered living materials. For this purpose, 30 wt% Plu/PluDA hydrogels with variable fraction of covalently crosslinkable PluDA in the hydrogel composition are used. The degree of covalent crosslinking and the consequent different mechanical properties of the hydrogels have been shown to affect bacteria growth, but a systematic investigation of the mechanical response of the hydrogels is still missing. Here we study the rheological response of 30 wt.% Plu/PluDA hydrogels with increasing PluDA fraction between 0 and 1. We quantify the range of viscoelastic properties that can be covered in this system by varying in the PluDA fraction. We present stress relaxation and creep-recovery experiments, and analyze the variation of the critical yield strain/stress, relaxation and recovery parameters of Plu/PluDA hydrogels as function of the covalent crosslinking degree using the Burgers and Weilbull models. We expect this study to help users of Plu/PluDA hydrogels to estimate the mechanical properties of their systems, and eventually to correlate them with the behaviour of bacteria in future Plu/PluDA devices of similar composition.

bioengineering↗