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Adam, K.

Publications and source records attributed to Adam, K..

7 recordsLinked to original sources

DeltaMut: An Integrative Database of AlphaFold2-Derived Missense Variant Structures

The widespread use of next-generation sequencing has led to a surge in the number of identified variants with uncertain effects on protein function. These variants pose a significant challenge in diagnostics and hinder patient treatment strategies. Numerous variant effect predictors (VEPs) are available to assess variant impact, but they primarily rely on sequence-derived information. The recent development of AlphaFold2 has raised questions about whether information retrieved from wild-type or predicted structures of missense variants can improve the predictive power of these algorithms. While the AlphaFold Protein Structure Database serves as a valuable resource for wild-type protein structures, a large-scale collection of missense variant structures is not available, limiting current efforts to wild-type conformations and a handful of modeled variants. To address this limitation, we developed DeltaMut, a comprehensive database containing over 77,000 protein structures, including 65,000 pathogenic and neutral missense variants. All structural models were generated using ParaFold, a high-performance computing-optimized implementation of AlphaFold2. The large-scale and systematic generation of variant protein structures distinguish DeltaMut as a unique resource for both expansive statistical studies and detailed, case-specific investigations of variant-induced structural changes. Furthermore, the DeltaMut database is freely accessible without registration. HighlightsO_LIDeltaMut is currently the largest database of AlphaFold2-predicted variant structures. C_LIO_LIContains 77,713 structures covering 12,101 wild-type and 65,612 variant proteins. C_LIO_LI70.6% of predicted structures have high or very high confidence (pLDDT [≥] 70). C_LIO_LIFreely accessible web server with visualization and download of variant models. C_LI

bioinformatics↗

Modulation of repopulating microglia in multiple sclerosis models with implications for neuroprotection

Microglia play a critical role in central nervous system (CNS) pathologies including multiple sclerosis (MS), and their modulation offers therapeutic potential especially during progressive disease courses. Using cell culture and experimental autoimmune encephalomyelitis (EAE) models, we investigated microglial dynamics during depletion and repopulation (MGrepo) and their modulation using siponimod (sipo), an established CNS penetrating MS medication. Repopulating microglia exhibited a transient reactive state (CD86, MHC-II, Il1b, Tnf). Sipo modulated microglia populations, increasing CD163+, CD206+, and CX3CR1+ while reducing CD86+MHC-II+ cells accompanied by a reduction of neuronal damage. Proteomic spinal cord analysis revealed protein expression alterations by MGrepo and sipo linked to inflammation, myelination, and neuronal structural organization, supported by RNA sequencing of the spinal cord. The neuroinflammation attenuating role of sipo could be linked to cell maintenance and myelin formation associated processes. These findings highlight the capacity of pharmacological interventions to modulate microglia, offering new insights into therapeutic strategies targeting microglial activity in neuroinflammatory diseases.

neuroscience↗

A drop-on-demand bioprinting approach to spatially arrange multiple cell types and monitor their cell-cell interactions towards vascularization based on endothelial cells and mesenchymal stem cells

Spheroids, organoids, or highly-dense cell-laden droplets are often used as building blocks for bioprinting, but so far little is known about the spatio-temporal cellular interactions post printing. We present a drop-on-demand approach to study the biological interactions of such building blocks in micrometer dimensions. Droplets (containing approximately 700 cells in 10 nl) of multiple cell types are patterned in a 3D hydrogel matrix with a precision of less than 70 m. It is applied to investigate interactions of cell types relevant for vascularization approaches. We show that a gap of 200 m between droplets containing endothelial cells (HUVECs) and adipose-derived mesenchymal stem cells (ASCs) leads to decreased sprouting of HUVECs towards ASCs and increased growth from ASCs towards HUVECs. For mixed aggregates containing both cell types, cellular interconnections of ASCs with up to approximately 0.8 millimeter length and inhibition of HUVEC sprouting are observed. When ASCs are differentiated into smooth muscle cells (SMCs), HUVECs display decreased sprouting towards SMCs in separate aggregates, whereas no cellular interconnections or inhibition of HUVEC sprouting are detected for mixed aggregates. These findings demonstrate that this approach acts as a new tool to investigate cell-cell interactions of different cell types in 3D bioprinted constructs.

bioengineering↗

Genomic adaptation in the CAZyome and specialised metabolism of the plant-associated Streptomyces violaceusniger clade

Streptomycetes are Gram-positive actinobacteria largely represented in the plant root microbiota. The genetic determinants involved in the presence of Streptomyces in the rhizosphere are mostly unknown but can rely on the ability to release phytohormones, degrade plant cell-wall polysaccharides and produce specialised metabolites. Here we sequenced the genome of the rhizospheric and plant defence-stimulating strain Streptomyces sp. AgN23. We found out that it belongs to the soil and plant root dwelling S. violaceusniger clade. The genome annotation of AgN23 revealed the ability of the bacterium to synthesise auxin, a major regulator of plant development, to degrade plant cell wall with a large repertoire of carbohydrate degrading enzymes and to produce antimicrobials (rustmicin, mediomycin, niphimycin, nigericin) and plant bioactive compounds (nigericin, echosides, elaiophylin) through a set of biosynthetic gene clusters. We also found that these genomic features are well-conserved among members of the S. violaceusniger clade. In addition, AgN23 display original events of biosynthetic gene clusters acquisitions and losses which may account for its beneficial effect on plants. Taken together, our work supports the hypothesis that hydrolytic enzymes and specialised metabolites repertoires underpin the interaction of bacteria belonging to the S. violaceusniger clade with plant roots within the rhizosphere. Impact statementStreptomycetes are filamentous Gram-positive bacteria universally found around and within host plant tissues. These actinobacteria have been extensively investigated for their tremendous ability to produce diverse specialised metabolites (e.g., antibiotics). By contrast their impact on host plant physiology is widely neglected. Whether specific lineage of Streptomyces colonise host plant and what are the underlying molecular mechanisms is poorly documented. Here we report a chromosome-scale assembly of AgN23 genome, a Streptomyces sp. strain previously characterised for its ability to activate the plant immune system. This reference sequence enabled us to position AgN23 in the S. violaceusniger clade from which several representatives have been isolated worldwide from the rhizosphere of unrelated plants. Comparative genomic studies suggest that S. violaceusniger spp. produce a prominent CAZyome with expansion of plant cell wall degrading enzymes families and a conserved specialised metabolism acting on host plant physiology and its rhizospheric microbiota. These genomic features may underly S. violaceusniger spp. adaptation to the rhizopsheric niche. Data summaryThe raw reads sequences of AgN23 genome are available at NCBI on the Sequence Read Archive portal for PacBio and MiSeq data (SRR13990229 and SRR14028548 respectively). The Genome assembly is available on the NCBI nucleotide portal under the accession NZ_CP007153.1. This genome sequence was uploaded on the MicroScope platform for genome annotation and analysis (https://mage.genoscope.cns.fr/microscope/home/index.php) [1]. The RNA-seq raw reads are archived in the NCBI Bioproject PRJNA745930. The following eight supplementary tables are included in the online version of this article. Supplementary Information 1: Genomes used in this study. The accession number used from the NCBI portal, name, size, number of contigs as well as the level of completeness of the assembly are indicated. Supplementary Information 2: List of the single copy core genes used by autoMLST to build the phylogenetic tree in Figure 1. O_FIG O_LINKSMALLFIG WIDTH=161 HEIGHT=200 SRC="FIGDIR/small/465742v2_fig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@e15f3org.highwire.dtl.DTLVardef@c34218org.highwire.dtl.DTLVardef@1286956org.highwire.dtl.DTLVardef@1bb5b3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Multi-locus sequence typing assigned AgN23 to the S. violaceusniger clade. Phylogenetic tree based on the multiple alignment of 85 single-copy homologous genes selected from genomic sequences with AutoMLST. The green node highlights the isolates considered to be from the same species (ANI>95%). The black node highlights the clade formed by isolates with ANI>90% as compared to AgN23. The black squares highlights the eight strains that were used for the BGC conservation study. The green logo indicates plant-isolated strains. Frankia alni ACN14a was used as outgroup, bootstrap=100. C_FIG Supplementary information 3: Annotation of AgN23 full chromosome. For each gene the frame of translation, sequence length and position on the chromosome are indicated. All genes were annotated according to the Microscope platform, see materials and methods. In addition, the expression for each gene is reported in transcripts per million (TPM) based on the the RNA-seq data from three biological replicates. Supplementary Information 4: Genomes having a Mash-based estimated ANI (Average Nucleotide Identity) superior or egal to 80% according to autoMLST. Supplementary Information 5: Prediction of the CAZyme encoding genes using HMMER dbCAN2. The genes are sorted according their CAZy families. For each gene, the begin position on the chromosome, the CAZy category, the annotation, the expression level in transcripts per million (TPM) and the predicted targets of the putative enzymes are described. Supplementary Information 6: Gene identified by antiSMASH in the region containing a biosynthetic gene cluster. Expression levels in transcripts per million (TPM) are indicated for each gene. Annotated central bioynthetic genes are indicated as Y. Those are the ones used for the calculation of mean BGC expression in Table 2. O_TBL View this table: org.highwire.dtl.DTLVardef@1362f24org.highwire.dtl.DTLVardef@50f792org.highwire.dtl.DTLVardef@1ad9681org.highwire.dtl.DTLVardef@1742e96org.highwire.dtl.DTLVardef@9e9b6c_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 2:C_FLOATNO O_TABLECAPTIONantiSMASH annotation of AgN23 chromosomal regions coding for Biosynthetic Gene Clusters. The functional category of each BGCs was determined by antiSMASH. The BGC type, best hit in the MIBiG database as its percentage of similarity to the query are indicated along with the bacterial strain from whom the cluster was described. The expression level of each BGCs was determined by doing the mean of the expression level in Transcripts Per Million (TPM) of the core biosynthetic genes of each BGC from the RNA-seq data (n=3). C_TABLECAPTION C_TBL Supplementary Information 7: Annotation of AgN23 genes putatively involved in biosynthetic pathways for Auxins related phytohomones. Expression levels in transcripts per million (TPM) are indicated for each gene. The genes were detected by blasting reference KEGG sequences for each KEGG ONTOLOGY against AgN23 genes. A cut off of 70% identity and 40% coverage was applied to detect positive hits. These biosynthetic pathways and the KEGG ONTOLOGY are indicated in column F and G. Supplementary Information 8: Inspection of BiG-FAM hits with AgN23 BGCs to identify homologous BGCs found outside the S. violaceusniger clade. BiG-FAM distance higher than 900 were excluded from the analysis. The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files.

genomics↗

Steady-state visually evoked potentials and feature-based attention: Pre-registered null results and a focused review of methodological considerations.

Feature-based attention is the ability to selectively attend to a particular feature (e.g., attend to red but not green items while looking for the ketchup bottle in your refrigerator), and steady-state visually evoked potentials (SSVEPs) measured from the human electroencephalogram (EEG) signal have been used to track the neural deployment of feature-based attention. Although many published studies suggest that we can use trial-by-trial cues to enhance relevant feature information (i.e., greater SSVEP response to the cued color), there is ongoing debate about whether participants may likewise use trial-by-trial cues to voluntarily ignore a particular feature. Here, we report the results of a pre-registered study in which participants either were cued to attend or to ignore a color. Counter to prior work, we found no attention-related modulation of the SSVEP response in either cue condition. However, positive control analyses revealed that participants paid some degree of attention to the cued color (i.e., we observed a greater P300 component to targets in the attended versus the unattended color). In light of these unexpected null results, we conducted a focused review of methodological considerations for studies of feature-based attention using SSVEPs. In the review, we quantify potentially important stimulus parameters that have been used in the past (e.g., stimulation frequency; trial counts) and we discuss the potential importance of these and other task factors (e.g., feature-based priming) for SSVEP studies.

neuroscience↗

Interplay between persistent activity and activity-silent dynamics in prefrontal cortex during working memory

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative, \"activity-silent\" substrates for memory. Using monkey and human electrophysiology, we show here that attractor dynamics that control neural spiking during mnemonic periods interact with activity-silent mechanisms in PFC. This interaction allows memory reactivation, which enhance serial biases in spatial working memory. Stimulus information was not decodable between trials, but remained present in activity-silent traces inferred from spiking synchrony in PFC. Just prior to the new stimulus, this latent trace was reignited into activity that recapitulated the previous stimulus representation. Importantly, the reactivation strength correlated with the strength of serial biases in both monkeys and humans, as predicted by a computational model integrating activity-based and activity-silent mechanisms. Finally, single-pulse TMS applied to human prefrontal cortex prior to trial start enhanced serial biases, demonstrating the causal role of prefrontal reactivations in determining working memory behavior.

neuroscience↗

A non-acidic method using hydroxyapatite and phosphohistidine monoclonal antibodies allows enrichment of phosphopeptides containing non-conventional phosphorylations for mass spectrometry analysis.

Four types of phosphate-protein linkage generate nine different phosphoresidues in living organisms. Histidine phosphorylation is a long-time established but largely unexplored post-translational modification, mainly because of the acid-lability of the phosphoramidate bonds. This lability means that standard phosphoproteomic methods used for conventional phosphate esters (phospho-Ser/Thr/Tyr) must be modified to analyze proteins containing the phosphoramidate-amino acids - phospho-His/Arg/Lys. We show that a non-acidic method allows enrichment of non-conventional phosphoresidue-containing peptides from tryptic digests of human cell lines, using hydroxyapatite binding and/or immobilized 1-pHis and 3-pHis monoclonal antibodies for enrichment. 425 unique non-conventional phosphorylation sites (i.e. pHis, pLys and pArg) were detected with a high probability of localization by LC-MS/MS analysis and identified using a customized MaxQuant configuration, contributing to a new era of study in post-translational modification and cell signaling in humans. This is the first fully non-acidic method for phosphopeptide enrichment which uses immunoaffinity purification and remains compatible with mass spectrometry analysis for a wider coverage of potential protein phosphorylation events.

biochemistry↗