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Schmidt, C.

Publications and source records attributed to Schmidt, C..

At least 55 records · Page 3Linked to original sources

Climate change, age acceleration, and the erosion of fitness in polar bears

Climate change is increasingly disrupting evolved life history strategies and reducing population viability in wild species. Using estimates of epigenetic age acceleration, a cellular biomarker of lifetime stress and the expression of age-related phenotypes, we found that polar bears aged approximately one year faster for each degree of warming since the 1960s. Age acceleration was also associated with reproducing early in life, linking this cellular process to well-established life history theory. However, we found evidence for the erosion of fitness as epigenetic aging accelerated and temperatures increased. Finally, using a large pedigree, we found adaptive potential in our study population was approximately zero. Global temperatures will soon reach the levels of warming currently experienced by Arctic species, which could impose widespread physiological costs and limit adaptive capacities worldwide.

ecology↗

MetalinksDB: a flexible and contextualizable resource of metabolite-protein interactions

Interactions between proteins and metabolites are key for cellular function, from the catalytic breakdown of nutrients to signaling. An important case is cell-cell communication, where cellular metabolites are secreted into the microenvironment and initiate a signaling cascade by binding to an intra- or extracellular receptor of another cell. While protein-protein mediated cell-cell communication is routinely inferred from transcriptomic data, for metabolite-protein interactions this is challenging due to the limitations of high-throughput single-cell and spatial metabolomics technologies, together with the absence of comprehensive prior knowledge resources that include metabolites. Here we report MetalinksDB, a comprehensive and flexible database of intercellular metabolite-protein interactions that is a magnitude larger than existing ones. MetalinksDB can be tailored to specific biological contexts such as diseases, pathways, or tissue/cellular locations by querying subsets of interactions using the web interface (https://metalinks.omnipathdb.org/) or the knowledge graph adapters. We showcase the use of MetalinksDB by identifying deregulated processes in renal cancer patients from multi-omics data as well as inferring metabolite-mediated cell-cell communication events driving acute kidney injury from spatial transcriptomic data. We anticipate that MetalinksDB will facilitate the study of metabolite-mediated communication processes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/573715v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@18c78aaorg.highwire.dtl.DTLVardef@145f21borg.highwire.dtl.DTLVardef@119d16borg.highwire.dtl.DTLVardef@3febb_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation

Endoplasmic reticulum unfolded protein responses (UPRER) contribute to cancer development and the activating transcription factor 6 (ATF6) is involved in microbiota-dependent tumorigenesis. Here, we substantiate the clinical relevance of ATF6 in early-onset and late colorectal cancer patient cohorts. Transcriptional analysis in intestinal epithelial cells (IEC) of ATF6 transgenic mice (nATF6IEC) identified bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype-labeling confirmed ATF6-related enrichment of long chain fatty acids in colonic tissue of patients, mice and organoid cultures. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirmed the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumor-relevant microbial taxa was mechanistically linked to long chain fatty acid exposure, using bioorthogonal non-canonical amino acid tagging (BONCAT) and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signaling in the epithelium to select for tumor-promoting microbiota by altering lipid metabolism. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/565267v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@be3756org.highwire.dtl.DTLVardef@231da4org.highwire.dtl.DTLVardef@16f3aaeorg.highwire.dtl.DTLVardef@1758fe3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Chronic ATF6 signaling in the colonic epithelium alters lipid metabolism to select a tumor-promoting microbiota C_FIG O_LIBiallelic expression of activated ATF6 (p50 nuclear fragment) in intestinal epithelial cells (nATF6IEC) induces spontaneous colon tumors in SPF but not GF mice C_LIO_LIMechanistically, biallelic SPF nATF6IEC mice alter colonic lipid metabolism, including the upregulation of LCFAs and Fasn C_LIO_LIInhibition of FASN prevents colon tumor formation in mice, and reduces the tumor-promoting potential of the intestinal microbiota (FMT) C_LIO_LIExposure of fl/fl control mouse microbiota to LCFAs ex vivo translationally activates tumor-associated bacteria, including Desulfovibrio fairfieldensis C_LIO_LIHuman CRC patients show ATF6 upregulation, FASN co-occurrence and increased LCFAs in T tissue C_LIO_LIATF6 activity links with CRC-associated microbiota in patients, including Desulfovibrio C_LI Created with BioRender.com nATF6: activated activating transcription factor 6; LCFA: long-chain fatty acids; SAFA: saturated fatty acids; Fasn: fatty acid synthase; C75 i.p.: intraperitoneal injection of the Fasn inhibitor C75.

cancer biology↗

Migration distance and mating system are not associated with genetic diversity and differentiation among bats (Chiroptera)

Genetic variation is critical for evolutionary responses to environmental change. Links between genetic variation and behavioural or life history traits may reveal how varied strategies influence evolutionary trends in speciation and adaptation. Traits associated with movement typically correlate with population genetic structure and could help predict populations vulnerability to geographic processes such as habitat fragmentation and disease spread. With their wide diversity in behaviours and ecologies, bats provide a useful testing ground for hypotheses about population structure related to species-specific movement patterns. We used a global sample of microsatellite data (n=233 sites from 17 bat species) associated with published studies to examine potential links between genetic variation and migration and mating strategies. The genetic measures we tested were population-specific differentiation, gene diversity, and allelic richness. Using Bayesian models that accounted for phylogenetic distances among species, we identified no correlations between migration or mating strategy and genetic variation. Our results do not support long-standing hypotheses about dispersal-mediated genetic structure, and contrast with prior studies on bat genetic diversity and differentiation. We discuss the need for continued research into the complex association of ecological, biogeographical, and behavioural factors that facilitate gene flow among populations, especially in species with diverse movement patterns.

zoology↗

Light-induced Trpin/Metout switching during BLUF domain activation in ATP-bound photoactivatable adenylate cyclase OaPAC

The understanding of signal transduction mechanisms in photoreceptor proteins is essential for elucidating how living organisms respond to light as environmental stimuli. In this study, we investigated the ATP binding, photoactivation and signal transduction process in the photoactivatable adenylate cyclase from Oscillatoria acuminata (OaPAC) upon blue light excitation. Structural models with ATP bound in the active site of native OaPAC at cryogenic as well as room temperature are presented. ATP is found in one conformation at cryogenic- and in two conformations at ambient-temperature, and is bound in a non-productive conformation. However, FTIR spectroscopic experiments confirm that the non-productive conformation is the native binding mode in dark state OaPAC and that transition to a productive conformation for ATP turnover only occurs after light activation. A combination of time-resolved crystallography experiments at synchrotron and X-ray Free Electron Lasers sheds light on the initial events around the Flavin Adenine Dinucleotide (FAD) chromophore in the light-sensitive BLUF domain of OaPAC. Initial changes involve the highly conserved amino acids Tyr6, Gln48 and Met92. Crucially, the Gln48 side chain performs a 180{degrees} rotation during activation, leading to the stabilization of the FAD chromophore. Cryo-trapping experiments allowed us to investigate a late light-activated state of the reaction and revealed significant conformational changes in the BLUF domain around the FAD chromophore. In particular, a Trpin/Metout transition upon illumination is observed for the first time in the BLUF domain and its role in signal transmission via -helix 3 and 4 in the linker region between sensor and effector domain is discussed.

biochemistry↗

PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression

SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

cancer biology↗

Napping and circadian sleep-wake regulation during healthy aging.

Study objectivesDaytime napping is frequently reported among the older population and has attracted increasing attention due to its association with multiple health conditions. Here, we tested whether napping in the aged is associated with altered circadian regulation of sleep, sleepiness and vigilance performance. MethodsSixty healthy older individuals (mean age: 69y., 39 women) were recruited with respect to their napping habits (30 nappers, 30 non-nappers). All participants underwent an in-lab 40-h multiple nap protocol (10 cycles of 80 mins of sleep opportunity alternating with 160 mins of wakefulness), preceded and followed by a baseline and recovery sleep period. Saliva samples for melatonin assessment, sleepiness and vigilance performance were collected during wakefulness and electrophysiological data were recorded to derive sleep parameters during scheduled sleep opportunities. ResultsThe circadian amplitude of melatonin secretion was reduced in nappers, compared to non-nappers. Furthermore, nappers were characterized by higher sleep efficiencies and REM sleep proportion during day-compared to night-time naps. The nap group also presented altered modulation in sleepiness and vigilance performance at specific circadian phases. DiscussionOur data indicate that napping is associated with an altered circadian sleep-wake propensity rhythm and thereby contribute to the understanding of the biological correlates underlying napping and/or sleep-wake cycle fragmentation during healthy aging. Altered circadian sleep-wake promotion can lead to a less distinct allocation of sleep into night-time and/or a reduced wakefulness drive during the day, thereby potentially triggering the need to sleep at adverse circadian phase. SIGNIFICANCE STATEMENTWhile napping has raised increasing interest as a health risk factor in epidemiological studies, its underlying regulation processes in the aged remain largely elusive. Here we assessed whether napping in the older population is associated with physiological and behavioral changes in circadian sleep-wake characteristics. Our data indicate that, concomitant to a reduced circadian amplitude in melatonin secretion, healthy older nappers are characterized by reduced day-night differences in sleep efficiency and more particularly in REM sleep, compared to their non-napping counterparts. These results suggest altered circadian response as a cause or consequence of chronic napping in the aged and thereby contribute to the understanding of nap regulation during healthy aging.

neuroscience↗

In vivo marker of brainstem myelin is associated to quantitative sleep parameters in healthy young men

Brain structural integrity has been suggested to contribute to the variability in human sleep quality and composition. The associations between sleep parameters and the regional integrity of subcortical structures implicated in sleep-wake regulation remain, however, largely unexplored. The present study aimed at assessing association between quantitative Magnetic Resonance Imaging (qMRI)-derived marker of the myelin content of the brainstem with the variability in the sleep electrophysiology in a large sample of healthy young men (N=321;[~]22y). Generalized Additive Model for Location, Scale and Shape (GAMLSS) was used to seek associations between sleep metrics and Magnetisation Transfer saturation (MTsat) qMRI values, proxy for myelin content. Separate GAMLSS revealed that sleep onset latency and slow wave sleep intensity were significantly associated with MTsat-derived myelin estimates in the brainstem (pcorrected[≤].03), with overall higher MTsat value associated with values reflecting better sleep quality. The association changed with age, however (MTsat-by-age interaction - pcorrected[≤].03), with higher MTsat value linked to better values in the two sleep metrics in the individuals of our sample aged [~]18 to 20y. Similar associations were detected across different parts of the brainstem (pcorrected[≤].03), suggesting that the overall maturation and integrity of the brainstem was associated with both sleep metrics. Our results suggest that myelination of the many reticular nuclei of the brainstem essential to regulation of sleep is associated with inter-individual differences in sleep characteristics during early adulthood. They may have implications for sleep disorders or neurological diseases related to myelin.

neuroscience↗

Uncovering the Environmental Conditions Required for Phyllachora maydis Infection and Tar Spot Development on Corn in the United States for Use as Predictive Models for Future Epidemics

Phyllachora maydis is a fungal pathogen causing tar spot of corn (Zea mays L.), a new and emerging, yield-limiting disease in the United States. Since being first reported in Illinois and Indiana in 2015, P. maydis can now be found across much of the corn growing of the United States. Knowledge of the epidemiology of P. maydis is limited but could be useful in developing tar spot prediction tools. The research presented here aims to elucidate the environmental conditions necessary for the development of tar spot in the field and the creation of predictive models to anticipate future tar spot epidemics. Extended periods (30-day windowpanes) of moderate ambient temperature were most significant for explaining the development of tar spot. Shorter periods (14- to 21-day windowpanes) of moisture (relative humidity, dew point, number of hours with predicted leaf wetness) were negatively correlated with tar spot development. These weather variables were used to develop multiple logistic regression models, an ensembled model, and two machine learning models for the prediction of tar spot development. This work has improved the understanding of P. maydis epidemiology and provided the foundation for the development of a predictive tool for anticipating future tar spot epidemics.

plant biology↗

Alternative splicing of its 5' untranslated region controls CD20 mRNA translation and enables resistance to CD20-directed immunotherapies

Aberrant skipping of coding exons in CD19 and CD22 compromises responses to immunotherapy for B-cell malignancies. Here, we show that the MS4A1 gene encoding human CD20 also produces several mRNA isoforms with distinct 5 untranslated regions (5-UTR). Four variants (V1-4) were detectable by RNA-seq in distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant by far. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform was found to contain upstream open reading frames (uORFs) and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching Morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, while V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed CAR T cells were able to kill both V3- and V1-expressing cells, but the bispecific T cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on four post-mosunetuzumab follicular lymphoma relapses and discovered that in two of them downregulation of CD20 was accompanied by the V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies. Key PointsO_LIIn normal & malignant human B cells, CD20 mRNA is alternatively spliced into four 5-UTR isoforms, some of which are translation-deficient. C_LIO_LIThe balance between translation-deficient and -competent isoforms modulates CD20 protein levels & responses to CD20-directed immunotherapies C_LI Explanation of NoveltyWe discovered that in normal and malignant B-cells, CD20 mRNA is alternatively spliced to generate four distinct 5-UTRs, including the longer translation-deficient V1 variant. Cells predominantly expressing V1 were still sensitive to CD20-targeting chimeric antigen receptor T-cells. However, they were resistant to the bispecific anti-CD3/CD20 antibody mosunetuzumab, and the shift to V1 were observed in CD20-negative post-mosunetuzumab relapses of follicular lymphoma.

immunology↗

Mix-and-extrude using 3D printed nozzles for time-resolved membrane protein crystallography

Time-resolved crystallography enabled the visualization of protein molecular motion during reaction. While light is commonly used to initiate reactions in time-resolved crystallography, only a small number of proteins can in fact be activated by light. However, many biological reactions can be triggered by the interaction of proteins with ligands. The sample delivery method presented here uses a mix-and-extrude approach based on 3D printed microchannels in conjunction with a micronozzle to study the dynamics of samples in viscous media that can be triggered by diffusive mixing. The device design allows for mixing of ligands and protein crystals in a time window of 2 to 20 seconds. The device characterization using a model system (fluorescence quenching of iq-mEmerald proteins by copper ions) demonstrated that ligand and protein crystals, each within the lipidic cubic phase, can be mixed efficiently. The potential use of this approach for time-resolved membrane protein crystallography to support in the development of new drugs is also discussed. Synopsis3D printed mixing-HVE devices address time-resolved membrane protein crystallography challenges via compact dual-flow LCP injection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/517685v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@12f6f68org.highwire.dtl.DTLVardef@13b198eorg.highwire.dtl.DTLVardef@10abe5eorg.highwire.dtl.DTLVardef@5810ee_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

Nucleotide-free structures of Kif20A illuminate the atypical allostery in this mitotic kinesin-6

KIF20A is a critical kinesin for cell division and a promising anti-cancer drug target. The mechanisms underlying its cellular roles remain elusive. Interestingly, unusual coupling between the nucleotide- and microtubule-binding sites of this kinesin-6 has been reported but little is known about how its divergent sequence leads to atypical motility properties. We present here the first high-resolution structure of its motor domain that delineates the highly unusual structural features of this motor, including a long L6 insertion that integrates into the core of the motor domain and that drastically affects allostery and ATPase activity. Together with the high-resolution cryo-EM microtubule-bound KIF20A structure that reveal the microtubule-binding interface, we dissect the peculiarities of the KIF20A sequence that work to favor fast dissociation of ADP, particularly in contrast to other kinesins. Structural and functional insights from the KIF20A pre-power stroke conformation thus highlight the role of extended insertions in shaping the motor mechanochemical cycle. Essential for force production and processivity is the length of the neck linker in kinesins. We highlight here the role of the sequence preceding the neck linker in controlling its backward docking and show that a neck linker 4-times longer than kinesin-1 is required for the activity of this motor.

biochemistry↗

Gene regulatory network inference in soybean upon infection by Phytophthora sojae

Phytophthora sojae is a soil-borne oomycete and the causal agent of Phytophthora root and stem rot (PRR) in soybean (Glycine max [L.] Merrill). Yield losses attributed to P. sojae are devastating in disease-conducive environments, with global estimates surpassing 1.1 million tonnes annually. Historically, management of PRR has entailed host genetic resistance (both vertical and horizontal) complemented by disease-suppressive cultural practices (e.g., oomicide application). However, the vast expansion of complex and/or diverse P. sojae pathotypes necessitates developing novel technologies to attenuate PRR in field environments. Therefore, the objective of the present study was to couple high-throughput sequencing data and deep learning to elucidate molecular features in soybean following infection by P. sojae. In doing so, we generated transcriptomes to identify differentially expressed genes (DEGs) during compatible and incompatible interactions with P. sojae and a mock inoculation. The expression data were then used to select two defense-related transcription factors (TFs) belonging to WRKY and RAV families. DNA Affinity Purification and sequencing (DAP-seq) data were obtained for each TF, providing putative DNA binding sites in the soybean genome. These bound sites were used to train Deep Neural Networks with convolutional and recurrent layers to predict new target sites of WRKY and RAV family members in the DEG set. Moreover, we leveraged publicly available Arabidopsis (Arabidopsis thaliana) DAP-seq data for five TF families enriched in our transcriptome analysis to train similar models. These Arabidopsis data-based models were used for cross-species TF binding site prediction on soybean. Finally, we created a gene regulatory network depicting TF-target gene interactions that orchestrate an immune response against P. sojae. Information herein provides novel insight into molecular plant-pathogen interaction and may prove useful in developing soybean cultivars with more durable resistance to P. sojae. Author SummaryGlobal food security is threatened continually by plant pathogens. One approach to circumvent these disease-causing agents entails understanding how hosts balance primary growth and defense upon pathogen perception. Molecular signatures of perception-rendered defense may be leveraged subsequently to develop resistant/tolerant crop plants. Additionally, evidence suggests that the plant immune system is characterized by tuning primary and secondary metabolic activity via transcription factor-mediated transcriptional reprogramming. Therefore, we investigated transcription factor-target gene interactions in soybean upon infection by compatible and incompatible races of Phytophthora sojae. Through transcriptome analysis, we found that the interactions elicited vast, overlapping transcriptional responses and identified overrepresented, defense-related transcription factor families. We then generated/acquired DNA-protein interactome data for the most represented transcription factor families in the transcriptome analysis and trained deep learning-based models to predict novel transcription factor targets. Transcription factor/target gene metrics were used to construct a gene regulatory network with prioritized components. We identified hub transcription factors belonging to WRKY and ERF families, the majority of which function in response to various biotic and abiotic stressors. These findings propose novel regulators in the soybean defense response to Phytophthora sojae and provide an avenue for the investigation of transcription factor-target gene interactions in plants.

plant biology↗

Evolutionary history of Euteliidae (Lepidoptera, Noctuoidea)

The Euteliidae stand apart in the Noctuoidea as the second smallest family, but most highly specialized in terms of larval hostplant relationships, favouring plant families with high levels of resin or latex, including the family dominant in Oriental lowland forests, the Dipterocarpaceae. Given the proportionally large foliage biomass represented by dipterocarps, exploitation of this abundant resource by lepidopteran defoliators is surprisingly low, and the Euteliidae may have achieved this through pre-adaption to dipterocarp chemical defences. Therefore, to assess this, we performed a molecular phylogenetic analysis on the family Euteliidae to clarify deep divergences and elucidate evolutionary relationships at the level of the subfamily, tribe, and genus. Our dataset consists of 6.3 kbp of one mitochondrial and seven nuclear DNA loci and was analyzed using model-based phylogenetic methods, i.e., maximum likelihood and Bayesian inference. We attempted to diagnose apomorphic morphological character states for Euteliidae and each monophyletic group within the family. Additionally, the evolution of hostplant use was reconstructed and a molecular-dating approach was conducted to assess the ages of major lineages within Euteliidae. We present an updated phylogenetic hypothesis for Euteliidae consisting of two strongly supported subfamilies: Euteliinae and Stictopterinae. Within Stictopterinae there are two tribes: Stictopterini and Odontodini. Several genera (e.g., Targalla, Paectes, Marathyssa, Eutelia) were found to be polyphyletic and require taxonomic revision. Two new genera (Niklastelia and Pellinentelia) are described and several taxonomic changes (e.g., new combinations and new synonymies) are made. The Neotropical genus Thyriodes, currently included in Euteliidae, is found to be associated with Erebinae (Erebidae). The divergence time estimate for the split between the Euteliidae and Noctuidae is at 53 my, and the Euteliidae split into the subfamilies Euteliinae and Stictopterinae at 42 my. In Stictopterinae, the tribes Stictopterini and Odontodini split at 31 my and the Euteliinae began a much more complex diversification at 34 my. Ancestral hostplant reconstruction identified Malpighiales (e.g., Clusiaceae) as the ancestral larval hostplant order for the family Euteliidae. The ancestors of Stictopterinae also appear to have been Malpighiales feeders, but then split into exclusive specialisms on Malvales (Odontodini) and Malpighiales (Stictopterini) hostplants. Larvae of Stictopterini appear to be restricted to Clusiaceae, apart from a few records from Dipterocarpaceae. In Euteliinae, Anacardiaceae are predominant as larval hosts. Thus, all hosts in the family are lactiferous, possibly providing some degree of pre-adaptation for exploiting Dipterocarpaceae.

evolutionary biology↗

Single-nuclei transcriptomics of mammalian prion diseases identifies dynamic gene signatures shared between species

Mammalian prion diseases are fatal and transmissible neurological conditions caused by the propagation of prions, self-replicating multimeric assemblies of misfolded forms of host cellular prion protein (PrP). The most common human form of the disease, sporadic Creutzfeldt-Jakob disease (sCJD), typically presents as a rapidly progressive dementia and has no effective treatments. Prion diseases are transmissible to laboratory rodents affording unprecedented opportunities to understand neurodegeneration in its evolving stages. Murine models are especially useful in prion research as they develop bona fide prion disease and recapitulate all biochemical and neuropathological hallmarks of human prion disease. Despite extensive studies investigating the changes in transcriptional profiles in prion diseases the mechanisms by which prion diseases induce cellular toxicity, including changes in gene expression profiles are yet to be fully characterized. This is at least in part because confounding effects related to brain cellular heterogeneity have not been resolved. Here, we took advantage of the recent developments in single-cell technologies and performed an unbiased whole-transcriptome single-nucleus transcriptomic analysis in prion disease.

neuroscience↗

Max is likely not at the Drosophila histone locus

The histone locus body (HLB) is a conserved nuclear body that regulates histone mRNA production in metazoans. While some HLB components are known, there are likely uncharacterized factors that target the histone locus. We identified the Drosophila melanogaster protein Max, which interacts with known HLB member Myc, as an HLB candidate. We mapped Max ChIP-seq and ChIP-nexus datasets, which revealed encouraging signal over the histone gene array. However, we discovered that Max does not colocalize with HLB components on polytene chromosomes. Therefore, we conclude that Max is likely not at the D. melanogaster histone locus.

genetics↗

Prion propagation is dependent on key amino acids in Charge cluster 2 within the prion protein

Prions consist of assemblies of aberrantly folded cellular prion protein (PrPC) upon template-assisted conversion and propagation of disease-associated PrP. To dissect the N-terminal residues critical for efficient prion propagation, we generated a library of point, double, or triple alanine replacements within residues 23-111 of PrP, stably expressed them in cells silenced for endogenous mouse PrPC and challenged the reconstituted cells with four mouse prion strains. Amino acids (aa) 105-111 of Charge Cluster 2 (CC2), which is disordered in PrPC, were required for propagation of all four prion strains; other residues had no effect or exhibited strain-specific effects. Replacements in CC2, including aa105-111, dominantly inhibited prion propagation in the presence of endogenous wild type PrPC whilst other changes were not inhibitory. Single alanine replacements within aa105-111 identified leucine 108 and valine 111 or the cluster of lysine 105, threonine 106 and asparagine 107 as critical for prion propagation. These residues mediate specific ordering of CC2 in the prion fibrils from Rocky Mountain Laboratory (RML) and ME7 mouse prion strains.

molecular biology↗

Multi-chamber cardioids unravel human heart development and cardiac defects

The number one cause of human fetal death are defects in heart development. Because the human embryonic heart is inaccessible, and the impacts of mutations, drugs, and environmental factors on the specialized functions of different heart compartments are not captured by in vitro models, determining the underlying causes is difficult. Here, we established a human cardioid platform that recapitulates the development of all major embryonic heart compartments, including right and left ventricles, atria, outflow tract, and atrioventricular canal. By leveraging both 2D and 3D differentiation, we efficiently generated progenitor subsets with distinct first, anterior, and posterior second heart field identities. This advance enabled the reproducible generation of cardioids with compartment-specific in vivo-like gene expression profiles, morphologies, and functions. We used this platform to unravel the ontogeny of signal and contraction propagation between interacting heart chambers and dissect how genetic and environmental factors cause region-specific defects in the developing human heart. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/499699v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@c9c629org.highwire.dtl.DTLVardef@f0d521org.highwire.dtl.DTLVardef@1389411org.highwire.dtl.DTLVardef@181098a_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTS- Mesoderm induction and patterning signals specify aSHF, pSHF, and FHF progenitors - Cardiac progenitors sort, co-develop and functionally connect in multi-chamber cardioids - Multi-chamber cardioids coordinate contraction propagation and share a lumen - Multi-chamber platform dissects genetic (ISL1, TBX5, FOXF1) and teratogenic defects

developmental biology↗