RESUMO
The relative and synergistic contributions of genetics and environment to interindividual immune response variation remain unclear, despite implications in evolutionary biology and medicine. Here we quantify interactive effects of genotype and environment on immune traits by investigating C57BL/6, 129S1 and PWK/PhJ inbred mice, rewilded in an outdoor enclosure and infected with the parasite Trichuris muris. Whereas cellular composition was shaped by interactions between genotype and environment, cytokine response heterogeneity including IFNγ concentrations was primarily driven by genotype with consequence on worm burden. In addition, we show that other traits, such as expression of CD44, were explained mostly by genetics on T cells, whereas expression of CD44 on B cells was explained more by environment across all strains. Notably, genetic differences under laboratory conditions were decreased following rewilding. These results indicate that nonheritable influences interact with genetic factors to shape immune variation and parasite burden.
Assuntos
Interação Gene-Ambiente , Camundongos Endogâmicos C57BL , Tricuríase , Trichuris , Animais , Trichuris/imunologia , Tricuríase/imunologia , Tricuríase/parasitologia , Camundongos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Linfócitos B/imunologia , Genótipo , Interferon gama/metabolismo , Linfócitos T/imunologia , Feminino , MasculinoRESUMO
There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
Assuntos
Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/metabolismo , Neoplasias/diagnóstico , Animais , Biomarcadores Tumorais/sangue , Linhagem Celular , Proteínas de Choque Térmico HSC70/metabolismo , Humanos , Aprendizado de Máquina , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Neoplasias/metabolismo , Proteoma/análise , Proteoma/metabolismo , Proteômica/métodos , Sensibilidade e Especificidade , Tetraspanina 29/metabolismo , Proteínas rap de Ligação ao GTP/metabolismoRESUMO
A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.
Assuntos
Proteína Forkhead Box O1 , Memória Imunológica , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Linfócitos T , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Cromatina/metabolismo , Cromatina/genética , Proteína Forkhead Box O1/metabolismo , Edição de Genes , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/citologiaRESUMO
Reaction rates at spatially heterogeneous, unstable interfaces are notoriously difficult to quantify, yet are essential in engineering many chemical systems, such as batteries1 and electrocatalysts2. Experimental characterizations of such materials by operando microscopy produce rich image datasets3-6, but data-driven methods to learn physics from these images are still lacking because of the complex coupling of reaction kinetics, surface chemistry and phase separation7. Here we show that heterogeneous reaction kinetics can be learned from in situ scanning transmission X-ray microscopy (STXM) images of carbon-coated lithium iron phosphate (LFP) nanoparticles. Combining a large dataset of STXM images with a thermodynamically consistent electrochemical phase-field model, partial differential equation (PDE)-constrained optimization and uncertainty quantification, we extract the free-energy landscape and reaction kinetics and verify their consistency with theoretical models. We also simultaneously learn the spatial heterogeneity of the reaction rate, which closely matches the carbon-coating thickness profiles obtained through Auger electron microscopy (AEM). Across 180,000 image pixels, the mean discrepancy with the learned model is remarkably small (<7%) and comparable with experimental noise. Our results open the possibility of learning nonequilibrium material properties beyond the reach of traditional experimental methods and offer a new non-destructive technique for characterizing and optimizing heterogeneous reactive surfaces.
RESUMO
Multicellular systems, from bacterial biofilms to human organs, form interfaces (or boundaries) between different cell collectives to spatially organize versatile functions1,2. The evolution of sufficiently descriptive genetic toolkits probably triggered the explosion of complex multicellular life and patterning3,4. Synthetic biology aims to engineer multicellular systems for practical applications and to serve as a build-to-understand methodology for natural systems5-8. However, our ability to engineer multicellular interface patterns2,9 is still very limited, as synthetic cell-cell adhesion toolkits and suitable patterning algorithms are underdeveloped5,7,10-13. Here we introduce a synthetic cell-cell adhesin logic with swarming bacteria and establish the precise engineering, predictive modelling and algorithmic programming of multicellular interface patterns. We demonstrate interface generation through a swarming adhesion mechanism, quantitative control over interface geometry and adhesion-mediated analogues of developmental organizers and morphogen fields. Using tiling and four-colour-mapping concepts, we identify algorithms for creating universal target patterns. This synthetic 4-bit adhesion logic advances practical applications such as human-readable molecular diagnostics, spatial fluid control on biological surfaces and programmable self-growing materials5-8,14. Notably, a minimal set of just four adhesins represents 4 bits of information that suffice to program universal tessellation patterns, implying a low critical threshold for the evolution and engineering of complex multicellular systems3,5.
Assuntos
Algoritmos , Células Artificiais , Adesão Celular , Lógica , Biologia Sintética , Células Artificiais/citologia , Biofilmes , Humanos , Biologia Sintética/métodosRESUMO
Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase5 to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.
Assuntos
Imunidade Materno-Adquirida , Imunoglobulina G , Espaço Intracelular , Listeria monocytogenes , Mães , Gravidez , Acetilesterase , Animais , Animais Recém-Nascidos , Linfócitos B , Feminino , Imunidade Materno-Adquirida/imunologia , Imunoglobulina G/imunologia , Interleucina-10/biossíntese , Espaço Intracelular/imunologia , Espaço Intracelular/microbiologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Listeriose/prevenção & controle , Camundongos , Ácido N-Acetilneuramínico/metabolismo , Gravidez/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Linfócitos TRESUMO
The SARS-CoV-2 Delta (Pango lineage B.1.617.2) variant of concern spread globally, causing resurgences of COVID-19 worldwide1,2. The emergence of the Delta variant in the UK occurred on the background of a heterogeneous landscape of immunity and relaxation of non-pharmaceutical interventions. Here we analyse 52,992 SARS-CoV-2 genomes from England together with 93,649 genomes from the rest of the world to reconstruct the emergence of Delta and quantify its introduction to and regional dissemination across England in the context of changing travel and social restrictions. Using analysis of human movement, contact tracing and virus genomic data, we find that the geographic focus of the expansion of Delta shifted from India to a more global pattern in early May 2021. In England, Delta lineages were introduced more than 1,000 times and spread nationally as non-pharmaceutical interventions were relaxed. We find that hotel quarantine for travellers reduced onward transmission from importations; however, the transmission chains that later dominated the Delta wave in England were seeded before travel restrictions were introduced. Increasing inter-regional travel within England drove the nationwide dissemination of Delta, with some cities receiving more than 2,000 observable lineage introductions from elsewhere. Subsequently, increased levels of local population mixing-and not the number of importations-were associated with the faster relative spread of Delta. The invasion dynamics of Delta depended on spatial heterogeneity in contact patterns, and our findings will inform optimal spatial interventions to reduce the transmission of current and future variants of concern, such as Omicron (Pango lineage B.1.1.529).
Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/transmissão , COVID-19/virologia , Cidades/epidemiologia , Busca de Comunicante , Inglaterra/epidemiologia , Genoma Viral/genética , Humanos , Quarentena/legislação & jurisprudência , SARS-CoV-2/genética , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/isolamento & purificação , Viagem/legislação & jurisprudênciaRESUMO
Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that ß-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Metabolismo Energético/genética , Lipólise/genética , Proteína Quinase 6 Ativada por Mitógeno/genética , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Obesidade/complicações , Células 3T3 , Tecido Adiposo/enzimologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Proteína Forkhead Box O1/metabolismo , Deleção de Genes , Células HEK293 , Humanos , Hipoglicemiantes/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipase/genética , Lipase/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genéticaRESUMO
Proteins mediate their functions through chemical interactions; modeling these interactions, which are typically through sidechains, is an important need in protein design. However, constructing an all-atom generative model requires an appropriate scheme for managing the jointly continuous and discrete nature of proteins encoded in the structure and sequence. We describe an all-atom diffusion model of protein structure, Protpardelle, which represents all sidechain states at once as a "superposition" state; superpositions defining a protein are collapsed into individual residue types and conformations during sample generation. When combined with sequence design methods, our model is able to codesign all-atom protein structure and sequence. Generated proteins are of good quality under the typical quality, diversity, and novelty metrics, and sidechains reproduce the chemical features and behavior of natural proteins. Finally, we explore the potential of our model to conduct all-atom protein design and scaffold functional motifs in a backbone- and rotamer-free way.
Assuntos
Modelos Moleculares , Conformação Proteica , Proteínas , Proteínas/química , Sequência de AminoácidosRESUMO
We developed a generally applicable method, CRISPR/Cas9-targeted long-read sequencing (CTLR-Seq), to resolve, haplotype-specifically, the large and complex regions in the human genome that had been previously impenetrable to sequencing analysis, such as large segmental duplications (SegDups) and their associated genome rearrangements. CTLR-Seq combines in vitro Cas9-mediated cutting of the genome and pulse-field gel electrophoresis to isolate intact large (i.e., up to 2,000 kb) genomic regions that encompass previously unresolvable genomic sequences. These targets are then sequenced (amplification-free) at high on-target coverage using long-read sequencing, allowing for their complete sequence assembly. We applied CTLR-Seq to the SegDup-mediated rearrangements that constitute the boundaries of, and give rise to, the 22q11.2 Deletion Syndrome (22q11DS), the most common human microdeletion disorder. We then performed de novo assembly to resolve, at base-pair resolution, the full sequence rearrangements and exact chromosomal breakpoints of 22q11.2DS (including all common subtypes). Across multiple patients, we found a high degree of variability for both the rearranged SegDup sequences and the exact chromosomal breakpoint locations, which coincide with various transposons within the 22q11.2 SegDups, suggesting that 22q11DS can be driven by transposon-mediated genome recombination. Guided by CTLR-Seq results from two 22q11DS patients, we performed three-dimensional chromosomal folding analysis for the 22q11.2 SegDups from patient-derived neurons and astrocytes and found chromosome interactions anchored within the SegDups to be both cell type-specific and patient-specific. Lastly, we demonstrated that CTLR-Seq enables cell-type specific analysis of DNA methylation patterns within the deletion haplotype of 22q11DS.
Assuntos
Síndrome de DiGeorge , Humanos , Síndrome de DiGeorge/genética , Sistemas CRISPR-Cas , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 22/genética , Genoma Humano , Rearranjo Gênico , Análise de Sequência de DNA/métodos , Deleção CromossômicaRESUMO
Although genomic research has predominantly relied on phenotypic ascertainment of individuals affected with heritable disease, the falling costs of sequencing allow consideration of genomic ascertainment and reverse phenotyping (the ascertainment of individuals with specific genomic variants and subsequent evaluation of physical characteristics). In this research modality, the scientific question is inverted: investigators gather individuals with a genomic variant and test the hypothesis that there is an associated phenotype via targeted phenotypic evaluations. Genomic ascertainment research is thus a model of predictive genomic medicine and genomic screening. Here, we provide our experience implementing this research method. We describe the infrastructure we developed to perform reverse phenotyping studies, including aggregating a super-cohort of sequenced individuals who consented to recontact for genomic ascertainment research. We assessed 13 studies completed at the National Institutes of Health (NIH) that piloted our reverse phenotyping approach. The studies can be broadly categorized as (1) facilitating novel genotype-disease associations, (2) expanding the phenotypic spectra, or (3) demonstrating ex vivo functional mechanisms of disease. We highlight three examples of reverse phenotyping studies in detail and describe how using a targeted reverse phenotyping approach (as opposed to phenotypic ascertainment or clinical informatics approaches) was crucial to the conclusions reached. Finally, we propose a framework and address challenges to building collaborative genomic ascertainment research programs at other institutions. Our goal is for more researchers to take advantage of this approach, which will expand our understanding of the predictive capability of genomic medicine and increase the opportunity to mitigate genomic disease.
Assuntos
Genoma , Informática Médica , Fenótipo , Genótipo , Genômica/métodosRESUMO
Virus discovery by genomics and metagenomics empowered studies of viromes, facilitated characterization of pathogen epidemiology, and redefined our understanding of the natural genetic diversity of viruses with profound functional and structural implications. Here we employed a data-driven virus discovery approach that directly queries unprocessed sequencing data in a highly parallelized way and involves a targeted viral genome assembly strategy in a wide range of sequence similarity. By screening more than 269,000 datasets of numerous authors from the Sequence Read Archive and using two metrics that quantitatively assess assembly quality, we discovered 40 nidoviruses from six virus families whose members infect vertebrate hosts. They form 13 and 32 putative viral subfamilies and genera, respectively, and include 11 coronaviruses with bisegmented genomes from fishes and amphibians, a giant 36.1 kilobase coronavirus genome with a duplicated spike glycoprotein (S) gene, 11 tobaniviruses and 17 additional corona-, arteri-, cremega-, nanhypo- and nangoshaviruses. Genome segmentation emerged in a single evolutionary event in the monophyletic lineage encompassing the subfamily Pitovirinae. We recovered the bisegmented genome sequences of two coronaviruses from RNA samples of 69 infected fishes and validated the presence of poly(A) tails at both segments using 3'RACE PCR and subsequent Sanger sequencing. We report a genetic linkage between accessory and structural proteins whose phylogenetic relationships and evolutionary distances are incongruent with the phylogeny of replicase proteins. We rationalize these observations in a model of inter-family S recombination involving at least five ancestral corona- and tobaniviruses of aquatic hosts. In support of this model, we describe an individual fish co-infected with members from the families Coronaviridae and Tobaniviridae. Our results expand the scale of the known extraordinary evolutionary plasticity in nidoviral genome architecture and call for revisiting fundamentals of genome expression, virus particle biology, host range and ecology of vertebrate nidoviruses.
Assuntos
Coronavirus , Genoma Viral , Nidovirales , Filogenia , Animais , Nidovirales/genética , Coronavirus/genética , Coronavirus/classificação , Vertebrados/virologia , Vertebrados/genética , Peixes/virologia , Evolução Molecular , Mineração de Dados , Infecções por Nidovirales/virologia , Infecções por Nidovirales/genéticaRESUMO
The characterization of a new group of innate pattern recognition receptors detected in >500 species across the tree of life by Li et al. reveals surprising commonalities and peculiarities shared with other innate receptors. Receptor diversity within and among species opens the way to reconsidering the costs and benefits of innate immune recognition.
Assuntos
Imunidade Inata , Receptores de Reconhecimento de Padrão , HumanosRESUMO
Identifying structural variation (SV) is essential for genome interpretation but has been historically difficult due to limitations inherent to available genome technologies. Detection methods that use ensemble algorithms and emerging sequencing technologies have enabled the discovery of thousands of SVs, uncovering information about their ubiquity, relationship to disease and possible effects on biological mechanisms. Given the variability in SV type and size, along with unique detection biases of emerging genomic platforms, multiplatform discovery is necessary to resolve the full spectrum of variation. Here, we review modern approaches for investigating SVs and proffer that, moving forwards, studies integrating biological information with detection will be necessary to comprehensively understand the impact of SV in the human genome.
Assuntos
Variação Estrutural do Genoma , Análise de Sequência/métodos , Algoritmos , Genoma Humano , HumanosRESUMO
hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral sclerosis [ALS] and frontotemporal dementia), muscle, and bone. Here we provide a unified structural view of hnRNPA2 self-assembly, aggregation, and interaction and the distinct effects of small chemical changes-disease mutations and arginine methylation-on these assemblies. The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer, retaining predominant disorder in a liquid-liquid phase-separated form. Disease mutations D290V and P298L induce aggregation by enhancing and extending, respectively, the aggregation-prone region. Co-aggregating in disease inclusions, hnRNPA2 LC directly interacts with and induces phase separation of TDP-43. Conversely, arginine methylation reduces hnRNPA2 phase separation, disrupting arginine-mediated contacts. These results highlight the mechanistic role of specific LC domain interactions and modifications conserved across many hnRNP family members but altered by aggregation-causing pathological mutations.
Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/química , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Arginina/genética , Arginina/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/metabolismo , Imageamento por Ressonância Magnética/métodos , Metilação , Mutação , Neurônios/metabolismo , Neurônios/patologia , Processamento de Proteína Pós-TraducionalRESUMO
The conserved Gsx homeodomain (HD) transcription factors specify neural cell fates in animals from flies to mammals. Like many HD proteins, Gsx factors bind A/T-rich DNA sequences prompting the following question: How do HD factors that bind similar DNA sequences in vitro regulate specific target genes in vivo? Prior studies revealed that Gsx factors bind DNA both as a monomer on individual A/T-rich sites and as a cooperative homodimer to two sites spaced precisely 7 bp apart. However, the mechanistic basis for Gsx-DNA binding and cooperativity is poorly understood. Here, we used biochemical, biophysical, structural and modeling approaches to (i) show that Gsx factors are monomers in solution and require DNA for cooperative complex formation, (ii) define the affinity and thermodynamic binding parameters of Gsx2/DNA interactions, (iii) solve a high-resolution monomer/DNA structure that reveals that Gsx2 induces a 20° bend in DNA, (iv) identify a Gsx2 protein-protein interface required for cooperative DNA binding and (v) determine that flexible spacer DNA sequences enhance Gsx2 cooperativity on dimer sites. Altogether, our results provide a mechanistic basis for understanding the protein and DNA structural determinants that underlie cooperative DNA binding by Gsx factors.
Assuntos
DNA , Proteínas de Homeodomínio , Ligação Proteica , DNA/metabolismo , DNA/química , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/genética , Animais , Sítios de Ligação , Conformação de Ácido Nucleico , Modelos Moleculares , Fatores de Transcrição/metabolismo , Fatores de Transcrição/química , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Humanos , TermodinâmicaRESUMO
We show how historical gypsum plaster preparation methods affect the microstructure and the wettability properties of the final stucco materials. We reproduced a traditional Persian recipe (Gach-e Koshteh, ~14th century AD), which involves a continuous mechanical treatment during plaster hydration. These samples were compared with a laboratory-replicated historical recipe from Renaissance Italy (Gesso Sottile, ~15th century AD) and contemporary low-strength plaster. The Koshteh recipe induces the formation of gypsum platelets, which exhibit preferential orientation in the plaster bulk. In contrast, the Italian and low-strength plasters comprise a typical needle-like morphology of gypsum crystals. The platelets in Koshteh expose the more hydrophilic {010} face of gypsum in a much more pronounced manner than needles. Consequently, the Iranian plaster displays enhanced wettability, enabling its direct use for water-based decoration purposes, or as a fine finishing thin layer, without the need of mixing it with a binder material. Contrary, in Sottile, gypsum crystals are left to equilibrate in large excess of water, which promotes the growth of long needles at the expense of smaller crystals. Typically, such needles are several times longer than those found in a control regular plaster. For this crystal habit, the total surface of hydrophilic faces is minimized. Consequently, such plaster layers tend to repel water, which can then be used, e.g., as a substrate for oil-based panel paintings. These findings highlight the development of advanced functional materials, by tuning their microtexture, already during the premodern era.
RESUMO
Venom systems are complex traits that have independently emerged multiple times in diverse plant and animal phyla. Within each venomous lineage there typically exists interspecific variation in venom composition where several factors have been proposed as drivers of variation, including phylogeny and diet. Understanding these factors is of broad biological interest and has implications for the development of antivenom therapies and venom-based drug discovery. Because of their high species richness and the presence of several major evolutionary prey shifts, venomous marine cone snails (genus Conus) provide an ideal system to investigate drivers of interspecific venom variation. Here, by analyzing the venom gland expression profiles of â¼3,000 toxin genes from 42 species of cone snail, we elucidate the role of prey-specific selection pressures in shaping venom variation. By analyzing overall venom composition and individual toxin structures, we demonstrate that the shifts from vermivory to piscivory in Conus are complemented by distinct changes in venom composition independent of phylogeny. In vivo injections of venom from piscivorous cone snails in fish further showed a higher potency compared with venom of nonpiscivores demonstrating a selective advantage. Together, our findings provide compelling evidence for the role of prey shifts in directing the venom composition of cone snails and expand our understanding of the mechanisms of venom variation and diversification.
Assuntos
Caramujo Conus , Venenos de Moluscos , Animais , Caramujo Conus/genética , Venenos de Moluscos/genética , Comportamento Predatório , Evolução Biológica , Filogenia , Evolução MolecularRESUMO
Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted owing to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole-genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice, and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN. By combining whole-genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2.