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1.
Cell ; 184(10): 2680-2695.e26, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33932340

RESUMEN

Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such "elimination damage" generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically.


Asunto(s)
Alanina/análogos & derivados , Aminobutiratos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Proteoma , Receptores Acoplados a Proteínas G/metabolismo , Alanina/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Femenino , Glutatión/metabolismo , Células HEK293 , Humanos , MAP Quinasa Quinasa 1/metabolismo , Masculino , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas de Unión a Fosfato/química , Proteínas de Unión a Fosfato/genética , Fosforilación , Dominios Proteicos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Sulfuros/metabolismo
2.
Immunity ; 52(6): 910-941, 2020 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-32505227

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Animales , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/terapia , Susceptibilidad a Enfermedades , Humanos , Inmunidad Innata , Memoria Inmunológica , Inflamación/inmunología , Inflamación/virología , Linfocitos/inmunología , Células Mieloides/inmunología , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/patología , Neumonía Viral/terapia , SARS-CoV-2
3.
Nature ; 617(7960): 265-270, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37165240

RESUMEN

Superposition, entanglement and non-locality constitute fundamental features of quantum physics. The fact that quantum physics does not follow the principle of local causality1-3 can be experimentally demonstrated in Bell tests4 performed on pairs of spatially separated, entangled quantum systems. Although Bell tests, which are widely regarded as a litmus test of quantum physics, have been explored using a broad range of quantum systems over the past 50 years, only relatively recently have experiments free of so-called loopholes5 succeeded. Such experiments have been performed with spins in nitrogen-vacancy centres6, optical photons7-9 and neutral atoms10. Here we demonstrate a loophole-free violation of Bell's inequality with superconducting circuits, which are a prime contender for realizing quantum computing technology11. To evaluate a Clauser-Horne-Shimony-Holt-type Bell inequality4, we deterministically entangle a pair of qubits12 and perform fast and high-fidelity measurements13 along randomly chosen bases on the qubits connected through a cryogenic link14 spanning a distance of 30 metres. Evaluating more than 1 million experimental trials, we find an average S value of 2.0747 ± 0.0033, violating Bell's inequality with a P value smaller than 10-108. Our work demonstrates that non-locality is a viable new resource in quantum information technology realized with superconducting circuits with potential applications in quantum communication, quantum computing and fundamental physics15.

4.
Nature ; 624(7992): 602-610, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38093003

RESUMEN

Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference datasets1-3. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here we apply population-scale whole-genome long-read sequencing4 to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large insertion-deletion variants (20-49 bp; n = 136,797), structural variants (50 b-50 kb; n = 159,912) and regions of variable copy number (>50 kb; n = 156). The majority of variants are composed of tandem repeat or interspersed mobile element sequences (up to 90%) and have not been previously annotated (up to 62%). A large fraction of structural variants appear to be exclusive to Indigenous Australians (12% lower-bound estimate) and most of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short tandem repeats throughout the genome to characterize allelic diversity at 50 known disease loci5, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among short tandem repeat sequences. Our study sheds new light on the dimensions and dynamics of genomic structural variation within and beyond Australia.


Asunto(s)
Aborigenas Australianos e Isleños del Estrecho de Torres , Genoma Humano , Variación Estructural del Genoma , Humanos , Alelos , Australia/etnología , Aborigenas Australianos e Isleños del Estrecho de Torres/genética , Conjuntos de Datos como Asunto , Variaciones en el Número de Copia de ADN/genética , Sitios Genéticos/genética , Genética Médica , Variación Estructural del Genoma/genética , Genómica , Mutación INDEL/genética , Secuencias Repetitivas Esparcidas/genética , Repeticiones de Microsatélite/genética , Genoma Humano/genética
5.
Nature ; 615(7954): 858-865, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36949201

RESUMEN

Human society is dependent on nature1,2, but whether our ecological foundations are at risk remains unknown in the absence of systematic monitoring of species' populations3. Knowledge of species fluctuations is particularly inadequate in the marine realm4. Here we assess the population trends of 1,057 common shallow reef species from multiple phyla at 1,636 sites around Australia over the past decade. Most populations decreased over this period, including many tropical fishes, temperate invertebrates (particularly echinoderms) and southwestern Australian macroalgae, whereas coral populations remained relatively stable. Population declines typically followed heatwave years, when local water temperatures were more than 0.5 °C above temperatures in 2008. Following heatwaves5,6, species abundances generally tended to decline near warm range edges, and increase near cool range edges. More than 30% of shallow invertebrate species in cool latitudes exhibited high extinction risk, with rapidly declining populations trapped by deep ocean barriers, preventing poleward retreat as temperatures rise. Greater conservation effort is needed to safeguard temperate marine ecosystems, which are disproportionately threatened and include species with deep evolutionary roots. Fundamental among such efforts, and broader societal needs to efficiently adapt to interacting anthropogenic and natural pressures, is greatly expanded monitoring of species' population trends7,8.


Asunto(s)
Antozoos , Arrecifes de Coral , Calor Extremo , Peces , Calentamiento Global , Invertebrados , Océanos y Mares , Agua de Mar , Algas Marinas , Animales , Australia , Peces/clasificación , Invertebrados/clasificación , Calentamiento Global/estadística & datos numéricos , Algas Marinas/clasificación , Dinámica Poblacional , Densidad de Población , Agua de Mar/análisis , Extinción Biológica , Conservación de los Recursos Naturales/tendencias , Equinodermos/clasificación
6.
Immunity ; 50(1): 212-224.e4, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30650377

RESUMEN

Microbiota are thought to influence the development and progression of inflammatory bowel disease (IBD), but determining generalizable effects of microbiota on IBD etiology requires larger-scale functional analyses. We colonized germ-free mice with intestinal microbiotas from 30 healthy and IBD donors and determined the homeostatic intestinal T cell response to each microbiota. Compared to microbiotas from healthy donors, transfer of IBD microbiotas into germ-free mice increased numbers of intestinal Th17 cells and Th2 cells and decreased numbers of RORγt+ Treg cells. Colonization with IBD microbiotas exacerbated disease in a model where colitis is induced upon transfer of naive T cells into Rag1-/- mice. The proportions of Th17 and RORγt+ Treg cells induced by each microbiota were predictive of human disease status and accounted for disease severity in the Rag1-/- colitis model. Thus, an impact on intestinal Th17 and RORγt+ Treg cell compartments emerges as a unifying feature of IBD microbiotas, suggesting a general mechanism for microbial contribution to IBD pathogenesis.


Asunto(s)
Colitis/microbiología , Microbioma Gastrointestinal/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , ARN Ribosómico 16S/genética , Linfocitos T Reguladores/inmunología , Células Th17/metabolismo , Animales , Diferenciación Celular , Colitis/inducido químicamente , Colitis/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Homeostasis , Humanos , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo
7.
Nature ; 605(7911): 669-674, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35614249

RESUMEN

Quantum computers hold the promise of solving computational problems that are intractable using conventional methods1. For fault-tolerant operation, quantum computers must correct errors occurring owing to unavoidable decoherence and limited control accuracy2. Here we demonstrate quantum error correction using the surface code, which is known for its exceptionally high tolerance to errors3-6. Using 17 physical qubits in a superconducting circuit, we encode quantum information in a distance-three logical qubit, building on recent distance-two error-detection experiments7-9. In an error-correction cycle taking only 1.1 µs, we demonstrate the preservation of four cardinal states of the logical qubit. Repeatedly executing the cycle, we measure and decode both bit-flip and phase-flip error syndromes using a minimum-weight perfect-matching algorithm in an error-model-free approach and apply corrections in post-processing. We find a low logical error probability of 3% per cycle when rejecting experimental runs in which leakage is detected. The measured characteristics of our device agree well with a numerical model. Our demonstration of repeated, fast and high-performance quantum error-correction cycles, together with recent advances in ion traps10, support our understanding that fault-tolerant quantum computation will be practically realizable.

8.
Nature ; 603(7900): 271-275, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35038718

RESUMEN

In oxidation reactions catalysed by supported metal nanoparticles with oxygen as the terminal oxidant, the rate of the oxygen reduction can be a limiting factor. This is exemplified by the oxidative dehydrogenation of alcohols, an important class of reactions with modern commercial applications1-3. Supported gold nanoparticles are highly active for the dehydrogenation of the alcohol to an aldehyde4 but are less effective for oxygen reduction5,6. By contrast, supported palladium nanoparticles offer high efficacy for oxygen reduction5,6. This imbalance can be overcome by alloying gold with palladium, which gives enhanced activity to both reactions7,8,9; however, the electrochemical potential of the alloy is a compromise between that of the two metals, meaning that although the oxygen reduction can be improved in the alloy, the dehydrogenation activity is often limited. Here we show that by separating the gold and palladium components in bimetallic carbon-supported catalysts, we can almost double the reaction rate compared with that achieved with the corresponding alloy catalyst. We demonstrate this using physical mixtures of carbon-supported monometallic gold and palladium catalysts and a bimetallic catalyst comprising separated gold and palladium regions. Furthermore, we demonstrate electrochemically that this enhancement is attributable to the coupling of separate redox processes occurring at isolated gold and palladium sites. The discovery of this catalytic effect-a cooperative redox enhancement-offers an approach to the design of multicomponent heterogeneous catalysts.


Asunto(s)
Oro , Nanopartículas del Metal , Alcoholes , Aleaciones , Carbono , Catálisis , Oxidación-Reducción , Oxígeno , Paladio
9.
Nature ; 604(7905): 354-361, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35355015

RESUMEN

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Animales , Animales Modificados Genéticamente , Carcinogénesis/genética , Pie , Mano , Humanos , Melanoma/patología , Uñas , Oncogenes/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Transcripción Genética , Pez Cebra/genética , Melanoma Cutáneo Maligno
10.
Nature ; 605(7909): 285-290, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35477765

RESUMEN

Comprehensive assessments of species' extinction risks have documented the extinction crisis1 and underpinned strategies for reducing those risks2. Global assessments reveal that, among tetrapods, 40.7% of amphibians, 25.4% of mammals and 13.6% of birds are threatened with extinction3. Because global assessments have been lacking, reptiles have been omitted from conservation-prioritization analyses that encompass other tetrapods4-7. Reptiles are unusually diverse in arid regions, suggesting that they may have different conservation needs6. Here we provide a comprehensive extinction-risk assessment of reptiles and show that at least 1,829 out of 10,196 species (21.1%) are threatened-confirming a previous extrapolation8 and representing 15.6 billion years of phylogenetic diversity. Reptiles are threatened by the same major factors that threaten other tetrapods-agriculture, logging, urban development and invasive species-although the threat posed by climate change remains uncertain. Reptiles inhabiting forests, where these threats are strongest, are more threatened than those in arid habitats, contrary to our prediction. Birds, mammals and amphibians are unexpectedly good surrogates for the conservation of reptiles, although threatened reptiles with the smallest ranges tend to be isolated from other threatened tetrapods. Although some reptiles-including most species of crocodiles and turtles-require urgent, targeted action to prevent extinctions, efforts to protect other tetrapods, such as habitat preservation and control of trade and invasive species, will probably also benefit many reptiles.


Asunto(s)
Conservación de los Recursos Naturales , Extinción Biológica , Reptiles , Caimanes y Cocodrilos , Anfibios , Animales , Biodiversidad , Aves , Mamíferos , Filogenia , Reptiles/clasificación , Medición de Riesgo , Tortugas
11.
Nature ; 591(7849): 281-287, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33568815

RESUMEN

Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals1. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.


Asunto(s)
Macrófagos/metabolismo , Músculo Esquelético/citología , Músculo Esquelético/lesiones , Mioblastos/citología , Nicotinamida Fosforribosiltransferasa/metabolismo , Nicho de Células Madre , Pez Cebra/metabolismo , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Macrófagos/citología , Masculino , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mioblastos/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Factor de Transcripción PAX7/metabolismo , RNA-Seq , Receptores CCR5/genética , Receptores CCR5/metabolismo , Regeneración/fisiología , Análisis de la Célula Individual , Pez Cebra/inmunología
12.
Proc Natl Acad Sci U S A ; 121(10): e2313205121, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38408235

RESUMEN

Marine protected areas (MPAs) are widely used for ocean conservation, yet the relative impacts of various types of MPAs are poorly understood. We estimated impacts on fish biomass from no-take and multiple-use (fished) MPAs, employing a rigorous matched counterfactual design with a global dataset of >14,000 surveys in and around 216 MPAs. Both no-take and multiple-use MPAs generated positive conservation outcomes relative to no protection (58.2% and 12.6% fish biomass increases, respectively), with smaller estimated differences between the two MPA types when controlling for additional confounding factors (8.3% increase). Relative performance depended on context and management: no-take MPAs performed better in areas of high human pressure but similar to multiple-use in remote locations. Multiple-use MPA performance was low in high-pressure areas but improved significantly with better management, producing similar outcomes to no-take MPAs when adequately staffed and appropriate use regulations were applied. For priority conservation areas where no-take restrictions are not possible or ethical, our findings show that a portfolio of well-designed and well-managed multiple-use MPAs represents a viable and potentially equitable pathway to advance local and global conservation.


Asunto(s)
Conservación de los Recursos Naturales , Explotaciones Pesqueras , Animales , Humanos , Biomasa , Peces , Ecosistema
13.
Proc Natl Acad Sci U S A ; 121(12): e2308478121, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38489389

RESUMEN

The marine cyanobacterium Prochlorococcus is a main contributor to global photosynthesis, whilst being limited by iron availability. Cyanobacterial genomes generally encode two different types of FutA iron-binding proteins: periplasmic FutA2 ABC transporter subunits bind Fe(III), while cytosolic FutA1 binds Fe(II). Owing to their small size and their economized genome Prochlorococcus ecotypes typically possess a single futA gene. How the encoded FutA protein might bind different Fe oxidation states was previously unknown. Here, we use structural biology techniques at room temperature to probe the dynamic behavior of FutA. Neutron diffraction confirmed four negatively charged tyrosinates, that together with a neutral water molecule coordinate iron in trigonal bipyramidal geometry. Positioning of the positively charged Arg103 side chain in the second coordination shell yields an overall charge-neutral Fe(III) binding state in structures determined by neutron diffraction and serial femtosecond crystallography. Conventional rotation X-ray crystallography using a home source revealed X-ray-induced photoreduction of the iron center with observation of the Fe(II) binding state; here, an additional positioning of the Arg203 side chain in the second coordination shell maintained an overall charge neutral Fe(II) binding site. Dose series using serial synchrotron crystallography and an XFEL X-ray pump-probe approach capture the transition between Fe(III) and Fe(II) states, revealing how Arg203 operates as a switch to accommodate the different iron oxidation states. This switching ability of the Prochlorococcus FutA protein may reflect ecological adaptation by genome streamlining and loss of specialized FutA proteins.


Asunto(s)
Compuestos Férricos , Prochlorococcus , Compuestos Férricos/química , Proteínas de Unión a Hierro/metabolismo , Prochlorococcus/metabolismo , Hierro/metabolismo , Oxidación-Reducción , Transferrina/metabolismo , Agua/química , Compuestos Ferrosos/química , Cristalografía por Rayos X
14.
PLoS Pathog ; 20(7): e1012039, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38950065

RESUMEN

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) not only caused the COVID-19 pandemic but also had a major impact on farmed mink production in several European countries. In Denmark, the entire population of farmed mink (over 15 million animals) was culled in late 2020. During the period of June to November 2020, mink on 290 farms (out of about 1100 in the country) were shown to be infected with SARS-CoV-2. Genome sequencing identified changes in the virus within the mink and it is estimated that about 4000 people in Denmark became infected with these mink virus variants. However, the routes of transmission of the virus to, and from, the mink have been unclear. Phylogenetic analysis revealed the generation of multiple clusters of the virus within the mink. Detailed analysis of changes in the virus during replication in mink and, in parallel, in the human population in Denmark, during the same time period, has been performed here. The majority of cases in mink involved variants with the Y453F substitution and the H69/V70 deletion within the Spike (S) protein; these changes emerged early in the outbreak. However, further introductions of the virus, by variants lacking these changes, from the human population into mink also occurred. Based on phylogenetic analysis of viral genome data, we estimate, using a conservative approach, that about 17 separate examples of mink to human transmission occurred in Denmark but up to 59 such events (90% credible interval: (39-77)) were identified using parsimony to count cross-species jumps on transmission trees inferred using Bayesian methods. Using the latter approach, 136 jumps (90% credible interval: (117-164)) from humans to mink were found, which may underlie the farm-to-farm spread. Thus, transmission of SARS-CoV-2 from humans to mink, mink to mink, from mink to humans and between humans were all observed.


Asunto(s)
COVID-19 , Visón , Filogenia , SARS-CoV-2 , Visón/virología , COVID-19/transmisión , COVID-19/virología , COVID-19/epidemiología , COVID-19/veterinaria , SARS-CoV-2/genética , Animales , Dinamarca/epidemiología , Humanos , Pandemias , Granjas , Betacoronavirus/genética , Betacoronavirus/clasificación , Genoma Viral , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/transmisión , Glicoproteína de la Espiga del Coronavirus/genética
15.
Annu Rev Microbiol ; 75: 223-242, 2021 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-34348027

RESUMEN

Despite identification of numerous associations between microbiomes and diseases, the complexity of the human microbiome has hindered identification of individual species and strains that are causative in host phenotype or disease. Uncovering causative microbes is vital to fully understand disease processes and to harness the potential therapeutic benefits of microbiota manipulation. Developments in sequencing technology, animal models, and bacterial culturing have facilitated the discovery of specific microbes that impact the host and are beginning to advance the characterization of host-microbiome interaction mechanisms. We summarize the historical and contemporary experimental approaches taken to uncover microbes from the microbiota that affect host biology and describe examples of commensals that have specific effects on the immune system, inflammation, and metabolism. There is still much to learn, and we lay out challenges faced by the field and suggest potential remedies for common pitfalls encountered in the hunt for causative commensal microbes.


Asunto(s)
Microbiota , Animales , Interacciones Microbiota-Huesped , Simbiosis
16.
Plant Cell ; 2023 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-37824826

RESUMEN

Model species continue to underpin groundbreaking plant science research. At the same time, the phylogenetic resolution of the land plant Tree of Life continues to improve. The intersection of these two research paths creates a unique opportunity to further extend the usefulness of model species across larger taxonomic groups. Here we promote the utility of the Arabidopsis thaliana model species, especially the ability to connect its genetic and functional resources, to species across the entire Brassicales order. We focus on the utility of using genomics and phylogenomics to bridge the evolution and diversification of several traits across the Brassicales to the resources in Arabidopsis, thereby extending scope from a model species by establishing a "model clade". These Brassicales-wide traits are discussed in the context of both the model species Arabidopsis thaliana and the family Brassicaceae. We promote the utility of such a "model clade" and make suggestions for building global networks to support future studies in the model order Brassicales.

17.
Nat Chem Biol ; 20(8): 991-999, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38902458

RESUMEN

Computational protein design is advancing rapidly. Here we describe efficient routes starting from validated parallel and antiparallel peptide assemblies to design two families of α-helical barrel proteins with central channels that bind small molecules. Computational designs are seeded by the sequences and structures of defined de novo oligomeric barrel-forming peptides, and adjacent helices are connected by loop building. For targets with antiparallel helices, short loops are sufficient. However, targets with parallel helices require longer connectors; namely, an outer layer of helix-turn-helix-turn-helix motifs that are packed onto the barrels. Throughout these computational pipelines, residues that define open states of the barrels are maintained. This minimizes sequence sampling, accelerating the design process. For each of six targets, just two to six synthetic genes are made for expression in Escherichia coli. On average, 70% of these genes express to give soluble monomeric proteins that are fully characterized, including high-resolution structures for most targets that match the design models with high accuracy.


Asunto(s)
Escherichia coli , Proteínas , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas/química , Proteínas/genética , Conformación Proteica en Hélice alfa , Ingeniería de Proteínas/métodos , Modelos Moleculares , Péptidos/química , Péptidos/genética , Biología Computacional/métodos , Secuencia de Aminoácidos , Pliegue de Proteína
18.
PLoS Biol ; 21(12): e3002392, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38079442

RESUMEN

The multifaceted effects of climate change on physical and biogeochemical processes are rapidly altering marine ecosystems but often are considered in isolation, leaving our understanding of interactions between these drivers of ecosystem change relatively poor. This is particularly true for shallow coastal ecosystems, which are fuelled by a combination of distinct pelagic and benthic energy pathways that may respond to climate change in fundamentally distinct ways. The fish production supported by these systems is likely to be impacted by climate change differently to those of offshore and shelf ecosystems, which have relatively simpler food webs and mostly lack benthic primary production sources. We developed a novel, multispecies size spectrum model for shallow coastal reefs, specifically designed to simulate potential interactive outcomes of changing benthic and pelagic energy inputs and temperatures and calculate the relative importance of these variables for the fish community. Our model, calibrated using field data from an extensive temperate reef monitoring program, predicts that changes in resource levels will have much stronger impacts on fish biomass and yields than changes driven by physiological responses to temperature. Under increased plankton abundance, species in all fish trophic groups were predicted to increase in biomass, average size, and yields. By contrast, changes in benthic resources produced variable responses across fish trophic groups. Increased benthic resources led to increasing benthivorous and piscivorous fish biomasses, yields, and mean body sizes, but biomass decreases among herbivore and planktivore species. When resource changes were combined with warming seas, physiological responses generally decreased species' biomass and yields. Our results suggest that understanding changes in benthic production and its implications for coastal fisheries should be a priority research area. Our modified size spectrum model provides a framework for further study of benthic and pelagic energy pathways that can be easily adapted to other ecosystems.


Asunto(s)
Cambio Climático , Ecosistema , Animales , Cadena Alimentaria , Biomasa , Océanos y Mares , Peces/fisiología
19.
Proc Natl Acad Sci U S A ; 120(12): e2215914120, 2023 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-36917674

RESUMEN

How bacterial strains within a complex human microbiota collectively shape intestinal T cell homeostasis is not well understood. Methods that quickly identify effector strains or species that drive specific mucosal T cell phenotypes are needed to define general principles for how the microbiota modulates host immunity. We colonize germ-free mice with defined communities of cultured strains and profile antigen-specific responses directed toward individual strains ex vivo. We find that lamina propria T cells are specific to bacterial strains at the species level and can discriminate between strains of the same species. Ex vivo restimulations consistently identify the strains within complex communities that induce Th17 responses in vivo, providing the potential to shape baseline immune tone via community composition. Using an adoptive transfer model of colitis, we find that lamina propria T cells respond to different bacterial strains in conditions of inflammation versus homeostasis. Collectively, our approach represents a unique method for efficiently predicting the relative impact of individual bacterial strains within a complex community and for parsing microbiota-dependent phenotypes into component fractions.


Asunto(s)
Intestinos , Microbiota , Humanos , Animales , Ratones , Intestinos/microbiología , Membrana Mucosa , Bacterias , Linfocitos T CD4-Positivos , Fenotipo , Mucosa Intestinal
20.
Acc Chem Res ; 57(1): 106-119, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38116936

RESUMEN

ConspectusHydrogen peroxide (H2O2) for industrial applications is manufactured through an indirect process that relies on the sequential reduction and reoxidation of quinone carriers. While highly effective, production is typically centralized and entails numerous energy-intensive concentration steps. Furthermore, the overhydrogenation of the quinone necessitates periodic replacement, leading to incomplete atom efficiency. These factors, in addition to the presence of propriety stabilizing agents and concerns associated with their separation from product streams, have driven interest in alternative technologies for chemical upgrading. The decoupling of oxidative transformations from commercially synthesized H2O2 may offer significant economic savings and a reduction in greenhouse gas emissions for several industrially relevant processes. Indeed, the production and utilization of the oxidant in situ, from the elements, would represent a positive step toward a more sustainable chemical synthesis sector, offering the potential for total atom efficiency, while avoiding the drawbacks associated with current industrial routes, which are inherently linked to commercial H2O2 production. Such interest is perhaps now more pertinent than ever given the rapidly improving viability of green hydrogen production.The application of in situ-generated H2O2 has been a long-standing goal in feedstock valorization, with perhaps the most significant interest placed on propylene epoxidation. Until very recently a viable in situ alternative to current industrial oxidative processes has been lacking, with prior approaches typically hindered by low rates of conversion or poor selectivity toward desired products, often resulting from competitive hydrogenation reactions. Based on over 20 years of research, which has led to the development of catalysts for the direct synthesis of H2O2 that offer high synthesis rates and >99% H2 utilization, we have recently turned our attention to a range of oxidative transformations where H2O2 is generated and utilized in situ. Indeed, we have recently demonstrated that it is possible to rival state-of-the-art industrial processes through in situ H2O2 synthesis, establishing the potential for significant process intensification and considerable decarbonization of the chemical synthesis sector.We have further established the potential of an in situ route to both bulk and fine chemical synthesis through a chemo-catalytic/enzymatic one-pot approach, where H2O2 is synthesized over heterogeneous surfaces and subsequently utilized by a class of unspecific peroxygenase enzymes for C-H bond functionalization. Strikingly, through careful control of the chemo-catalyst, it is possible to ensure that competitive, nonenzymatic pathways are inhibited while also avoiding the regiospecific and selectivity concerns associated with current energy-intensive industrial processes, with further cost savings associated with the operation of the chemo-enzymatic approach at near-ambient temperatures and pressures. Beyond traditional applications of chemo-catalysis, the efficacy of in situ-generated H2O2 (and associated oxygen-based radical species) for the remediation of environmental pollutants has also been a major interest of our laboratory, with such technology offering considerable improvements over conventional disinfection processes.We hope that this Account, which highlights the key contributions of our laboratory to the field over recent years, demonstrates the chemistries that may be unlocked and improved upon via in situ H2O2 synthesis and it inspires broader interest from the scientific community.

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