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Fungi are among the most diverse and ecologically important kingdoms in life. However, the distributional ranges of fungi remain largely unknown as do the ecological mechanisms that shape their distributions1,2. To provide an integrated view of the spatial and seasonal dynamics of fungi, we implemented a globally distributed standardized aerial sampling of fungal spores3. The vast majority of operational taxonomic units were detected within only one climatic zone, and the spatiotemporal patterns of species richness and community composition were mostly explained by annual mean air temperature. Tropical regions hosted the highest fungal diversity except for lichenized, ericoid mycorrhizal and ectomycorrhizal fungi, which reached their peak diversity in temperate regions. The sensitivity in climatic responses was associated with phylogenetic relatedness, suggesting that large-scale distributions of some fungal groups are partially constrained by their ancestral niche. There was a strong phylogenetic signal in seasonal sensitivity, suggesting that some groups of fungi have retained their ancestral trait of sporulating for only a short period. Overall, our results show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude. Our study reports patterns resembling those described for other major groups of organisms, thus making a major contribution to the long-standing debate on whether organisms with a microbial lifestyle follow the global biodiversity paradigms known for macroorganisms4,5.
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Microbiologia do Ar , Biodiversidade , DNA Fúngico , Fungos , Estações do Ano , Análise Espaço-Temporal , DNA Fúngico/análise , DNA Fúngico/genética , Fungos/genética , Fungos/classificação , Fungos/isolamento & purificação , Micorrizas/genética , Micorrizas/classificação , Micorrizas/isolamento & purificação , Filogenia , Esporos Fúngicos/classificação , Esporos Fúngicos/isolamento & purificação , Temperatura , Clima Tropical , Mapeamento GeográficoRESUMO
The structural diversity of glycans on cells-the glycome-is vast and complex to decipher. Glycan arrays display oligosaccharides and are used to report glycan hapten binding epitopes. Glycan arrays are limited resources and present saccharides without the context of other glycans and glycoconjugates. We used maps of glycosylation pathways to generate a library of isogenic HEK293 cells with combinatorially engineered glycosylation capacities designed to display and dissect the genetic, biosynthetic, and structural basis for glycan binding in a natural context. The cell-based glycan array is self-renewable and reports glycosyltransferase genes required (or blocking) for interactions through logical sequential biosynthetic steps, which is predictive of structural glycan features involved and provides instructions for synthesis, recombinant production, and genetic dissection strategies. Broad utility of the cell-based glycan array is demonstrated, and we uncover higher order binding of microbial adhesins to clustered patches of O-glycans organized by their presentation on proteins.
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Engenharia Genética , Redes e Vias Metabólicas/genética , Polissacarídeos/química , Proteínas/genética , Epitopos/genética , Epitopos/imunologia , Glicosilação , Glicosiltransferases/genética , Células HEK293 , Humanos , Oligossacarídeos/genética , Polissacarídeos/classificação , Polissacarídeos/genética , Polissacarídeos/imunologia , Proteínas/imunologiaRESUMO
In applications critical to the geological, materials, and engineering sciences, deformation occurs at strain rates too small to be accessible experimentally. Instead, extrapolations of empirical relationships are used, leading to epistemic uncertainties in predictions. To address these problems, we construct a theory of the fundamental processes affecting dislocations: storage and recovery. We then validate our theory for olivine deformation. This model explains the empirical relationships among strain rate, applied stress, and dislocation density in disparate laboratory regimes. It predicts the previously unexplained dependence of dislocation density on applied stress in olivine. The predictions of our model for Earth conditions differ from extrapolated empirical relationships. For example, it predicts rapid, transient deformation in the upper mantle, consistent with recent measurements of postseismic creep.
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Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.
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Manose , Manosiltransferases , Animais , Glicosilação , Mamíferos/metabolismo , Manose/metabolismo , Manosiltransferases/genética , Manosiltransferases/metabolismoRESUMO
Evaluating metagenomic software is key for optimizing metagenome interpretation and focus of the Initiative for the Critical Assessment of Metagenome Interpretation (CAMI). The CAMI II challenge engaged the community to assess methods on realistic and complex datasets with long- and short-read sequences, created computationally from around 1,700 new and known genomes, as well as 600 new plasmids and viruses. Here we analyze 5,002 results by 76 program versions. Substantial improvements were seen in assembly, some due to long-read data. Related strains still were challenging for assembly and genome recovery through binning, as was assembly quality for the latter. Profilers markedly matured, with taxon profilers and binners excelling at higher bacterial ranks, but underperforming for viruses and Archaea. Clinical pathogen detection results revealed a need to improve reproducibility. Runtime and memory usage analyses identified efficient programs, including top performers with other metrics. The results identify challenges and guide researchers in selecting methods for analyses.
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Metagenoma , Metagenômica , Archaea/genética , Metagenômica/métodos , Reprodutibilidade dos Testes , Análise de Sequência de DNA , SoftwareRESUMO
Deazaguanine DNA modifications are widespread in phages, particularly in those with pathogenic hosts. Pseudomonas phage iggy substitutes â¼16.5% of its genomic 2'-deoxyguanosine (G) with dPreQ0, and the iggy deazaguanine transglycosylase (DpdA) is unique in having a strict GA target motif, not observed previously. The iggy PreQ0 modification is shown to provide protection against both restriction endonucleases and Cas9 (when present in PAM), thus expanding our understanding of the deazaguanine modification system, its potential, and diversity. Phage iggy represents a new genus of Pseudomonas phages within the Queuovirinae subfamily; which have very little in common with other published phage genomes in terms of nucleotide similarity (<10%) and common proteins (<2%). Interestingly, shared similarity is concentrated in dpdA and preQ0 biosynthesis genes. TEM imaging confirmed a siphovirus morphology with a prolate icosahedral head and a non-contractile flexible tail with one long central tail spike. The observed protective effect of the deazaguanine modification on the iggy DNA may contribute to its broad within-species host range. Phage iggy was isolated on Pseudomonas aeruginosa PAO1, but also infects PDO300, PAK, PA14, as well as 10 of 27 tested environmental isolates and 13 of 20 tested clinical isolates of P. aeruginosa from patients with cystic fibrosis.
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Bacteriófagos , DNA Viral , Desoxiguanosina , Fagos de Pseudomonas , Humanos , Bacteriófagos/genética , Sistemas CRISPR-Cas , Fagos de Pseudomonas/genética , Desoxiguanosina/análogos & derivados , DNA Viral/químicaRESUMO
BACKGROUND: Patients with diabetes have increased rates of major adverse cardiac events (MACEs). We hypothesized that this is explained by diabetes-associated differences in coronary plaque morphology and lipid content. METHODS: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), 898 patients with acute myocardial infarction with or without ST-segment elevation underwent 3-vessel quantitative coronary angiography and coregistered near-infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Subsequent MACEs were adjudicated to either treated culprit lesions or untreated nonculprit lesions. This substudy stratified patients by diabetes status and assessed baseline culprit and nonculprit prevalence of high-risk plaque characteristics defined as maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Separate covariate-adjusted multivariable models were performed to identify whether diabetes was associated with nonculprit lesion-related MACEs and high-risk plaque characteristics. RESULTS: Diabetes was present in 109 of 898 patients (12.1%). During a median 3.7-year follow-up, MACEs occurred more frequently in patients with versus without diabetes (20.1% versus 13.5% [odds ratio (OR), 1.94 (95% CI, 1.14-3.30)]), primarily attributable to increased risk of myocardial infarction related to culprit lesion restenosis (4.3% versus 1.1% [OR, 3.78 (95% CI, 1.12-12.77)]) and nonculprit lesion-related spontaneous myocardial infarction (9.3% versus 3.8% [OR, 2.74 (95% CI, 1.25-6.04)]). However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes concerning culprit (maximum plaque burden ≥70%: 90% versus 93%, P=0.34; maximum lipid core burden index ≥324.7: 66% versus 70%, P=0.49) and nonculprit lesions (maximum plaque burden ≥70%: 23% versus 22%, P=0.37; maximum lipid core burden index ≥324.7: 26% versus 24%, P=0.47). In multivariable models, diabetes was associated with MACEs in nonculprit lesions (adjusted OR, 2.47 [95% CI, 1.21-5.04]) but not with prevalence of high-risk plaque characteristics (adjusted OR, 1.21 [95% CI, 0.86-1.69]). CONCLUSIONS: Among patients with recent myocardial infarction, both treated and untreated lesions contributed to the diabetes-associated ≈2-fold increased MACE rate during the 3.7-year follow-up. Diabetes-related plaque characteristics that might underlie this increased risk were not identified by multimodality imaging. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02171065.
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Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Diabetes Mellitus , Infarto do Miocárdio , Intervenção Coronária Percutânea , Placa Aterosclerótica , Humanos , Doença da Artéria Coronariana/complicações , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , Síndrome Coronariana Aguda/terapia , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Infarto do Miocárdio/complicações , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Angiografia Coronária/métodos , Intervenção Coronária Percutânea/efeitos adversos , Lipídeos , Valor Preditivo dos Testes , Resultado do TratamentoRESUMO
Our ability to assess biodiversity at relevant spatial and temporal scales for informing management is of increasing importance given this is foundational to identify and mitigate the impacts of global change. Collecting baseline information and tracking ecological changes are particularly important for areas experiencing rapid changes and representing data gaps such as Arctic marine ecosystems. Environmental DNA has the potential to provide such data. We extracted environmental DNA from 90 surface sediment samples to assess eukaryote diversity around Greenland and Svalbard using two separate primer pairs amplifying different sections of the 18S rRNA gene. We detected 27 different phyla and 99 different orders and found that temperature and the change in temperature explained the most variation in the community in a single linear model, while latitude, sea ice cover and change in temperature explained the most variation in the community when assessed by individual non-linear models. We identified potential indicator taxa for Arctic climate change, including a terebellid annelid worm. In conclusion, our study demonstrates that environmental DNA offers a feasible method to assess biodiversity and identifies warming as a key driver of differences in biodiversity across these remote ecosystems.
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DNA Ambiental , Ecossistema , Biodiversidade , Clima , Sedimentos GeológicosRESUMO
AIMS: To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist, in early-phase studies. MATERIALS AND METHODS: We conducted a phase 2a, single-centre, randomized, placebo-controlled trial in overweight and obese adults with type 2 diabetes. Following a 16-day single-blind placebo run-in, participants were randomized 2:1 to double-blind 42-day subcutaneous treatment with cotadutide (100-300 µg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE). RESULTS: A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was -4.0% (-4.9%, -3.1%) and -1.4% (-2.7%, -0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (-41.3% [-66.7, -15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI -8.4, 10.4; p = 0.784), assessed by doubly labelled water, and -6.5% (90% CI -9.3, -3.7; p < 0.001), assessed by indirect calorimetry. CONCLUSION: Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.
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Diabetes Mellitus Tipo 2 , Ingestão de Energia , Metabolismo Energético , Obesidade , Redução de Peso , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Obesidade/tratamento farmacológico , Obesidade/complicações , Ingestão de Energia/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Adulto , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Receptores de Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/agonistas , Método Simples-Cego , Idoso , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Resultado do Tratamento , PeptídeosRESUMO
In an attempt to discover and characterize the plethora of xenobiotic substances, this study investigates chemical compounds released into the environment with wastewater effluents. A novel non-targeted screening methodology based on ultra-high resolution Orbitrap mass spectrometry and nanoflow ultra-high performance liquid chromatography together with a newly optimized data-processing pipeline were applied to effluent samples from two state-of-the-art and one small wastewater treatment facility. In total, 785 molecular structures were obtained, of which 38 were identified as single compounds, while 480 structures were identified at a putative level. Most of these substances were therapeutics and drugs, present as parent compounds and metabolites. Using R packages Phyloseq and MetacodeR, originally developed for bioinformatics, significant differences in xenobiotic presence in the wastewater effluents between the three sites were demonstrated.
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Monitoramento Ambiental , Águas Residuárias , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Monitoramento Ambiental/métodos , Águas Residuárias/química , Águas Residuárias/análise , Dinamarca , Cromatografia Líquida de Alta Pressão , Eliminação de Resíduos Líquidos , Espectrometria de Massas/métodos , Xenobióticos/análiseRESUMO
Policymaking during a pandemic can be extremely challenging. As COVID-19 is a new disease and its global impacts are unprecedented, decisions are taken in a highly uncertain, complex, and rapidly changing environment. In such a context, in which human lives and the economy are at stake, we argue that using ideas and constructs from modern decision theory, even informally, will make policymaking a more responsible and transparent process.
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COVID-19 , Formulação de Políticas , COVID-19/prevenção & controle , Política de Saúde , Humanos , Modelos Teóricos , Pandemias , Quarentena/métodos , Instituições Acadêmicas , IncertezaRESUMO
It remains a challenge to obtain the desired phenotypic traits in aquacultural production of Atlantic salmon, and part of the challenge might come from the effect that host-associated microorganisms have on the fish phenotype. To manipulate the microbiota towards the desired host traits, it is critical to understand the factors that shape it. The bacterial gut microbiota composition can vary greatly among fish, even when reared in the same closed system. While such microbiota differences can be linked to diseases, the molecular effect of disease on host-microbiota interactions and the potential involvement of epigenetic factors remain largely unknown. The aim of this study was to investigate the DNA methylation differences associated with a tenacibaculosis outbreak and microbiota displacement in the gut of Atlantic salmon. Using Whole Genome Bisulfite Sequencing (WGBS) of distal gut tissue from 20 salmon, we compared the genome-wide DNA methylation levels between uninfected individuals and sick fish suffering from tenacibaculosis and microbiota displacement. We discovered >19,000 differentially methylated cytosine sites, often located in differentially methylated regions, and aggregated around genes. The 68 genes connected to the most significant regions had functions related to the ulcerous disease such as epor and slc48a1a but also included prkcda and LOC106590732 whose orthologs are linked to microbiota changes in other species. Although the expression level was not analysed, our epigenetic analysis suggests specific genes potentially involved in host-microbiota interactions and more broadly it highlights the value of considering epigenetic factors in efforts to manipulate the microbiota of farmed fish.
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Microbioma Gastrointestinal , Salmo salar , Epigenômica , Genótipo , Salmo salar/genética , Animais , Intestinos/microbiologia , Metilação de DNA , GenomaRESUMO
The human genome contains at least 35 genes that encode Golgi sulfotransferases that function in the secretory pathway, where they are involved in decorating glycosaminoglycans, glycolipids, and glycoproteins with sulfate groups. Although a number of important interactions by proteins such as selectins, galectins, and sialic acid-binding immunoglobulin-like lectins are thought to mainly rely on sulfated O-glycans, our insight into the sulfotransferases that modify these glycoproteins, and in particular GalNAc-type O-glycoproteins, is limited. Moreover, sulfated mucins appear to accumulate in respiratory diseases, arthritis, and cancer. To explore further the genetic and biosynthetic regulation of sulfated O-glycans, here we expanded a cell-based glycan array in the human embryonic kidney 293 (HEK293) cell line with sulfation capacities. We stably engineered O-glycan sulfation capacities in HEK293 cells by site-directed knockin of sulfotransferase genes in combination with knockout of genes to eliminate endogenous O-glycan branching (core2 synthase gene GCNT1) and/or sialylation capacities in order to provide simplified substrates (core1 Galß1-3GalNAcα1-O-Ser/Thr) for the introduced sulfotransferases. Expression of the galactose 3-O-sulfotransferase 2 in HEK293 cells resulted in sulfation of core1 and core2 O-glycans, whereas expression of galactose 3-O-sulfotransferase 4 resulted in sulfation of core1 only. We used the engineered cell library to dissect the binding specificity of galectin-4 and confirmed binding to the 3-O-sulfo-core1 O-glycan. This is a first step toward expanding the emerging cell-based glycan arrays with the important sulfation modification for display and production of glycoconjugates with sulfated O-glycans.
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Mucinas , Sulfatos , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Rim/metabolismo , Mucinas/metabolismo , Polissacarídeos/metabolismo , Sulfatos/metabolismo , Sulfotransferases/metabolismoRESUMO
There is widespread concern that cessation of grazing in historically grazed ecosystems is causing biotic homogenization and biodiversity loss. We used 12 montane grassland sites along an 800 km north-south gradient across the UK, to test whether cessation of grazing affects local α- and ß-diversity of below-ground food webs. We show cessation of grazing leads to strongly decreased α-diversity of most groups of soil microbes and fauna, particularly of relatively rare taxa. By contrast, the ß-diversity varied between groups of soil organisms. While most soil microbial communities exhibited increased homogenization after cessation of grazing, we observed decreased homogenization for soil fauna after cessation of grazing. Overall, our results indicate that exclusion of domesticated herbivores from historically grazed montane grasslands has far-ranging negative consequences for diversity of below-ground food webs. This underscores the importance of grazers for maintaining the diversity of below-ground communities, which play a central role in ecosystem functioning.
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Microbiota , Solo , Cadeia Alimentar , Pradaria , BiodiversidadeRESUMO
RNA and DNA modifications occur in eukaryotes and prokaryotes, as well as in their viruses, and serve a wide range of functions, from gene regulation to nucleic acid protection. Although the first nucleotide modification was discovered almost 100 years ago, new and unusual modifications are still being described. Nucleotide modifications have also received more attention lately because of their increased significance, but also because new sequencing approaches have eased their detection. Chiefly, third generation sequencing platforms PacBio and Nanopore offer direct detection of modified bases by measuring deviations of the signals. These unusual modifications are especially prevalent in bacteriophage genomes, the viruses of bacteria, where they mostly appear to protect DNA against degradation from host nucleases. In this Opinion article, we highlight and discuss current approaches to detect nucleotide modifications, including hardwares and softwares, and look onward to future applications, especially for studying unusual, rare, or complex genome modifications in bacteriophages. The ability to distinguish between several types of nucleotide modifications may even shed new light on metagenomic studies.
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Bacteriófagos , Nucleotídeos , Nucleotídeos/metabolismo , Bacteriófagos/genética , Software , Metagenoma , Bactérias/genética , Bactérias/metabolismo , DNA/genéticaRESUMO
Shotgun metagenomics is an increasingly cost-effective approach for profiling environmental and host-associated microbial communities. However, due to the complexity of both microbiomes and the molecular techniques required to analyze them, the reliability and representativeness of the results are contingent upon the field, laboratory, and bioinformatic procedures employed. Here, we consider 15 field and laboratory issues that critically impact downstream bioinformatic and statistical data processing, as well as result interpretation, in bacterial shotgun metagenomic studies. The issues we consider encompass intrinsic properties of samples, study design, and laboratory-processing strategies. We identify the links of field and laboratory steps with downstream analytical procedures, explain the means for detecting potential pitfalls, and propose mitigation measures to overcome or minimize their impact in metagenomic studies. We anticipate that our guidelines will assist data scientists in appropriately processing and interpreting their data, while aiding field and laboratory researchers to implement strategies for improving the quality of the generated results.
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Temporal synchrony between facial motion and acoustic modulations is a hallmark feature of audiovisual speech. The moving face and mouth during natural speech is known to be correlated with low-frequency acoustic envelope fluctuations (below 10 Hz), but the precise rates at which envelope information is synchronized with motion in different parts of the face are less clear. Here, we used regularized canonical correlation analysis (rCCA) to learn speech envelope filters whose outputs correlate with motion in different parts of the speakers face. We leveraged recent advances in video-based 3D facial landmark estimation allowing us to examine statistical envelope-face correlations across a large number of speakers (â¼4000). Specifically, rCCA was used to learn modulation transfer functions (MTFs) for the speech envelope that significantly predict correlation with facial motion across different speakers. The AV analysis revealed bandpass speech envelope filters at distinct temporal scales. A first set of MTFs showed peaks around 3-4 Hz and were correlated with mouth movements. A second set of MTFs captured envelope fluctuations in the 1-2 Hz range correlated with more global face and head motion. These two distinctive timescales emerged only as a property of natural AV speech statistics across many speakers. A similar analysis of fewer speakers performing a controlled speech task highlighted only the well-known temporal modulations around 4 Hz correlated with orofacial motion. The different bandpass ranges of AV correlation align notably with the average rates at which syllables (3-4 Hz) and phrases (1-2 Hz) are produced in natural speech. Whereas periodicities at the syllable rate are evident in the envelope spectrum of the speech signal itself, slower 1-2 Hz regularities thus only become prominent when considering crossmodal signal statistics. This may indicate a motor origin of temporal regularities at the timescales of syllables and phrases in natural speech.
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Percepção da Fala , Fala , Estimulação Acústica , Acústica , Fatores de TempoRESUMO
AIM: To assess the safety/tolerability, efficacy and pharmacokinetics of once-daily, 600-µg cotadutide in Japanese type 2 diabetes patients with a body mass index of 25 kg/m2 or higher. MATERIALS AND METHODS: This phase I, randomized, double-blind, placebo-controlled study (NCT04208620) enrolled patients to receive subcutaneous cotadutide at an escalating dose to determine the highest tolerated clinical dose (Cohort 1), then applied in Cohort 2. The primary endpoint was safety, including treatment-emergent adverse events (TEAEs); secondary endpoints included glycaemic control and body weight. RESULTS: Sixteen patients were randomly allocated to receive cotadutide or placebo in a 3:1 ratio. All patients were Asian, 62.5% were male, and the median age and body mass index were 60 years and 27.2 kg/m2 , respectively. Through the follow-up period of the study, 11/12 (91.7%) patients in the cotadutide group experienced a TEAE versus 1/4 (25.0%) patients in the placebo group. All TEAEs were mild, except for one moderate event. There were no deaths, serious TEAEs or TEAEs leading to study discontinuation. Gastrointestinal-related events were the most common TEAEs. Cotadutide-treated patients achieved significantly improved 7-day mean glucose measured by continuous glucose monitoring; the 7-day mean (standard deviation) at the end of treatment (day 70) was 112.23 (20.79) versus 206.85 (3.62) mg/dL for placebo. Mean respective changes in HbA1c were -1.13% (0.64%) and -0.17% (0.65%); and mean percentage changes in body weight were -6.93% (3.44%) and -1.23% (1.20%). CONCLUSIONS: Cotadutide was well tolerated at doses up to 600 µg; efficacy versus placebo for weight loss and glycaemic control was shown.
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Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Feminino , Humanos , Masculino , Glicemia/análise , Automonitorização da Glicemia , Índice de Massa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , População do Leste Asiático , Hemoglobinas Glicadas , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Resultado do Tratamento , Pessoa de Meia-Idade , Injeções Subcutâneas , Relação Dose-Resposta a DrogaRESUMO
Animal habitat selection-central in both theoretical and applied ecology-may depend on behavioural motivations such as foraging, predator avoidance, and thermoregulation. Step-selection functions (SSFs) enable assessment of fine-scale habitat selection as a function of an animal's movement capacities and spatiotemporal variation in extrinsic conditions. If animal location data can be associated with behaviour, SSFs are an intuitive approach to quantify behaviour-specific habitat selection. Fitting SSFs separately for distinct behavioural states helped to uncover state-specific selection patterns. However, while the definition of the availability domain has been highlighted as the most critical aspect of SSFs, the influence of accounting for behaviour in the use-availability design has not been quantified yet. Using a predator-free population of high-arctic muskoxen Ovibos moschatus as a case study, we aimed to evaluate how (1) defining behaviour-specific availability domains, and/or (2) fitting separate behaviour-specific models impacts (a) model structure, (b) estimated selection coefficients and (c) model predictive performance as opposed to behaviour-unspecific approaches. To do so, we first applied hidden Markov models to infer different behavioural modes (resting, foraging, relocating) from hourly GPS positions (19 individuals, 153-1062 observation days/animal). Using SSFs, we then compared behaviour-specific versus behaviour-unspecific habitat selection in relation to terrain features, vegetation and snow conditions. Our results show that incorporating behaviour into the definition of the availability domain primarily impacts model structure (i.e. variable selection), whereas fitting separate behaviour-specific models mainly influences selection strength. Behaviour-specific availability domains improved predictive performance for foraging and relocating models (i.e. behaviours with medium to large spatial displacement), but decreased performance for resting models. Thus, even for a predator-free population subject to only negligible interspecific competition and human disturbance we found that accounting for behaviour in SSFs impacted model structure, selection coefficients and predictive performance. Our results indicate that for robust inference, both a behaviour-specific availability domain and behaviour-specific model fitting should be explored, especially for populations where strong spatiotemporal selection trade-offs are expected. This is particularly critical if wildlife habitat preferences are estimated to inform management and conservation initiatives.
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RATIONALE: Analysis of stable isotopes in tissue and excreta may provide information about animal diets and their nutritional state. As body condition may have a major influence on reproduction, linking stable isotope values to animal demographic rates may help unravel the drivers behind animal population dynamics. METHODS: We performed sequential analysis of δ15 N values in guard hair from 21 muskoxen (Ovibos moschatus) from Zackenberg in high arctic Greenland. We were able to reconstruct the dietary history for the population over a 5-year period with contrasting environmental conditions. We examined the linkage between guard hair δ15 N values in 12 three-month periods and muskox calf recruitment to detect critical periods for muskox reproduction. Finally, we conducted similar analyses of the correlation between environmental conditions (snow depth and air temperature) and calf recruitment. RESULTS: δ15 N values exhibited a clear seasonal pattern with high levels in summer and low levels in winter. However, large inter-annual variation was found in winter values, suggesting varying levels of catabolism depending on snow conditions. In particular δ15 N values during January-March were linked to muskox recruitment rates, with higher values coinciding with lower calf recruitment. δ15 N values were a better predictor of muskox recruitment rates than environmental conditions. CONCLUSIONS: Although environmental conditions may ultimately determine the dietary δ15 N signal in muskox guard hairs, muskox calf recruitment was more strongly correlated with δ15 N values than ambient snow and temperature. The period January-March, corresponding to late gestation, appears particularly critical for muskox reproduction.