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Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.
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Mielofibrosis Primaria , Humanos , Pronóstico , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/genética , Mutación , Janus Quinasa 2/genética , Frecuencia de los GenesRESUMEN
Prosopis laevigata (mesquite; Fabaceae) forms fertility islands in soils of semi-arid lands where microbial diversity concentrates in response to the accumulation of resources in the soil beneath individual plants, promoting organic matter decomposition and nutrient cycling. This phenomenon provides suitable conditions for the proliferation of key edaphic elements such as fungi and mites. Mite-fungal interactions are central for our understanding of nutrient cycling processes in resource-limited arid food webs; yet, no information is available about fertility islands in semi-arid lands. Thus, we aimed to determine in vitro fungal-based feeding preferences and molecular gut content of the oribatid mite species Zygoribatula cf. floridana and Scheloribates cf. laevigatus, which are abundant under the canopy of P. laevigata in an intertropical semi-arid zone in Central Mexico. Our results on the gut content analysis of these oribatid species resulted in the ITS-based identification of the following fungi: Aspergillus homomorphus, Beauveria bassiana, Filobasidium sp., Mortierella sp., Roussoella sp., Saccharomyces cerevisiae, Sclerotiniaceae sp. and Triparticalcar sp. Furthermore, under laboratory conditions both oribatid mite species exhibited feeding preferences on melanized fungi, such as Cladosporium spp., whereas A. homomorphus and Fusarium penzigi were avoided. Our findings indicated that the analyzed oribatid mite species have similar feeding preferences for melanized fungi, which might suggest resource partitioning and a degree of preference, explaining the coexistence of both oribatid species.
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Fabaceae , Ácaros , Prosopis , Animales , Cadena Alimentaria , Fertilidad , SueloRESUMEN
Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.
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Mielofibrosis Primaria , Trombocitemia Esencial , Trombosis , Humanos , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Trombosis/epidemiología , Trombosis/etiología , Trombosis/diagnóstico , Hemorragia/diagnóstico , Sistema de Registros , Factores de RiesgoRESUMEN
Hematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time (< 45%) was observed in 36%, 44%, and 32% of the patients at 6, 12, and 24 months, respectively. More than 5 phlebotomies per year in the maintenance phase were required in 19% of patients. Worsening thrombocytosis, age > 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.
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Leucemia Mieloide Aguda , Policitemia Vera , Mielofibrosis Primaria , Trombosis , Humanos , Leucemia Mieloide Aguda/complicaciones , Persona de Mediana Edad , Flebotomía/efectos adversos , Policitemia Vera/complicaciones , Policitemia Vera/diagnóstico , Policitemia Vera/cirugía , Mielofibrosis Primaria/diagnóstico , Sistema de Registros , Trombosis/complicaciones , Trombosis/etiologíaRESUMEN
A collection of 29 cultivable fungal strains isolated from deep-sea sediments of the Gulf of Mexico were cultivated under the "one strain, many compounds" approach to explore their chemical diversity and antimicrobial potential. From the 87 extracts tested, over 50% showed antimicrobial activity, and the most active ones were those from cultures grown at 4 °C in darkness for 60 days (resembling deep-sea temperature). PCA analysis of the LC-MS data of all the extracts confirmed that culture temperature is the primary factor in the variation of the 4462 metabolite features, accounting for 21.3% of the variation. The bioactivity-guided and conventional chemical studies of selected fungal strains allowed the identification of several active and specialized metabolites. Finally, metabolomics analysis by GNPS molecular networking and manual dereplication revealed the biosynthetic potential of these species to produce interesting chemistry. This work uncovers the chemical and biological study of marine-derived fungal strains from deep-sea sediments of the Gulf of Mexico.
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Antiinfecciosos/química , Hongos/química , Antiinfecciosos/metabolismo , Antiinfecciosos/farmacología , Productos Biológicos/química , Productos Biológicos/metabolismo , Productos Biológicos/farmacología , Hongos/metabolismo , Sedimentos Geológicos/microbiología , Golfo de México , MetabolomaRESUMEN
BACKGROUND: Repetitive DNA sequences (Repeats) are significant regions in the human genome that have a specific genomic distribution, structure, and several binding sites for genome architecture and function. In consequence, the possible configurations of Repeats in specific and dynamic regions like the gene promoters could define footprints for molecular mechanisms, pathways, and cell function beyond their density in the genome. Here we explored the distribution of Repeats in the upstream promoter region of the human coding genes with the aim to identify specific configurations, clusters and functional meaning of those elements. Our method includes structural descriptions, hierarchical clustering, pathway association, and functional enrichment analysis. RESULTS: We report here several configurations of Repeats in the upstream promoter region (UPR), which define 2729 patterns for the 80% of the human coding genes. There are 47 types of Repeats in these configurations, where the most frequent were Alu, Low_complexity, MIR, Simple_repeat, LINE/L2, LINE/L1, hAT-Charlie, and ERV1. The distribution, length, and the high frequency of Repeats in the UPR defines several patterns and clusters, where the minimum frequency of configuration among Repeats was higher than 0.7. We found those clusters associated with cellular pathways and ontologies; thus, it was plausible to determine groups of Repeats to specific functional insights, for example, pathways for Genetic Information Processing or Metabolism shows particular groups of Repeats with specific configurations. CONCLUSION: Based on these findings, we propose that specific configurations of repetitive elements describe frequent patterns in the upstream promoter for sets of human coding genes, which those correlated to specific and essential cell pathways and functions.
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Algoritmos , Genoma Humano , Sistemas de Lectura Abierta , Regiones Promotoras Genéticas , Secuencias Repetitivas de Ácidos Nucleicos , Análisis por Conglomerados , Ontología de Genes , HumanosRESUMEN
Prognostic models are widely used in clinical practice for transplant decision-making in myelofibrosis (MF). We have compared the performance of the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus in a series of 544 patients with primary or secondary MF aged ≤ 70 years at the time of diagnosis. The median projected survival of the overall series was 9.46 years (95% confidence interval 7.44-10.59). Median survival for the highest risk groups was less than 4 years in the three prognostic models. By contrast, the projected survival for patients in the intermediate-2 categories by the IPSS, DIPSS, and DIPSS-plus was 6.6, 5.6, and 6.5 years, respectively. The number of patients in the intermediate-2 and high-risk categories was smaller in the DIPSS than in the IPSS or the DIPSS-plus. The IPSS and DIPSS-plus were the best models to discriminate between the intermediate-1 and intermediate-2 risk categories, which is a critical cut-off point for patient selection to transplant. Among patients assigned at diagnosis to the intermediate-2 or high-risk groups by the IPSS, DIPSS, and DIPSS-plus, only 17, 21, and 20%, respectively, were subsequently transplanted. In conclusion, in our contemporary series of younger MF patients only the highest risk categories of the current prognostication systems have a median survival below the 5-year threshold recommended for considering transplantation. Patient selection for transplantation can significantly differ depending on which prognostication model is used for disease risk stratification.
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Toma de Decisiones Clínicas/métodos , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/terapia , Trasplante de Células Madre/métodos , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/epidemiología , Pronóstico , Sistema de Registros , Factores de Riesgo , España/epidemiología , Trasplante Homólogo/métodosRESUMEN
OBJECTIVE: Somatic mutations in ASXL1 seem to have a negative prognostic impact in patients with several myeloid neoplasms, including myelofibrosis (MF). The aim of this work was to determine the prevalence and profile of ASXL1 mutations in MF. METHODS: We analyzed mutations in ASXL1 in 70 consecutive MF patients from 8 Spanish hospitals by means of Sanger sequencing, as well as JAK2, CALR, and MPL mutations. RESULTS: ASXL1 mutations were found in 16/70 (23%) of cases, most commonly p.Gly646TrpfsX12 (5/16). Most mutations (13/16) were frameshift mutations. Of 54 ASXL1- wild-type patients, 32 (59%) had at least one single nucleotide polymorphism (SNP), 27 of them had g.78128C>T, g.79017A>C, and g.79085T>C [triple SNP (TSNP) patients]. The 5-yr overall survival probability of TSNP patients was 67% (95% CI, 43-91%) vs. 90% (95% CI, 77-100%) in ASXL1-WT patients (P = 0.152). CONCLUSION: ASXL1 mutations were found in 23% of cases, p.Gly646TrpfsX12 being the most frequent. About 85% of mutations were found only in individual cases and 46% had not previously been reported, a pattern also seen in other series. Fifty percent of ASXL1-WT patients had a combination of three specific SNPs that might have a prognostic correlation that needs to be determined in larger series.
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Mutación , Mielofibrosis Primaria/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Exones , Femenino , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , Adulto JovenRESUMEN
Oxygen minimum zones (OMZ) represent ~8% of the ocean, with the Pacific as the largest and top expanding area. These regions influence marine ecosystems, promoting anaerobic microbial communities. Nevertheless, only a fraction of microbial diversity has been studied, with fungi being the less explored component. So, herein we analyzed fungal diversity patterns in surface and subsurface sediments along a bathymetric transect using metabarcoding of the ITS1 region in the OMZ of the Mexican Pacific off Mazatlán. We identified 353 amplicon sequence variants (ASV), within the Ascomycota, Basidiomycota, and Rozellomycota. Spatial patterns evidenced higher alpha diversity in nearshore and subsurface subsamples, probably due to temporal fluctuations in organic matter inputs. Small-scale heterogeneity characterized the community with the majority of ASV (269 ASV) occurring in a single subsample, hinting at the influence of local biogeochemical conditions. This baseline data evidenced a remarkable fungal diversity presenting high variation along a bathymetric and vertical transects.
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Biodiversidad , Código de Barras del ADN Taxonómico , Hongos , Sedimentos Geológicos , Oxígeno , Sedimentos Geológicos/microbiología , Oxígeno/metabolismo , Oxígeno/análisis , Hongos/genética , Hongos/clasificación , Hongos/aislamiento & purificación , Océano Pacífico , FilogeniaAsunto(s)
Mielofibrosis Primaria , Sistema de Registros , Trombocitopenia , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/sangre , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/terapia , España/epidemiología , Tasa de Supervivencia , Trombocitopenia/sangre , Trombocitopenia/diagnóstico , Trombocitopenia/mortalidad , Trombocitopenia/terapiaRESUMEN
Background and Aims: A noninterventional prospective study was performed in Colombia and Peru. The aim was to describe the impact of access to treatment on Patient-reported outcomes (PRO) in patients with Rheumatoid arthritis (RA) after failure to conventional disease-modifying antirheumatic drugs (DMARDs) in real-life conditions. Methods: The impact of access to treatment was measured by access barriers, time to supply (TtS) and interruption evaluating their effect in changes of PROs between baseline and 6-month follow-up between February 2017 and November 2019. The association of access to care with disease activity, functional status, health-related quality of life was assessed using bivariate and multivariable analysis. Results are expressed in least mean difference; TtS in mean number of days for delivery of treatment at baseline. Variability measures were standard deviation and standard error. Results: One hundred seventy patients were recruited, 70 treated with tofacitinib and 100 with biological DMARDs. Thirty-nine patients reported access barriers. The mean of TtS was 23 ± 38.83 days. The difference from baseline to 6-month visit in PROs were affected by access barriers and interruptions. There was not statistically significant difference in the of PRO's score among visits in patients that reported delay of supply of more than 23 days compared to patients with less days of delay. Conclusion: This study suggested the access to treatment can affect the response to the treatment at 6 months of follow-up. There seems to be no effect in the PROs for delay of TtS during the studied period.
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Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.
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The International Prognostic Score of thrombosis in Essential Thrombocythemia (IPSET-thrombosis) and its revised version have been proposed to guide thrombosis prevention strategies. We evaluated both classifications to prognosticate thrombosis in 1366 contemporary essential thrombocythemia (ET) patients prospectively followed from the Spanish Registry of ET. The cumulative incidence of thrombosis at 10 years, taking death as a competing risk, was 11.4%. The risk of thrombosis was significantly higher in the high-risk IPSET-thrombosis and high-risk revised IPSET-thrombosis, but no differences were observed among the lower risk categories. Patients allocated in high-risk IPSET-thrombosis (subdistribution hazard ratios [SHR], 3.7 [95% confidence interval, CI, 1.6-8.7]) and high-risk revised IPSET-thrombosis (SHR, 3.2 [95% CI, 1.4-7.45]) showed an increased risk of arterial thrombosis, whereas both scoring systems failed to predict venous thrombosis. The incidence rate of thrombosis in intermediate risk revised IPSET-thrombosis (aged >60 years, JAK2-negative, and no history of thrombosis) was very low regardless of the treatment administered (0.9% and 0% per year with and without cytoreduction, respectively). Dynamic application of the revised IPSET-thrombosis showed a low rate of thrombosis when patients without history of prior thrombosis switched to a higher risk category after reaching 60 years of age. In conclusion, IPSET-thrombosis scores are useful for identifying patients at high risk of arterial thrombosis, whereas they fail to predict venous thrombosis. Controlled studies are needed to determine the appropriate treatment of ET patients assigned to the non-high-risk categories.
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Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs.
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Molecular and cytogenetic studies are essential for diagnosis and prognosis in patients with myelodysplastic syndromes (MDSs). Cell-free DNA (cfDNA) analysis has been reported to be a reliable noninvasive approach for detecting molecular abnormalities in MDS; however, there is limited information about cytogenetic alterations and monitoring in cfDNA. We assessed the molecular and cytogenetic profile of a cohort of 70 patients with MDS by next-generation sequencing (NGS) of cfDNA and compared the results to sequencing of paired bone marrow (BM) DNA. Sequencing of BM DNA and cfDNA showed a comparable mutational profile (92.1% concordance), and variant allele frequencies (VAFs) strongly correlated between both sample types. Of note, SF3B1 mutations were detected with significantly higher VAFs in cfDNA than in BM DNA. NGS and microarrays were highly concordant in detecting chromosomal alterations although with lower sensitivity than karyotype and fluorescence in situ hybridization. Nevertheless, all cytogenetic aberrations detected by NGS in BM DNA were also detected in cfDNA. In addition, we monitored molecular and cytogenetic alterations and observed an excellent correlation between the VAFs of mutations in BM DNA and cfDNA across multiple matched time points. A decrease in the cfDNA VAFs was detected in patients responding to therapy, but not in nonresponding patients. Of note, cfDNA analysis also showed cytogenetic evolution in 2 nonresponsive cases. In summary, although further studies with larger cohorts are needed, our results support the analysis of cfDNA as a promising strategy for performing molecular characterization, detection of chromosomal aberrations and monitoring of patients with MDS.
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Ácidos Nucleicos Libres de Células , Síndromes Mielodisplásicos , Aberraciones Cromosómicas , Humanos , Hibridación Fluorescente in Situ , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genéticaRESUMEN
We evaluated the microbial diversity and metabolome profile of an uncommon hypersaline elastic microbial mat from Cuatro Ciénegas Basin (CCB) in the Chihuahuan Desert of Coahuila, México. We collected ten samples on a small scale transect (1.5-m) and described its microbial diversity through NGS-based ITS and 16S rDNA gene sequencing. A very low number of taxa comprised a considerable proportion of the mat and were shared across all sampling points, whereas the rare biosphere was more phylogenetically diverse (Faith's Phylogenetic Diversity (FPD) index) and phylogenetically disperse (using a null model distribution of Phylogenetic Species Clustering (nmdPSC)) than the abundant (high read count) taxa for both analyzed libraries. We also found a distinctive metabolome profile for each sample and were able to tentatively annotate several classes of compounds with relevant biological properties.
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Ambiente , Filogenia , ADN Ribosómico , MéxicoRESUMEN
BACKGROUND: Several studies have shown that genomes can be studied via a multifractal formalism. Recently, we used a multifractal approach to study the genetic information content of the Caenorhabditis elegans genome. Here we investigate the possibility that the human genome shows a similar behavior to that observed in the nematode. RESULTS: We report here multifractality in the human genome sequence. This behavior correlates strongly on the presence of Alu elements and to a lesser extent on CpG islands and (G+C) content. In contrast, no or low relationship was found for LINE, MIR, MER, LTRs elements and DNA regions poor in genetic information. Gene function, cluster of orthologous genes, metabolic pathways, and exons tended to increase their frequencies with ranges of multifractality and large gene families were located in genomic regions with varied multifractality. Additionally, a multifractal map and classification for human chromosomes are proposed. CONCLUSIONS: Based on these findings, we propose a descriptive non-linear model for the structure of the human genome, with some biological implications. This model reveals 1) a multifractal regionalization where many regions coexist that are far from equilibrium and 2) this non-linear organization has significant molecular and medical genetic implications for understanding the role of Alu elements in genome stability and structure of the human genome. Given the role of Alu sequences in gene regulation, genetic diseases, human genetic diversity, adaptation and phylogenetic analyses, these quantifications are especially useful.
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Fractales , Genoma Humano , Elementos Alu , Composición de Base , Mapeo Cromosómico , Cromosomas Humanos/genética , Islas de CpG , Bases de Datos Genéticas , Análisis Discriminante , Humanos , Modelos Genéticos , Familia de Multigenes , Análisis de Secuencia de ADNRESUMEN
Montane cloud forests are fragile biodiversity hotspots. To attain their conservation, disentangling diversity patterns at all levels of ecosystem organization is mandatory. Biotic communities are regularly structured by environmental factors even at small spatial scales. However, studies at this scale have received less attention with respect to larger macroscale explorations, hampering the robust view of ecosystem functioning. In this sense, fungal small-scale processes remain poorly understood in montane cloud forests, despite their relevance. Herein, we analyzed soil fungal diversity and ecological patterns at the small-scale (within a 10 m triangular transect) in a pristine montane cloud forest of Mexico, using ITS rRNA gene amplicon Illumina sequencing and biogeochemical profiling. We detected a taxonomically and functionally diverse fungal community, dominated by few taxa and a large majority of rare species (81%). Undefined saprotrophs represented the most abundant trophic guild. Moreover, soil biogeochemical data showed an environmentally heterogeneous setting with patchy clustering, where enzymatic activities suggest distinctive small-scale soil patterns. Our results revealed that in this system, deterministic processes largely drive the assemblage of fungal communities at the small-scale, through multifactorial environmental filtering.
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Genetic mechanisms controlling root development are well-understood in plant model species, and emerging frontier research is currently dissecting how some of these mechanisms control root development in cacti. Here we show the patterns of root architecture development in a gradient of divergent lineages, from populations to species in Mammillaria. First, we show the patterns of variation in natural variants of the species Mammillaria haageana. Then we compare this variation to closely related species within the Series Supertexta in Mammillaria (diverging for the last 2.1 million years) in which M. haageana is inserted. Finally, we compared these patterns of variation to what is found in a set of Mammillaria species belonging to different Series (diverging for the last 8 million years). When plants were grown in controlled environments, we found that the variation in root architecture observed at the intra-specific level, partially recapitulates the variation observed at the inter-specific level. These phenotypic outcomes at different evolutionary time-scales can be interpreted as macroevolution being the cumulative outcome of microevolutionary phenotypic divergence, such as the one observed in Mammillaria accessions and species.