RESUMEN
While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.
Asunto(s)
Variación Estructural del Genoma/genética , Neoplasias de la Próstata/genética , Anciano , Anciano de 80 o más Años , Proteína BRCA2/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Variaciones en el Número de Copia de ADN , Exoma , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Secuencias Repetidas en Tándem/genética , Proteína p53 Supresora de Tumor/metabolismo , Secuenciación Completa del Genoma/métodosRESUMEN
Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.
Asunto(s)
Inflamación/inmunología , Pulmón/inmunología , Activación de Macrófagos/inmunología , Macrófagos Alveolares/inmunología , Animales , Inflamación/genética , Inflamación/metabolismo , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-4/metabolismo , Larva/inmunología , Larva/fisiología , Pulmón/metabolismo , Pulmón/patología , Activación de Macrófagos/genética , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/parasitología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Mucina 5B/genética , Mucina 5B/inmunología , Mucina 5B/metabolismo , Nippostrongylus/inmunología , Nippostrongylus/fisiología , Proteína D Asociada a Surfactante Pulmonar/genética , Proteína D Asociada a Surfactante Pulmonar/inmunología , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Infecciones por Strongylida/genética , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitologíaRESUMEN
In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution.
Asunto(s)
Arqueología , Industria Lechera , Enfermedad , Genética de Población , Lactasa , Leche , Selección Genética , Animales , Animales Salvajes , Bancos de Muestras Biológicas , Cerámica/historia , Estudios de Cohortes , Industria Lechera/historia , Europa (Continente)/epidemiología , Europa (Continente)/etnología , Hambruna/estadística & datos numéricos , Frecuencia de los Genes , Genotipo , Historia Antigua , Humanos , Lactasa/genética , Leche/metabolismo , Reino UnidoRESUMEN
Mucus is made of enormous mucin glycoproteins that polymerize by disulfide crosslinking in the Golgi apparatus. QSOX1 is a catalyst of disulfide bond formation localized to the Golgi. Both QSOX1 and mucins are highly expressed in goblet cells of mucosal tissues, leading to the hypothesis that QSOX1 catalyzes disulfide-mediated mucin polymerization. We found that knockout mice lacking QSOX1 had impaired mucus barrier function due to production of defective mucus. However, an investigation on the molecular level revealed normal disulfide-mediated polymerization of mucins and related glycoproteins. Instead, we detected a drastic decrease in sialic acid in the gut mucus glycome of the QSOX1 knockout mice, leading to the discovery that QSOX1 forms regulatory disulfides in Golgi glycosyltransferases. Sialylation defects in the colon are known to cause colitis in humans. Here we show that QSOX1 redox control of sialylation is essential for maintaining mucosal function.
Asunto(s)
Glicosiltransferasas , Aparato de Golgi , Mucosa Intestinal , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro , Animales , Ratones , Colon/metabolismo , Disulfuros/metabolismo , Glicoproteínas , Glicosiltransferasas/metabolismo , Aparato de Golgi/metabolismo , Mucinas/química , Mucinas/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupos Sulfuro/metabolismo , Mucosa Intestinal/metabolismoRESUMEN
Within biofilms, gradients of electron acceptors such as oxygen stimulate the formation of physiological subpopulations. This heterogeneity can enable cross-feeding and promote drug resilience, features of the multicellular lifestyle that make biofilm-based infections difficult to treat. The pathogenic bacterium Pseudomonas aeruginosa produces pigments called phenazines that can support metabolic activity in hypoxic/anoxic biofilm subzones, but these compounds also include methylated derivatives that are toxic to their producer under some conditions. In this study, we uncover roles for the global regulators RpoS and Hfq/Crc in controlling the beneficial and detrimental effects of methylated phenazines in biofilms. Our results indicate that RpoS controls phenazine methylation by modulating activity of the carbon catabolite repression pathway, in which the Hfq/Crc complex inhibits translation of the phenazine methyltransferase PhzM. We find that RpoS indirectly inhibits expression of CrcZ, a small RNA that binds to and sequesters Hfq/Crc, specifically in the oxic subzone of P. aeruginosa biofilms. Deletion of rpoS or crc therefore leads to overproduction of methylated phenazines, which we show leads to increased metabolic activity-an apparent beneficial effect-in hypoxic/anoxic subpopulations within biofilms. However, we also find that under specific conditions, biofilms lacking RpoS and/or Crc show increased sensitivity to phenazines indicating that the increased metabolic activity in these mutants comes at a cost. Together, these results suggest that complex regulation of PhzM allows P. aeruginosa to simultaneously exploit the benefits and limit the toxic effects of methylated phenazines.
Asunto(s)
Fenazinas , ARN , Metilación , Fenazinas/farmacología , ARN/metabolismo , Biopelículas , Pseudomonas aeruginosa/metabolismo , Proteínas Bacterianas/metabolismoRESUMEN
Ion transport is essential to energy storage, cellular signalling and desalination. Polymers have been explored for decades as solid-state electrolytes by either adding salt to polar polymers or tethering ions to the backbone to create less flammable and more robust systems. New design paradigms are needed to advance the performance of solid polymer electrolytes beyond conventional systems. Here the role of a helical secondary structure is shown to greatly enhance the conductivity of solvent-free polymer electrolytes using cationic polypeptides with a mobile anion. Longer helices lead to higher conductivity, and random coil peptides show substantially lower conductivity. The macrodipole of the helix increases with peptide length, leading to larger dielectric constants. The hydrogen bonding of the helix also imparts thermal and electrochemical stability, while allowing for facile dissolution back to monomer in acid. Peptide polymer electrolytes present a promising platform for the design of next-generation ion-transporting materials.
RESUMEN
Gene expression noise (heterogeneity) leads to phenotypic diversity among isogenic individual cells. Our current understanding of gene expression noise is mostly limited to transcription, as separating translational noise from transcriptional noise has been challenging. It also remains unclear how translational heterogeneity originates. Using a transcription-normalized reporter system, we discovered that stop codon readthrough is heterogeneous among single cells, and individual cells with higher UGA readthrough grow faster from stationary phase. Our work also revealed that individual cells with lower protein synthesis levels exhibited higher UGA readthrough, which was confirmed with ribosome-targeting antibiotics (e.g., chloramphenicol). Further experiments and mathematical modeling suggest that varied competition between ternary complexes and release factors perturbs the UGA readthrough level. Our results indicate that fluctuations in the concentrations of translational components lead to UGA readthrough heterogeneity among single cells, which enhances phenotypic diversity of the genetically identical population and facilitates its adaptation to changing environments.
Asunto(s)
Codón de Terminación , Proteínas de Escherichia coli/biosíntesis , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Genes Reporteros , Microscopía Fluorescente , Transferasas del Grupo 1-Carbono , Proteínas Bacterianas/biosíntesis , Proteínas Bacterianas/genética , Escherichia coli/crecimiento & desarrollo , Regulación Bacteriana de la Expresión Génica , Aptitud Genética , Genotipo , Cinética , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Modelos Genéticos , Fenotipo , ARN Bacteriano/biosíntesis , ARN Bacteriano/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transcripción Genética , Proteína Fluorescente RojaRESUMEN
Understanding the activated transport of penetrant or tracer atoms and molecules in condensed phases is a challenging problem in chemistry, materials science, physics, and biophysics. Many angstrom- and nanometer-scale features enter due to the highly variable shape, size, interaction, and conformational flexibility of the penetrant and matrix species, leading to a dramatic diversity of penetrant dynamics. Based on a minimalist model of a spherical penetrant in equilibrated dense matrices of hard spheres, a recent microscopic theory that relates hopping transport to local structure has predicted a novel correlation between penetrant diffusivity and the matrix thermodynamic dimensionless compressibility, S0(T) (which also quantifies the amplitude of long wavelength density fluctuations), as a consequence of a fundamental statistical mechanical relationship between structure and thermodynamics. Moreover, the penetrant activation barrier is predicted to have a factorized/multiplicative form, scaling as the product of an inverse power law of S0(T) and a linear/logarithmic function of the penetrant-to-matrix size ratio. This implies an enormous reduction in chemical complexity that is verified based solely on experimental data for diverse classes of chemically complex penetrants dissolved in molecular and polymeric liquids over a wide range of temperatures down to the kinetic glass transition. The predicted corollary that the penetrant diffusion constant decreases exponentially with inverse temperature raised to an exponent determined solely by how S0(T) decreases with cooling is also verified experimentally. Our findings are relevant to fundamental questions in glassy dynamics, self-averaging of angstrom-scale chemical features, and applications such as membrane separations, barrier coatings, drug delivery, and self-healing.
Asunto(s)
Vidrio , Física , Difusión , Vidrio/química , Transición de Fase , TermodinámicaRESUMEN
Rapid developments in high-performance computing and high-power electronics are driving needs for highly thermal conductive polymers and their composites for encapsulants and interface materials. However, polymers typically have low thermal conductivities of â¼0.2 W/(m K). We studied the thermal conductivity of a series of epoxy resins cured by one diamine hardener and seven diepoxide monomers with different precise ethylene linker lengths (x = 2-8). We found pronounced odd-even effects of the ethylene linker length on the liquid crystalline order, mass density, and thermal conductivity. Epoxy resins with even x have liquid crystalline structure with the highest density of 1.44 g/cm3 and highest thermal conductivity of 1.0 W/(m K). Epoxy resins with odd x are amorphous with the lowest density of 1.10 g/cm3 and lowest thermal conductivity of 0.17 W/(m K). These findings indicate that controlling precise linker length in dense networks is a powerful route to molecular design of thermally conductive polymers.
Asunto(s)
Resinas Epoxi , Cristales Líquidos , Resinas Epoxi/química , Conductividad Térmica , Polímeros , EtilenosRESUMEN
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with neurological sequelae including haemorrhage, thrombosis and ischaemic necrosis and encephalitis. However, the mechanism by which this occurs is unclear. Neurological disease associated with COVID-19 has been proposed to occur following direct infection of the central nervous system and/or indirectly by local or systemic immune activation. We evaluated the expression of angiotensin-converting enzyme-2 and transmembrane protease, serine 2 (TMPRSS2) in brain tissue from five healthy human donors and observed low-level expression of these proteins in cells morphologically consistent with astrocytes, neurons and choroidal ependymal cells within the frontal cortex and medulla oblongata. Primary human astrocytes, neurons, choroid plexus epithelial cells and pericytes supported productive SARS-CoV-2 infection with ancestral, Alpha, Delta and Omicron variants. Infected cells supported the full viral life cycle, releasing infectious virus particles. In contrast, primary brain microvascular endothelial cells and microglia were refractory to SARS-CoV-2 infection. These data support a model whereby SARS-CoV-2 can infect human brain cells, and the mechanism of viral entry warrants further investigation.
Asunto(s)
Enzima Convertidora de Angiotensina 2 , Astrocitos , COVID-19 , Plexo Coroideo , Células Epiteliales , Neuronas , Pericitos , SARS-CoV-2 , Serina Endopeptidasas , Humanos , Pericitos/virología , SARS-CoV-2/fisiología , Astrocitos/virología , Plexo Coroideo/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Neuronas/virología , COVID-19/virología , COVID-19/patología , Células Epiteliales/virología , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Células Cultivadas , Encéfalo/virología , Encéfalo/patología , Sistema Nervioso Central/virologíaRESUMEN
Emphysema, the progressive destruction of gas exchange surfaces in the lungs, is a hallmark of chronic obstructive pulmonary disease (COPD) that is presently incurable. This therapeutic gap is largely due to a poor understanding of potential drivers of impaired tissue regeneration, such as abnormal lung epithelial progenitor cells, including alveolar type II (ATII) and airway club cells. We discovered an emphysema-specific sub-population of ATII cells located in enlarged distal alveolar sacs, termed asATII cells. Single cell RNA-seq and in situ localisation revealed that asATII cells co-express the alveolar marker surfactant protein C (SPC) and the club cell marker secretaglobin-3A2 (SCGB3A2). A similar ATII sub-population derived from club cells was also identified in mouse COPD models using lineage labeling. Human and mouse ATII sub-populations formed 80-90% fewer alveolar organoids than healthy controls, indicating reduced progenitor function. Targeting asATII cells or their progenitor club cells could reveal novel COPD treatment strategies.
RESUMEN
PURPOSE: This work reports for the first time on the implementation and application of cardiac diffusion-weighted MRI on a Connectom MR scanner with a maximum gradient strength of 300 mT/m. It evaluates the benefits of the increased gradient performance for the investigation of the myocardial microstructure. METHODS: Cardiac diffusion-weighted imaging (DWI) experiments were performed on 10 healthy volunteers using a spin-echo sequence with up to second- and third-order motion compensation ( M 2 $$ {M}_2 $$ and M 3 $$ {M}_3 $$ ) and b = 100 , 450 $$ b=100,450 $$ , and 1000 s / m m 2 $$ \mathrm{s}/\mathrm{m}{\mathrm{m}}^2 $$ (twice the b max $$ {b}_{\mathrm{max}} $$ commonly used on clinical scanners). Mean diffusivity (MD), fractional anisotropy (FA), helix angle (HA), and secondary eigenvector angle (E2A) were calculated for b = [100, 450] s / m m 2 $$ \mathrm{s}/\mathrm{m}{\mathrm{m}}^2 $$ and b = [100, 1000] s / m m 2 $$ \mathrm{s}/\mathrm{m}{\mathrm{m}}^2 $$ for both M 2 $$ {M}_2 $$ and M 3 $$ {M}_3 $$ . RESULTS: The MD values with M 3 $$ {M}_3 $$ are slightly higher than with M 2 $$ {M}_2 $$ with Δ MD = 0 . 05 ± 0 . 05 [ × 1 0 - 3 mm 2 / s ] ( p = 4 e - 5 ) $$ \Delta \mathrm{MD}=0.05\pm 0.05\kern0.3em \left[\times 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=4e-5\right) $$ for b max = 450 s / mm 2 $$ {b}_{\mathrm{max}}=450\kern0.3em \mathrm{s}/{\mathrm{mm}}^2 $$ and Δ MD = 0 . 03 ± 0 . 03 [ × 1 0 - 3 mm 2 / s ] ( p = 4 e - 4 ) $$ \Delta \mathrm{MD}=0.03\pm 0.03\kern0.3em \left[\times \kern0.3em 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=4e-4\right) $$ for b max = 1000 s / mm 2 $$ {b}_{\mathrm{max}}=1000\kern0.3em \mathrm{s}/{\mathrm{mm}}^2 $$ . A reduction in MD is observed by increasing the b max $$ {b}_{\mathrm{max}} $$ from 450 to 1000 s / mm 2 $$ \mathrm{s}/{\mathrm{mm}}^2 $$ ( Δ MD = 0 . 06 ± 0 . 04 [ × 1 0 - 3 mm 2 / s ] ( p = 1 . 6 e - 9 ) $$ \Delta \mathrm{MD}=0.06\pm 0.04\kern0.3em \left[\times \kern0.3em 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=1.6e-9\right) $$ for M 2 $$ {M}_2 $$ and Δ MD = 0 . 08 ± 0 . 05 [ × 1 0 - 3 mm 2 / s ] ( p = 1 e - 9 ) $$ \Delta \mathrm{MD}=0.08\pm 0.05\kern0.3em \left[\times \kern0.3em 1{0}^{-3}\kern0.3em {\mathrm{mm}}^2/\mathrm{s}\right]\kern0.3em \left(p=1e-9\right) $$ for M 3 $$ {M}_3 $$ ). The difference between FA, E2A, and HA was not significant in different schemes ( p > 0 . 05 $$ p>0.05 $$ ). CONCLUSION: This work demonstrates cardiac DWI in vivo with higher b-value and higher order of motion compensated diffusion gradient waveforms than is commonly used. Increasing the motion compensation order from M 2 $$ {M}_2 $$ to M 3 $$ {M}_3 $$ and the maximum b-value from 450 to 1000 s / mm 2 $$ \mathrm{s}/{\mathrm{mm}}^2 $$ affected the MD values but FA and the angular metrics (HA and E2A) remained unchanged. Our work paves the way for cardiac DWI on the next-generation MR scanners with high-performance gradient systems.
Asunto(s)
Imagen de Difusión por Resonancia Magnética , Corazón , Humanos , Masculino , Adulto , Corazón/diagnóstico por imagen , Femenino , Voluntarios Sanos , Procesamiento de Imagen Asistido por Computador/métodos , Reproducibilidad de los Resultados , Anisotropía , Algoritmos , Interpretación de Imagen Asistida por Computador/métodosRESUMEN
Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours.
Asunto(s)
Afecto/efectos de los fármacos , Analgésicos Opioides/farmacología , Encéfalo/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Encéfalo/metabolismo , Humanos , Receptores Opioides/metabolismoRESUMEN
BACKGROUND: Child anxiety before general anaesthesia and surgery is common. Midazolam is a commonly used premedication to address this. Melatonin is an alternative anxiolytic, however trials evaluating its efficacy in children have delivered conflicting results. METHODS: This multicentre, double-blind randomised trial was performed in 20 UK NHS Trusts. A sample size of 624 was required to declare noninferiority of melatonin. Anxious children, awaiting day case elective surgery under general anaesthesia, were randomly assigned 1:1 to midazolam or melatonin premedication (0.5 mg kg-1, maximum 20 mg) 30 min before transfer to the operating room. The primary outcome was the modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF). Secondary outcomes included safety. Results are presented as n (%) and adjusted mean differences with 95% confidence intervals. RESULTS: The trial was stopped prematurely (n=110; 55 per group) because of recruitment futility. Participants had a median age of 7 (6-10) yr, and 57 (52%) were female. Intention-to-treat and per-protocol modified Yale Preoperative Anxiety Scale-Short Form analyses showed adjusted mean differences of 13.1 (3.7-22.4) and 12.9 (3.1-22.6), respectively, in favour of midazolam. The upper 95% confidence interval limits exceeded the predefined margin of 4.3 in both cases, whereas the lower 95% confidence interval excluded zero, indicating that melatonin was inferior to midazolam, with a difference considered to be clinically relevant. No serious adverse events were seen in either arm. CONCLUSION: Melatonin was less effective than midazolam at reducing preoperative anxiety in children, although the early termination of the trial increases the likelihood of bias. CLINICAL TRIAL REGISTRATION: ISRCTN registry: ISRCTN18296119.
Asunto(s)
Melatonina , Midazolam , Niño , Humanos , Femenino , Masculino , Midazolam/uso terapéutico , Melatonina/uso terapéutico , Premedicación/métodos , Ansiedad/prevención & control , Anestesia General , Método Doble CiegoRESUMEN
Highly collimated parsec-scale jets, which are generally linked to the presence of an accretion disk, are commonly observed in low-mass young stellar objects. In the past two decades, a few of these jets have been directly (or indirectly) observed from higher-mass (larger than eight solar masses) young stellar objects, adding to the growing evidence that disk-mediated accretion also occurs in high-mass stars, the formation mechanism of which is still poorly understood. Of the observed jets from massive young stars, none is in the optical regime (massive young stars are typically highly obscured by their natal material), and none is found outside of the Milky Way. Here we report observations of HH 1177, an optical ionized jet that originates from a massive young stellar object located in the Large Magellanic Cloud. The jet is highly collimated over its entire measured length of at least ten parsecs and has a bipolar geometry. The presence of a jet indicates ongoing, disk-mediated accretion and, together with the high degree of collimation, implies that this system is probably formed through a scaled-up version of the formation mechanism of low-mass stars. We conclude that the physics that govern jet launching and collimation is independent of stellar mass.
RESUMEN
This corrects the article DOI: 10.1038/nature25738.
RESUMEN
From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.
Asunto(s)
Evolución Cultural/historia , Genoma Humano/genética , Genómica , Migración Humana/historia , Cromosomas Humanos Y/genética , ADN Antiguo , Europa (Continente) , Pool de Genes , Genética de Población , Haplotipos , Historia Antigua , Humanos , Masculino , Análisis Espacio-TemporalRESUMEN
An estimated 100,000 patients each year in the United States suffer severe disability from bone defects that fail to heal, a condition where bone-regenerative therapies could provide substantial clinical benefits. Although recombinant human bone morphogenetic protein-2 (rhBMP2) is an osteogenic growth factor that is clinically approved for this purpose, it is only effective when used at exceedingly high doses that incur substantial costs, induce severe inflammation, produce adverse side effects, and form morphologically abnormal bone. Using a validated rat femoral segmental defect model, we show that bone formed in response to clinically relevant doses of rhBMP2 is accompanied by elevated expression of interleukin-1 (IL-1). Local delivery of cDNA encoding the IL-1 receptor antagonist (IL-1Ra) achieved bridging of segmental, critical size defects in bone with a 90% lower dose of rhBMP2. Unlike use of high-dose rhBMP2, bone formation in the presence of IL-1Ra occurred via the native process of endochondral ossification, resulting in improved quality without sacrificing the mechanical properties of the regenerated bone. Our results demonstrate that local immunomodulation may permit effective use of growth factors at lower doses to recapitulate more precisely the native biology of healing, leading to higher-quality tissue regeneration.
Asunto(s)
Proteína Antagonista del Receptor de Interleucina 1 , Osteogénesis , Humanos , Ratas , Animales , Osteogénesis/genética , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Factor de Crecimiento Transformador beta/farmacología , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Regeneración Ósea/genética , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 2/farmacologíaRESUMEN
BACKGROUND: Overactive bladder (OAB) is a condition defined by urgency with or without incontinence which disproportionately affects female patients and has a negative impact on sexual enjoyment and avoidance behaviour. Pharmacotherapy can be considered one of the main options for treating OAB. This research set out to determine the impact of pharmacotherapy on sexual function in females with OAB. METHODS: This research used the robust methodology of a systematic review. The clinical question was formulated using the PICO (population, intervention, control, and outcomes) format to include females being treated with pharmacotherapy (anticholinergics or beta-3 adrenergic agonists) for idiopathic OAB with the use of a validated questionnaire assessing self-reported sexual function at baseline and post-treatment. The review incorporated the MEDLINE, PubMed and EMBASE databases. The AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) appraisal tool was used to guide the review process. Two reviewers worked independently in screening abstracts, deciding on the inclusion of full-texts, data extraction and risk of bias assessment. RESULTS: In female patients with OAB, pharmacotherapy does seem to offer at least partial improvement in self-reported sexual function outcomes after 12 weeks of therapy. Still, the value of this finding is limited by an overall poor quality of evidence. Patients with a higher degree of bother at baseline stand to benefit the most from treatment when an improvement within this health-related quality of life domain is sought. CONCLUSION: This research should form the basis for a well-conducted randomized controlled study to accurately assess sexual function improvements in females being treated with pharmacotherapy for OAB.