RESUMEN
Autophagy is an essential cellular recycling process that maintains protein and organelle homeostasis. ATG9A vesicle recruitment is a critical early step in autophagy to initiate autophagosome biogenesis. The mechanisms of ATG9A vesicle recruitment are best understood in the context of starvation-induced non-selective autophagy, whereas less is known about the signals driving ATG9A vesicle recruitment to autophagy initiation sites in the absence of nutrient stress. Here we demonstrate that loss of ATG9A or the lipid transfer protein ATG2 leads to the accumulation of phosphorylated p62 aggregates in the context of basal autophagy. Furthermore, we show that p62 degradation requires the lipid scramblase activity of ATG9A. Lastly, we present evidence that poly-ubiquitin is an essential signal that recruits ATG9A and mediates autophagy foci assembly in nutrient replete cells. Together, our data support a ubiquitin-driven model of ATG9A recruitment and autophagosome formation during basal autophagy.
RESUMEN
Understanding quantum thermalization through entanglement build up in isolated quantum systems addresses fundamental questions on how unitary dynamics connects to statistical physics. Spin systems made of long-range interacting atoms offer an ideal experimental platform to investigate this question. Here, we study the spin dynamics and approach towards local thermal equilibrium of a macroscopic ensemble of S = 3 chromium atoms pinned in a three dimensional optical lattice and prepared in a pure coherent spin state, under the effect of magnetic dipole-dipole interactions. Our isolated system thermalizes under its own dynamics, reaching a steady state consistent with a thermal ensemble with a temperature dictated from the system's energy. The build up of quantum correlations during the dynamics is supported by comparison with an improved numerical quantum phase-space method. Our observations are consistent with a scenario of quantum thermalization linked to the growth of entanglement entropy.
RESUMEN
Attractive Bose-Einstein condensates can host two types of macroscopic self-bound states: bright solitons and quantum droplets. Here, we investigate the connection between them with a Bose-Bose mixture confined in an optical waveguide. We show theoretically that, depending on atom number and interaction strength, solitons and droplets can be smoothly connected or remain distinct states coexisting only in a bistable region. We measure their spin composition, extract their density for a broad range of parameters, and map out the boundary of the region separating solitons from droplets.
RESUMEN
Quantum droplets are small clusters of atoms self-bound by the balance of attractive and repulsive forces. Here, we report on the observation of droplets solely stabilized by contact interactions in a mixture of two Bose-Einstein condensates. We demonstrate that they are several orders of magnitude more dilute than liquid helium by directly measuring their size and density via in situ imaging. We show that the droplets are stablized against collapse by quantum fluctuations and that they require a minimum atom number to be stable. Below that number, quantum pressure drives a liquid-to-gas transition that we map out as a function of interaction strength. These ultradilute isotropic liquids remain weakly interacting and constitute an ideal platform to benchmark quantum many-body theories.
RESUMEN
This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigor and transparency in development and application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a model's development, underpinning biological knowledge, and analyses of model behaviors are constructed to determine the confidence that a model is fit for the purpose for which it will be applied.
Asunto(s)
Ingeniería Biomédica/métodos , Modelos Biológicos , Biología de Sistemas/métodos , Animales , Antiprotozoarios/inmunología , Antiprotozoarios/uso terapéutico , Ingeniería Biomédica/tendencias , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/terapia , Biología de Sistemas/tendenciasRESUMEN
We study the impact of spin-exchange collisions on the dynamics of Bose-Einstein condensation by rapidly cooling a chromium multicomponent Bose gas. Despite relatively strong spin-dependent interactions, the critical temperature for Bose-Einstein condensation is reached before the spin degrees of freedom fully thermalize. The increase in density due to Bose-Einstein condensation then triggers spin dynamics, hampering the formation of condensates in spin-excited states. Small metastable spinor condensates are, nevertheless, produced, and they manifest in strong spin fluctuations.
RESUMEN
Invasion by exotic grasses is a severe threat to the integrity of grassland ecosystems all over the world. Because grasslands are typically grazed by livestock and wildlife, the invasion is a community process modulated by herbivory. We hypothesized that the invasion of native South American grasslands by Eragrostis plana Nees, an exotic tussock-forming grass from Africa, could be deterred by grazing if grazers switched dietary preferences and included the invasive grass as a large proportion of their diets. Bos taurus (heifers) and Ovis aries (ewes) grazed plots with varying degrees of invasion by E. plana in a replicated manipulative experiment. Animal positions and species grazed were observed every minute in 45-min grazing session. Proportion of bites and steps in and out of E. plana tussocks were measured and used to calculate several indices of selectivity. Both heifers and ewes exhibited increasing probability of grazing E. plana as the proportion of area covered by tussocks increased, but they behaved differently. In agreement with expectations based on the allometry of dietary preferences and morphology, ewes consumed a low proportion of E. plana, except in areas that had more than 90% E. plana cover. Heifers consumed proportionally more E. plana than ewes. Contrary to our hypothesis, herbivores did not exhibit dietary switching towards the invasive grass. Moreover, they exhibited avoidance of the invasive grass and preference for short-statured native species, both of which should tend to enhance invasion. Unless invasive plants are highly palatable to livestock, the effect of grazing to deter the invasion is limited, due to the inherent avoidance of the invasive grass by the main grazers in the ecosystem, particularly sheep.
Asunto(s)
Bovinos/psicología , Dieta , Eragrostis , Conducta Alimentaria , Herbivoria , Especies Introducidas , Ovinos/psicología , Distribución Animal , Animales , Biodiversidad , Tamaño Corporal , Brasil , Bovinos/fisiología , Ecosistema , Femenino , Preferencias Alimentarias , Dispersión de las Plantas , Ovinos/fisiología , Especificidad de la EspecieRESUMEN
We propose and experimentally demonstrate a new cooling mechanism leading to purification of a Bose-Einstein condensate (BEC). Our scheme starts with a BEC polarized in the lowest energy spin state. Spin excited states are thermally populated by lowering the single particle energy gap set by the magnetic field. Then, these spin-excited thermal components are filtered out, which leads to an increase of the BEC fraction. We experimentally demonstrate such cooling for a spin 3 ^{52}Cr dipolar BEC. Our scheme should be applicable to Na or Rb, with the perspective to reach temperatures below 1 nK.
RESUMEN
Massive present-day early-type (elliptical and lenticular) galaxies probably gained the bulk of their stellar mass and heavy elements through intense, dust-enshrouded starbursts--that is, increased rates of star formation--in the most massive dark-matter haloes at early epochs. However, it remains unknown how soon after the Big Bang massive starburst progenitors exist. The measured redshift (z) distribution of dusty, massive starbursts has long been suspected to be biased low in z owing to selection effects, as confirmed by recent findings of systems with redshifts as high as ~5 (refs 2-4). Here we report the identification of a massive starburst galaxy at z = 6.34 through a submillimetre colour-selection technique. We unambiguously determined the redshift from a suite of molecular and atomic fine-structure cooling lines. These measurements reveal a hundred billion solar masses of highly excited, chemically evolved interstellar medium in this galaxy, which constitutes at least 40 per cent of the baryonic mass. A 'maximum starburst' converts the gas into stars at a rate more than 2,000 times that of the Milky Way, a rate among the highest observed at any epoch. Despite the overall downturn in cosmic star formation towards the highest redshifts, it seems that environments mature enough to form the most massive, intense starbursts existed at least as early as 880 million years after the Big Bang.
RESUMEN
The indolequinone EO9 demonstrated good preclinical activity but failed to show clinical efficacy against a range of tumours following intravenous drug administration. A significant factor in EO9's failure in the clinic has been attributed to its rapid pharmacokinetic elimination resulting in poor drug delivery to tumours. Intravesical administration of EO9 would circumvent the problem of drug delivery to tumours and the principal objective of this study is to determine whether or not bladder tumours have elevated levels of the enzyme NQO1 (NAD(P)H:quinone oxidoreductase) which plays a key role in activating EO9 under aerobic conditions. Elevated NQO1 levels in human bladder tumour tissue exist in a subset of patients as measured by both immunohistochemical and enzymatic assays. In a panel of human tumour cell lines, EO9 is selectively toxic towards NQO1 rich cell lines under aerobic conditions and potency can be enhanced by reducing extracellular pH. These studies suggest that a subset of bladder cancer patients exist whose tumours possess the appropriate biochemical machinery required to activate EO9. Administration of EO9 in an acidic vehicle could be employed to reduce possible systemic toxicity as any drug absorbed into the blood stream would become relatively inactive due to an increase in pH.
Asunto(s)
Antineoplásicos/uso terapéutico , Aziridinas/uso terapéutico , Indolquinonas , Indoles/uso terapéutico , Quinona Reductasas/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Aziridinas/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Inmunohistoquímica , Indoles/farmacocinética , Especificidad por Sustrato , Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/enzimologíaRESUMEN
Zooplankton of the Laurentian Great Lakes developed hernial protrusions whose gross appearance matches those on zooplankton described elsewhere in the world. We have carried out a histologic and cytologic analysis of the protrusions and found that they are composed of apparently degenerating or necrotic tissue(s) that has been expressed from the organism through the process of herniation. At their base the protrusions are continuous with viable tissue(s) within the organism through a fissure in the exoskeleton. Our observations lead us to suspect that these hernial protrusions are lethal. The development of such protrusions in zooplankton may be a worldwide phenomenon, but the cause of the herniation remains a mystery.
Asunto(s)
Crustáceos/citología , Zooplancton/citología , Animales , Femenino , Agua Dulce , Great Lakes RegionRESUMEN
By the end of the 19th century, exfoliated cancer cells had been described in all of the types of specimen in which we find them today. However, it was not until Drs. Papanicolaou and Traut published their account of the diagnosis of uterine cancer from exfoliated cells (1941 and 1943) that cytopathology acquired the momentum to develop into the powerful presence that it has in human medicine today. These and the subsequent publications by Papanicolaou stimulated the development and application of cytopathology worldwide, resulting in abundant literature on the subject and a galaxy of outstanding practitioners. The 1980s saw the development and widespread use of aspiration cytology. This was followed in the 1990s by the development of automated screening systems, marking the latest stage in the evolution of cytopathology. These and other events and achievements in cytopathology, from its meager beginnings in the early 20th century to its worldwide use and acceptance today, mark this century as the "century for cytopathology."
Asunto(s)
Biología Celular/historia , Patología/historia , Técnicas de Laboratorio Clínico/historia , Grecia , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Publicaciones Periódicas como Asunto/historia , Edición/historia , Edición/organización & administración , Estados UnidosRESUMEN
OBJECTIVE: To describe and illustrate the characteristic features of amyloid in cytologic preparations and point out its diagnostic pitfalls. STUDY DESIGN: Five fine needle aspirates and one bronchial washing that contained amyloid were retrospectively reviewed. The aspirates were obtained from each of the five following sites: lung, occipital lymph node, thyroid gland, proximal humerus and subcutaneous soft tissue. Smears of all of the aspirates were stained with Papanicolaou stain, and in two cases they were also stained with Diff-Quik. Cell block sections were stained with hematoxylin and eosin. Congo red, CD45 and CD20 were used on selected cases. RESULTS: Amyloid appears as either flocculent material or irregularly shaped fragments with scalloped and pointed edges. The amorphous fragments are acellular and frequently associated with connective tissue cells. They stain eosinophilic to cyanophilic with Papanicolaou stain and deep blue with Diff-Quik. In two cases an exuberant giant cell reaction almost obscured the amyloid. In the thyroid aspirate, the amyloid was misinterpreted as colloid. In bronchial washings and lung aspirates, amyloid has to be distinguished from mucus, alveolar proteinosis, chondroid material and corpora amylacea. When circumferentially surrounded by lymphocytes or plasma cells, flocculent amyloid deposits may simulate adenoid cystic carcinoma. CONCLUSION: Amyloid can be easily overlooked or mistaken for other entities with similar staining qualities. Congo red staining can help to confirm the diagnosis.
Asunto(s)
Amiloide/análisis , Amiloidosis/patología , Biopsia con Aguja/métodos , Anciano , Anciano de 80 o más Años , Líquido del Lavado Bronquioalveolar/química , Calcinosis/patología , Colorantes , Técnicas Citológicas , Diagnóstico Diferencial , Femenino , Humanos , Húmero/patología , Pulmón/patología , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Piel/patología , Glándula Tiroides/patologíaRESUMEN
Epstein-Barr virus (EBV), the cause of infectious mononucleosis, is involved in the pathogenesis of several human cancers, the highest frequency of association being found in undifferentiated nasopharyngeal carcinoma and endemic Burkitt's lymphoma. The development of animal models in which potential vaccines can be tested is important. EBV infection of the common marmoset, using the M81 strain originally derived from a patient with nasopharyngeal carcinoma, induces a carrier state in this animal. Persistent infection is characterized by the production of antibodies to viral antigens, and the secretion of EBV DNA into buccal fluids. Following immunization with envelope glycoprotein gp340 derived from a bovine papilloma virus expression vector, prior to EBV infection, viral DNA was detected significantly less frequently in the buccal fluids of immunized, than of nonimmunized, infected animals, indicating that although the carrier state had not been abolished, it had been altered. A reduction in virus load was also observed when offspring of seronegative, and on occasion seropositive, parents were immunized neonatally, before EBV challenge.
Asunto(s)
Anticuerpos Antivirales/sangre , Proteínas de la Cápside , Infecciones por Herpesviridae/inmunología , Herpesvirus Humano 4/inmunología , Inmunización , Proteínas de la Matriz Viral/inmunología , Vacunas Virales/inmunología , Animales , Antígenos Virales/inmunología , Callithrix , ADN Viral/análisis , Femenino , Infecciones por Herpesviridae/virología , Herpesvirus Humano 4/fisiología , Masculino , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Carga Viral , Esparcimiento de VirusRESUMEN
Epstein-Barr virus (EBV) is the cause of infectious mononucleosis and is associated with a variety of life-threatening diseases in humans. Therefore the development of an effective vaccine is an important objective. Many of the initial studies of vaccine efficacy analyse the ability of vaccine preparations to prevent the induction of lymphomas in cottontop tamarins by the B95-8 strain of EBV. We used a vaccinia virus recombinant expressing gp340, vMA1, tested previously in the cotton-top tamarin, to evaluate a common marmoset model in which the challenge virus, M81, resembles more closely the wild-type strains of EBV in the general population than does the standard B95-8 strain. We characterised the M81 strain of EBV with respect to the sequence of its gp340/220 gene and in regard to the presence of a region deleted in B95-8. Replication of the challenge virus in the group vaccinated with vMA1 was decreased when compared to control groups.
Asunto(s)
Vectores Genéticos , Herpesvirus Humano 4/inmunología , Mononucleosis Infecciosa/prevención & control , Vacunas Sintéticas/inmunología , Virus Vaccinia/genética , Proteínas de la Matriz Viral/inmunología , Vacunas Virales/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Antivirales/análisis , Callithrix , Línea Celular , ADN Viral/análisis , Modelos Animales de Enfermedad , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Inmunización , Masculino , Datos de Secuencia Molecular , Mucosa Bucal/virología , Vacunas Sintéticas/genética , Proteínas de la Matriz Viral/genética , Vacunas Virales/genéticaRESUMEN
Podiatric medicine faces some significant challenges that threaten its future growth and development. The California Liaison Committee for Podiatric Medical Education and Training exemplifies an innovative approach to meeting these challenges. The California Liaison Committee has established a dialogue among California's college-based and community-based podiatric medical educators, licensing board members, and private practitioners. The work of the California Liaison Committee, unprecedented in the state, effectively facilitates the curriculum transformation process through cooperation and collaboration.
Asunto(s)
Podiatría/educación , California , Curriculum , Humanos , Internado no Médico , Objetivos Organizacionales , Rol del Médico , Atención Primaria de Salud , EspecializaciónRESUMEN
The effects of cocaine on the development of neurons containing tyrosine hydroxylase (TH) were investigated in fetal rhesus macaques. Pregnant monkeys were treated with cocaine 3 mg/kg or saline i.m., four times a day from day 18 of pregnancy until days 40 or 60. Cocaine concentration in plasma from females thus treated was approximately 800 ng/ml 10-20 min following injection. At the time of C-section, plasma levels of cocaine in fetal blood were 231 +/- 70 ng/ml. The brains from 40 and 60 d old fetuses were examined using immunocytochemistry and in situ hybridization. The appearance of neurons containing TH by day 40 of gestation was not different between control and cocaine-treated fetal monkeys. In both groups (N = 3 each) TH-IR neurons and TH mRNA were located in the mesencephalon and dorsal hypothalamus by day 40, and fiber projections extended to the developing striatum. Also in the day 60 fetuses, the TH-IR neurons were distributed similarly in both groups (N = 5 each), but the TH mRNA content, measured by quantitative in situ hybridization, was reduced in the substantia nigra (SN) and ventral tegmental area (VTA) after cocaine treatment. These data suggest that exposure to cocaine in fetal life does not affect the development of TH or the expression of its mRNA on day 40 of gestation. By day 60, however, the expression of TH mRNA was significantly reduced. This latter effect can be explained by reduced dopamine synthesis in the cocaine-treated fetuses.
Asunto(s)
Encéfalo/embriología , Cocaína/farmacología , Dopamina/fisiología , Feto/efectos de los fármacos , Neuronas/fisiología , Animales , Secuencia de Bases , Líquidos Corporales/metabolismo , Encéfalo/citología , Encéfalo/efectos de los fármacos , Cocaína/farmacocinética , Femenino , Feto/citología , Inmunohistoquímica , Hibridación in Situ , Macaca mulatta/embriología , Datos de Secuencia Molecular , Sondas de Oligonucleótidos/genética , Embarazo , ARN Mensajero/metabolismo , Factores de Tiempo , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
OBJECTIVE: To assess the prognostic significance of presentation serum albumin, clinical stage and CA125 levels in ovarian cancer. DESIGN: Retrospective analysis of data using a Cox proportional hazards model. SETTING: A district general hospital oncology unit. SUBJECTS: One hundred and fourteen consecutive patients with epithelial ovarian cancer. INTERVENTIONS: Cytotoxic chemotherapy and surgery. MAIN OUTCOME MEASURE: Survival. RESULTS: A linear increase in risk was observed with high log CA125 (P < 0.0001) and with low albumin (P < 0.0001). In late stage patients (III and IV) albumin is the best predictor of survival (P = 0.0006). The presence of ascites, blood transfusion, type of surgery or chemotherapy did not improve the predictive model. CONCLUSIONS: CA125 and albumin can be used to identify prognostic subgroups independently of stage. Albumin alone can also be used as a predictor of survival. A simple classification of patients into three groups based on serum albumin of 41 g/l or more, 35 to 40 g/l and 34 g/l or less provides a clear separation of survival curves in the present group of patients.