Combining machine learning and SMILEs to classify, better understand, and project changes in ENSO events

The El Niño Southern Oscillation (ENSO) occurs in three phases: neutral, warm (El Niño) and cool (La Niña). While classifying El Niño and La Niña is relatively straightforward, El Niño events can be broadly classified into two types: Central Pacific (CP) and Eastern Pacific (EP). Differentiating between CP and EP events is currently dependent on both the method and observational dataset used. In this study, we create a new classification scheme using supervised machine learning trained on 18 observational and reanalysis products. This builds on previous work by identifying classes of events using the temporal evolution of sea surface temperature in multiple regions across the tropical Pacific. By applying this new classifier to seven single model initial-condition large ensembles (SMILEs) we investigate both the internal variability and forced changes in each type of ENSO event, where events identified behave similar to those observed. It is currently debated whether the observed increase in the frequency of CP events after the late 1970s is due to climate change. We found it to be within the range of internal variability in the SMILEs. When considering future changes, we do not project a change in CP frequency or amplitude under a strong warming scenario (RCP8.5/SSP370) and we find model differences in EP El Niño and La Niña frequency and amplitude projections. Finally, we find that models show differences in projected precipitation and SST pattern changes for each event type that do not seem to be linked to the Pacific mean state SST change, although the SST and precipitation changes in individual SMILEs are linked. Our work demonstrates the value of combining machine learning with climate models, and highlights the need to use SMILEs when evaluating ENSO in climate models due to the large spread of results found within a single model due to internal variability alone

Endocrinology in the time of COVID-19: Management of Cushing’s syndrome

Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing’s syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2–3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic

The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms

Objectives: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. Methods: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1−/−) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. Results: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1−/− mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1−/− mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1−/− mice. Conclusions: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity

Meio Ambiente E Sociedade de Risco: Proteção Integral e Prevenção na Tutela Inibitória Além do Ilícito

TCC(graduação) - Universidade Federal de Santa Catarina. Centro de Ciências Jurídicas. Direito.Esta monografia tem como objetivo principal estudar a concepção de tutela inibitória e a possibilidade de sua aplicação na área do direito ambiental brasileiro, não somente diante da prática de atividades ilícitas, mas também de atividades lícitas, levando-se em conta a problemática do risco, sua tolerabilidade e intolerabilidade. Desse modo, no primeiro capítulo se apresentam noções sobre meio ambiente, teoria da sociedade de risco, de Ulrich Beck, e a preocupação da ordem jurídica com o risco. Já no segundo capítulo, destacam-se a prevenção e a proteção integral como valores essenciais e necessários em sede de direito ambiental, aliados às formas de tutela adequada dos direitos, estas incluídas entre os principais escopos do processo civil moderno. Por fim, no terceiro capítulo, abordam-se as linhas gerais da tutela inibitória, frisando-se seu feitio preventivo e específico, tal como propõe Luiz Guilherme Marinoni, inspirado na doutrina italiana. Procura-se verificar, utilizando-se o método indutivo, se é possível a utilização da teoria da tutela inibitória para se evitar o cometimento de ilícitos (e conseqüentemente a ocorrência eventual de danos), sua continuação ou repetição e, ainda, impedir a prática de lícitos, caso estes não encontrem mais amparo na tolerabilidade do risco a que expõem o meio ambiente

Electron photodetachment dissociation of DNA anions with covalently or noncovalently bound chromophores

Double stranded DNA multiply charged anions coupled to chromophores were subjected to UV-Vis photoactivation. in a quadrupole ion trap mass spectrometer. The chromophores included noncovalently bound minor groove binders (activated in the near UV), noncovalently bound intercalators (activated with visible light), and covalently linked fluorophores and quenchers (activated at their maximum absorption wavelength). We found that the activation of only chromophores having long fluorescence lifetimes did result in efficient electron photodetachment from the DNA complexes. In the case of ethidium-dsDNA complex excited at 500 nm, photodetachment is a multiphoton process. The MS3 fragmentation of radicals produced by photodetachment at lambda = 260 nm (DNA excitation) and by photodetachment at lambda > 300 nm (chromophore excitation) were compared. The radicals keep no memory of the way they were produced. A weakly bound noncovalent ligand (m-amsacrine) allowed probing experimentally that a fraction of the electronic internal energy was converted into vibrational internal energy. This fragmentation channel was used to demonstrate that excitation of the quencher DABSYL resulted in internal conversion, unlike the fluorophore 6-FAM. Altogether, photodetachment of the DNA complexes upon chromophore excitation can be interpreted by the following mechanism: (1) ligands with sufficiently long excited-state lifetime undergo resonant two-photon excitation to reach the level of the DNA excited states, then (2) the excited-state must be coupled to the DNA excited states for photodetachment to occur. Our experiments also pave the way towards photodissociation probes of biomolecule conformation in the gas-phase by Forster resonance energy transfer (FRET)

Production of the urban space in São João da Boa Vista/SP between 2000 and 2016: allotments and urban segregation

A produção do espaço urbano no contexto da sociedade capitalista reproduz na cidade as desigualdades inerentes ao modo de produção, por meio da ação de agentes produtores do espaço, que moldam a cidade para a concretização dos seus interesses. São João da Boa Vista, estudo de caso desse artigo, localiza-se no interior de São Paulo, faz parte da mesorregião de Campinas e é centro da microrregião de São João da Boa Vista, dista-se a 220 km da capital do estado e possui uma população de 90.089 (IBGE, 2017). Assim como outras cidades médias, São João da Boa Vista apresentou grande crescimento econômico e urbano nos últimos anos, modificando a dinâmica urbana da cidade. Na última década, inúmeros novos loteamentos foram implantados no município, principalmente condomínios fechados de médio e alto padrão e moradias de interesse social, que se refletiu em novos fenômenos urbanos, como a segregação socioespacial. Visto isso, essa pesquisa visou contribuir na discussão e compreensão da produção do espaço urbano de São João da Boa Vista (SP), por meio do estudo intraurbano da mancha contínua da cidade, da verificação das ações dos agentes produtores do espaço urbano e da espacialização de fenômenos, abordando especialmente a instalação de novos loteamentos na última década e suas consequências. Para isso, foi realizado um levantamento bibliográfico sobre os temas abordados, coleta de dados em variadas fontes, construção de mapas, que em conjunto com trabalhos de campo, entrevistas e verificação de jornais, possibilitaram a obtenção do resultado apresentado. Por fim, foram analisadas tendências de empreendimentos nas periferias da cidade, tanto os voltados a populações de média e alta renda, quanto às de baixa renda, além da investigação das ações dos agentes produtores do espaço urbano, como o Estado e os agentes imobiliários, baseados nos interesses capitalistas.The production of urban space in the context of capitalist society reproduces in the city the inequalities inherent in the mode of production, through the action of space-producing agents that shape the city for the realization of its interests. São João da Boa Vista, the case study of this article, is located in the interior of São Paulo and has a population of 90,637 (IBGE, 2018). Like other medium-sized cities, São João da Boa Vista has presented great economic and urban growth in recent years, modifying the urban dynamics of the city. In the last decade, innumerable new allotments were implanted in the municipality, mainly closed condominiums of middle and high standard and houses of social interest, which was reflected in new urban phenomenon, as the socio-spatial segregation. Considering this, this research aimed to contribute to the discussion and understanding of the production of the urban space of São João da Boa Vista (SP), through the intraurban study of the continuous spot of the city, the verification of the actions of the agents producing the urban space and spatialization of phenomenon, especially addressing the installation of new allotments in the last decade and its consequences. For this, a bibliographical survey was carried out on the topics covered, data collection in various sources, construction of maps, which together with fieldwork, interviews and verification of newspapers, made it possible to obtain the presented result. Finally, trends of real estate development in the periphery of the city were analyzed, both those aimed at medium and high-income populations, as well as low-income populations, additionally the investigation of the actions of agents producing urban space, such as the State and real estate agents, based on capitalist interests

Efficacy and safety of high-dose long-acting repeatable octreotide as monotherapy or in combination with pegvisomant or cabergoline in patients with acromegaly not adequately controlled by conventional regimens: results of an open-label, multicentre study

Introduction: Long-acting repeatable (LAR) octreotide i.m. is a potent, synthetic somatostatin analogue (SSA) that requires less frequent dosing and offers quality of life (QoL) benefits in acromegaly patients compared to its shorter-acting predecessor. This study investigated the efficacy and safety of high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline in acromegalic patients with pituitary adenomas following previous failure of conventional SSA treatment. Material and methods: After three months of high-dose Sandostatin® LAR® monotherapy (40 mg), patients who achieved biochemical control (n = 7) continued to receive the same treatment for an additional four months, whereas uncontrolled patients were randomised to receive high-dose Sandostatin® LAR® in combination with pegvisomant (n = 31) or cabergoline (n = 32). Outcomes included biochemical response at eight months, QoL, and safety. Results: After three months, 3 of 68 (4.4%) evaluable patients achieved a biochemical control (BC) as assessed by levels of growth hormone and insulin-like growth factor-1. At eight months, 4 of 67 (6.0%) patients achieved BC, including one receiving monotherapy and three receiving Sandostatin® LAR® plus cabergoline. Partial response rate, improvements in acromegaly signs and symptoms, and changes in QoL were similar for all three groups. All treatments were well tolerated with a slight excess of adverse events in the combination arms. There were no deaths or serious adverse events leading to treatment discontinuation. Conclusion: These data demonstrate that high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline is a feasible salvage option in patients with pituitary adenomas not adequately controlled on conventional SSA regimens

Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease

Objective Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease. Design Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906). Methods Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time. Results At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN. Conclusion mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled

Towards a representative reference for MRI-based human axon radius assessment using light microscopy

Non-invasive assessment of axon radii via MRI bears great potential for clinical and neuroscience research as it is a main determinant of the neuronal conduction velocity. However, there is a lack of representative histological reference data at the scale of the cross-section of MRI voxels for validating the MRI-visible, effective radius (reff). Because the current gold standard stems from neuroanatomical studies designed to estimate the bulk-determined arithmetic mean radius (rarith) on small ensembles of axons, it is unsuited to estimate the tail-weighted reff. We propose CNN-based segmentation on high-resolution, large-scale light microscopy (lsLM) data to generate a representative reference for reff. In a human corpus callosum, we assessed estimation accuracy and bias of rarith and reff. Furthermore, we investigated whether mapping anatomy-related variation of rarith and reff is confounded by low-frequency variation of the image intensity, e.g., due to staining heterogeneity. Finally, we analyzed the error due to outstandingly large axons in reff. Compared to rarith, reff was estimated with higher accuracy (maximum normalized-root-mean-square-error of reff: 8.5 %; rarith: 19.5 %) and lower bias (maximum absolute normalized-mean-bias-error of reff: 4.8 %; rarith: 13.4 %). While rarith was confounded by variation of the image intensity, variation of reff seemed anatomy-related. The largest axons contributed between 0.8 % and 2.9 % to reff. In conclusion, the proposed method is a step towards representatively estimating reff at MRI voxel resolution. Further investigations are required to assess generalization to other brains and brain areas with different axon radii distributions