The Spectral Dimension of Non-generic Branched Polymer Ensembles

We show that the spectral dimension on non-generic branched polymer models with susceptibility exponent $\gamma$ is given by $2/(1+\gamma)$. For those models with negative $\gamma$ we find that the spectral dimension is 2.Comment: 10 pages plain LateX2e, 1 eps figures included using eps

The core-periphery model with three regions

We study a 3-region core-periphery model à la Krugman and compare our results with those of the standard 2-region model. The conditions for the stability of the dispersion and concentration configurations are established. Like in the 2-region model, dispersion and concentration can be simultaneously stable. We show that the 2- region (3-region) model favors the dispersion (concentration) of economic activity. Finally, we extend the core-periphery model to the case of n regions and show that stability of concentration with 2 regions implies stability of concentration with any even number of regions.new economic geography, core-periphery

Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[Tc-99m(CO)(3)](+): effect of cyclization on tumor-seeking properties

Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized alpha-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of alpha-MSH (Ac-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of alpha-MSH analogs by comparing the pharmacokinetics profile of the (99)mTc-labeled cyclic peptide beta Ala-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2 with that of the linear analog beta Ala-Nle-Asp-His-DPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of beta Ala, and the resulting pz-peptide conjugates were reacted with the fac-[Tc-99m(CO)(3)](+) moiety. The Tc-99m(CO)(3)-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic Tc-99m(CO)(3)-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degrees C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +/- 0.83 and 11.31 +/- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear Tc-99m(CO)(3)-pz-peptide presented lower values for both cellular internalization and tumor uptake. Receptor blocking studies with the potent (Nle(4),DPhe(7))-alpha MSH agonist demonstrated the specificity of the radioconjugates to MC1R (74.8 and 44.5% reduction of tumor uptake at 4 h after injection for cyclic and linear radioconjugates, respectively)

Computational approaches in antibody-drug conjugate optimization for targeted cancer therapy

WOS: 000444683500007PubMed ID: 30068276Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second-and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme [IF/00578/2014]; European Social Fund; Programa Operacional Potencial Humano; Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]; European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme [CENTRO-01-0145-FEDER-000008]; European Regional Development Fund (ERDF), COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation; Portuguese national funds via FCT [POCI-01-0145-FEDER-007440]; FCT [FCT-SFRH/BPD/97650/2013]; Fundacao para a Ciencia e Tecnologia (FCT), Portugal [UID/Multi/04349/2013]Irina S. Moreira acknowledges support by the Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme - IF/00578/2014 (co-financed by European Social Fund and Programa Operacional Potencial Humano), and a Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]. This work was also financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project CENTRO-01-0145-FEDER-000008: Brain-Health 2020, and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-007440. Rita Melo acknowledges support from the FCT (FCT-SFRH/BPD/97650/2013). This work has been partially supported by the Fundacao para a Ciencia e Tecnologia (FCT), Portugal, through the UID/Multi/04349/2013 project in Centre for Nuclear Sciences and Technologies (C2TN)

Functionalization of Ruthenium(II) terpyridine complexes with cyclic RGD peptides to target integrin receptors in cancer cells

The lack of selectivity for cancer cells and the resulting negative impact on healthy tissue is a severe drawback of actual cancer chemotherapy. Tethering of cytotoxic drugs to targeting vectors such as peptides, which recognize receptors overexpressed on the surface of tumor cells, is one possible strategy to overcome such a problem. The pentapeptide cyc(RGDfK) targets the integrin receptor αvβ3, important for tumor growth and metastasis formation. In this work, two terpyridine based Ru(II) complexes were prepared and for the first time conjugated to cyc(RGDfK) via amide bond formation resulting in a monomeric and a dimeric bioconjugate. Both Ru(II) complexes bind strongly and selectively to integrin αvβ3, with the dimeric molecule displaying a 20-fold higher affinity to the receptor than the monomeric one. However, the cytotoxicity of the complexes and related bioconjugates against human A549 and SKOV-3 cell lines is still not sufficient for application as anticancer agents. Nevertheless, considering the high selectivity for integrin receptor αvβ3, the synthesis of Ru-based bioconjugates with cyc(RGDfK) paves a promising way towards the design of effective targeted anticancer agents

Learning to Evolve Structural Ensembles of Unfolded and Disordered Proteins Using Experimental Solution Data

We have developed a Generative Recurrent Neural Networks (GRNN) that learns the probability of the next residue torsions $X_{i+1}=\ [\phi_{i+1},\psi_{i+1},\omega _{i+1}, \chi_{i+1}]$from the previous residue in the sequence$X_i$ to generate new IDP conformations. In addition, we couple the GRNN with a Bayesian model, X-EISD, in a reinforcement learning step that biases the probability distributions of torsions to take advantage of experimental data types such as J-couplingss, NOEs and PREs. We show that updating the generative model parameters according to the reward feedback on the basis of the agreement between structures and data improves upon existing approaches that simply reweight static structural pools for disordered proteins. Instead the GRNN "DynamICE" model learns to physically change the conformations of the underlying pool to those that better agree with experiment

Assessment of numerical simulations of deep circulation and variability in the Gulf of Mexico using recent observations

Author Posting. © American Meteorological Society, 2020. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 50(4), (2020): 1045-1064, doi:10.1175/JPO-D-19-0137.1.Three simulations of the circulation in the Gulf of Mexico (the “Gulf”) using different numerical general circulation models are compared with results of recent large-scale observational campaigns conducted throughout the deep (>1500 m) Gulf. Analyses of these observations have provided new understanding of large-scale mean circulation features and variability throughout the deep Gulf. Important features include cyclonic flow along the continental slope, deep cyclonic circulation in the western Gulf, a counterrotating pair of cells under the Loop Current region, and a cyclonic cell to the south of this pair. These dominant circulation features are represented in each of the ocean model simulations, although with some obvious differences. A striking difference between all the models and the observations is that the simulated deep eddy kinetic energy under the Loop Current region is generally less than one-half of that computed from observations. A multidecadal integration of one of these numerical simulations is used to evaluate the uncertainty of estimates of velocity statistics in the deep Gulf computed from limited-length (4 years) observational or model records. This analysis shows that the main deep circulation features identified from the observational studies appear to be robust and are not substantially impacted by variability on time scales longer than the observational records. Differences in strengths and structures of the circulation features are identified, however, and quantified through standard error analysis of the statistical estimates using the model solutions.This work was supported by the Gulf Research Program of the National Academy of Sciences under Awards 2000006422 and 2000009966. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Gulf Research Program or the National Academy of Sciences. The authors acknowledge the GLORYS project for providing the ocean reanalysis data used in the ROMS simulation. GLORYS is jointly conducted by MERCATOR OCEAN, CORIOLIS, and CNRS/INSU. Installation, recovery, data acquisition, and processing of the CANEK group current-meter moorings were possible because of CICESE-PetróleosMexicanos Grant PEP-CICESE 428229851 and the dedicated work of the crew of the B/O Justo Sierra and scientists of the CANEK group. The authors thank Dr. Aljaz Maslo, CICESE, for assistance with analysis of model data. The Bureau of Ocean Energy Management (BOEM), U.S. Dept. of the Interior, provided funding for the Lagrangian Study of the Deep Circulation in the Gulf of Mexico and the Observations and Dynamics of the Loop Current study. HYCOM simulation data are available from the HYCOM data server (https://www.hycom.org/data/goml0pt04/expt-02pt2), MITgcm data are available from the ECCO data server (http://ecco.ucsd.edu/gom_results2.html), and the ROMS simulation data are available from GRIIDC (NA.x837.000:0001)

The same storm but not the same boat: Effects of COVID ‐19 stay‐at‐home order on mental health in individuals with overweight

Objective: To describe the effects of stay‐at‐home orders and social distancing during the coronavirus disease (COVID‐19) outbreak on mental health and to compare these outcomes between individuals with normal weight and overweight. Methods: This cross‐sectional study included 1857 Brazilian adults, who were invited through social media to answer an online questionnaire from 5 May 2020 to 17 May 2020. The instrument included questions related to health behaviour, mental health (anxiety, depression, self‐esteem, sadness and stress) and overall health. Overweight was defined as body mass index (BMI) ≥ 25 Kg/m2. Multiple logistic regression was conducted to identify whether overweight is associated with mental health variables. Results: Women reported increased anxiety (36.5% vs 22.2%, P < .01), depression (16.2% vs 8.8%, P < .01), low self‐esteem (19.8% vs 10.6%, P < .01), sadness (17.7% vs 10.2%, P < .01), and stress (29.5% vs 19.3%, P < .01) relative to men. Women with overweight are more likely to report higher feeling of anxiety (OR 1.62, CI 95% 1.22‐2.14), depression (OR 1.79, CI 95% 1.25‐2.55), low self‐esteem (OR 1.82, CI95% 1.28‐2.58) and sadness (OR 1.51, CI 95% 1.08‐2.10), adjusted for age, social isolation days, educational level, chronic diseases, smoke, alcohol intake and physical activity. Conclusion: Women, specially those with overweight are more vulnerable to the deleterious effects of stay‐at‐home orders on mental health during the COVID‐19 pandemic

Physical Activity Is Associated With Improved Eating Habits During the COVID-19 Pandemic

The aim of this study was to analyze the association between physical activity andeating habits during the COVID-19 pandemic among Brazilian adults. A sample of1,929 participants answered an online survey, however 1,874 were included in theanalysis. The impact of the COVID-19 pandemic on eating habits was assessedinquiring about participants’ intake of fruits, vegetables, fried foods, and sweetsduring the pandemic. Physical activity was assessed by asking participants abouttheir weekly frequency, intensity and number of minutes/hours engaging in structuredphysical activities per week. Participants were then stratified into categories based onmoderate-to-vigorous intensity (0–30; 31–90; 91–150; 151–300; and >300 min/week)and into active (≥150 min) or inactive (<150 min). Increased sweets consumption wasthe most commonly reported change to eating habits (42.5%), followed by an increase inthe consumption of vegetables (26.6%), fruits (25.9%), and fried foods (17.9%). Physicalactivity practice was related to lower consumption of fried foods (OR = 0.60; p < 0.001)and sweets (OR = 0.53; p < 0.001). A cluster analysis revealed subjects with higherthe level of physical activity was more likely to follow a healthy diet (p < 0.001). Thus,physical activity was positively associated with healthier eating habits. Health authoritiesmust recommend regular physical as a strategy to improve overall health during theCOVID-19 pandemic. Future studies should address the physical activity interventionsto improve health status during a pandemic

Increased Screen Time Is Associated With Alcohol Desire and Sweetened Foods Consumption During the COVID-19 Pandemic

Background: Elevated screen time has been associated with addictive behaviors, such as alcohol and sugar intake and smoking. Considering the substantial increase in screen time caused by social isolation policies, this study aimed to analyze the association of increased screen time in different devices during the COVID-19 pandemic with consumption and increased desire of alcohol, smoking, and sweetened foods in adults. Methods: A sample of 1,897 adults with a mean age of 37.9 (13.3) years was assessed by an online survey, being composed by 58% of women. Participants were asked whether screen time in television, cell phone, and computer increased during the pandemic, as well as how much time is spent in each device. Closed questions assessed the frequency of alcohol and sweetened food consumption, smoking, and an increased desire to drink and smoke during the pandemic. Educational level, age, sex, feeling of stress, anxiety, depression, and use of a screen device for physical activity were covariates. Binary logistic regression models considered adjustment for covariates and for mutual habits. Results: Increased television time was associated with increased desire to drink (OR = 1.46, 95% CI: 1.12; 1.89) and increased sweetened food consumption (OR = 1.53, 95% CI: 1.18; 1.99), while an increase in computer use was negatively associated with consumption of alcohol (OR = 0.68, 95% CI: 0.53; 0.86) and sweetened foods (OR = 0.78, 95% CI: 0.62; 0.98). Increased cell phone time was associated with increased sweetened food consumption during the pandemic (OR = 1.78, 95% CI: 1.18; 2.67). Participants with increased time in the three devices were less likely to consume sweetened foods for ≥5 days per week (OR = 0.63, 95% CI: 0.39; 0.99) but were twice as likely to have sweetened food consumption increased during pandemic (OR = 2.04, 95% CI: 1.07; 3.88). Conclusion: Increased screen time was differently associated with consumption and desire for alcohol and sweets according to screen devices. Increased time in television and cell phones need to be considered for further investigations of behavioral impairments caused by the pandemic