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Isac Rodrigues Comia,1– 3,&ast; Leonardo Manuel,1– 3,&ast; Regina Daniel Miambo,3,4 Awa Abdul Carimo,3,5 Percílio da Floca Manjate,3,5 Ana Edith Maholela,3,6 Lucas Raimundo Banze,2,3 Titos Paulo Buene,2,3 Noémia Nhancupe,2,3 Irina M Sousa,3,7 Constance A Benson,8 Robert T Schooley,9 Jahit Sacarlal,2 Emília Virgínia Noormahomed2,3,9 1Department of Research and Extension, Faculty of Health Sciences, Lúrio University, Nampula, Mozambique; 2Department of Microbiology, Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique; 3Mozambique Institute for Health Education and Research (MIHER), Maputo, Mozambique; 4Department of Para-Clinics, Faculty of Veterinary, Eduardo Mondlane University, Maputo, Mozambique; 5Department of Medicine, Eduardo Mondlane University, Maputo, Mozambique; 6Department of Medicine, Maputo Central Hospital, Maputo, Mozambique; 7Department of Biological Sciences, Faculty of Sciences, Eduardo Mondlane University, Maputo, Mozambique; 8Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, CA, USA; 9Department of Medicine, Division of Infectious Diseases, University of California, San Diego, CA, USA&ast;These authors contributed equally to this workCorrespondence: Emília Virgínia Noormahomed, Av. Salvador Allende, 702, Maputo, Mozambique, Tel +258828810907, Fax +25821304684, Email enoormahomed@gmail.comIntroduction: This study aims to determine the baseline seroprevalence of leptospirosis, a zoonotic and neglected disease, in people living with HIV (PWH) in Maputo, Mozambique, and to evaluate the relationship between selected HIV-related factors that might influence risk of coinfection with leptospirosis, such as degree of immunosuppression, as assessed by CD4 cell count, World Health Organization (WHO) HIV/AIDS clinical stage and antiretroviral therapy (ART) intake.Methods: This was a descriptive cross-sectional analysis of 157 PWH, aged over 18 years old, admitted to the Maputo Central Hospital, in Maputo, Mozambique, between March 2020 and October 2021. The study participants were recruited as a convenience sample regardless of the reasons for their admission. We collected sociodemographic and clinical data, including ART and WHO HIV/AIDS clinical stage, and blood for CD4 cell count and detection of Leptospira IgG antibodies using a commercial Kit ab247199 Leptospira IgG ELISA (www.abcam.com/ab247199) with sensitivity and specificity of 100% and 97.3%, respectively. Laboratory testing was performed at the Faculty of Medicine, Eduardo Mondlane University and Laboratory of Clinical Analysis, in Maputo.Results: Participants were aged 18 to 72 years (median age 39 years; SD ± 10.5), the majority were female 100 (63.7%), from urban areas 138 (87.9%), with secondary-level education 80 (51%). The overall seroprevalence of Leptospira IgG antibodies was 40.1%. The median CD4 cell count was 385 cells/μl (02 to 2297; SD ± 378.47). Higher seroprevalence of Leptospira antibodies was found among participants with CD4 cell counts < 250 cells/μl (54.8%), WHO HIV/AIDS stage IV (70.2%) and those on ART (92%), though there were no statistically significant differences between groups with and without Leptospira antibodies.Conclusion: Our study confirmed that Leptospira antibodies are highly prevalent in PWH in Maputo; however, Leptospira infection was not associated with the degree of immunosuppression, WHO HIV/AIDS clinical stage, or the use of ART. Our data support the need for routine screening for leptospirosis in PWH in Mozambique. Future studies are warranted to characterize the incidence and outcomes of symptomatic leptospirosis in this patient population and to identify circulating serovars and species in the country and region, as well as the implicated reservoirs.Keywords: leptospirosis, co-infection Leptospira and HIV, Leptospira IgG, Mozambique

ABSTRACTThe current land cover (LC) mapping paradigm relies on automatic satellite imagery classification, predominantly through supervised methods, which depend on training data to calibrate classification algorithms. Hence, training data have a critical influence on classification accuracy. Although research on specific aspects of training data in the LC classification context exists, a study that organizes and synthetizes the multiplicity of aspects and findings of these researches is needed. In this article, we review the training data used for LC classification of satellite imagery. A protocol of identification and selection of relevant documents was followed, resulting in 114 peer-reviewed studies included. Main research topics were identified and documents were characterized according to their contribution to each topic, which allowed uncovering subtopics and categories and synthetizing the main findings regarding different aspects of the training dataset. The analysis found four research topics, namely construction of the training dataset, sample quality, sampling design and advanced learning techniques. Subtopics included sample collection method, sample cleaning procedures, sample size, sampling method, class balance and distribution, among others. A summary of the main findings and approaches provided an overview of the research in this area, which may serve as a starting point for new LC mapping initiatives.

Abstract Burundi has one of the highest prevalence of stunting in the world. This study aimed to identify determinants of stunting among children under age five in Burundi. A total of 4993 children with anthropometric measurements from the 2016–2017 Burundi Demographic and Health Survey were included in the study. Stunting was assessed from the height‐for‐age Z‐scores (HAZ). Logistic regression models were analyzed to identify demographic, maternal, child‐related, and structural variables that influence stunting. In total, 56.9% of children under age five were stunted, of those 31.0% moderately and 25.9% severely. Multivariable logistic regression indicated that older children, male children (adjusted OR (aOR) = 1.41, 95% CI 1.24–1.61), and children who were perceived as small (aOR = 2.00, 95% CI 1.55–2.59) or very small at birth (aOR = 2.37, 95% CI 1.57–3.59) were significantly more likely to be stunted. Moreover, children of single mothers, with lower levels of education, who were underweight at the time of the survey (aOR = 1.95, 95% CI 1.42–2.68), who had short stature (aOR = 3.76, 95% CI 2.50–5.66) or who conceived more than four children (aOR = 1.22, 95% CI 1.05–1.42) were more commonly stunted. Stunting was more prevalent in rural areas (aOR = 2.53, 95% CI 1.72–3.73) and in households with no access to improved types of toilet facilities (aOR = 1.27, 95% CI 1.10–1.45). The results of this study show that the prevalence of stunting in children under age five in Burundi is alarmingly high and underscores the urgent need for decisive and determined action.

Introduction During acute kidney injury (AKI) due to sepsis, the intestinal microbiota changes to dysbiosis, which affects the kidney function recovery (KFR) and amplifies the injury. Therefore, the administration of probiotics could improve dysbiosis and thereby increase the probability of KFR.Methods In this double-blind clinical trial, patients with AKI associated with sepsis were randomized (1:1) to receive probiotics or placebo for 7 consecutive days, with the objectives of evaluate the effect on KFR, mortality, kidney replacement therapy (KRT), urea, urine volume, serum electrolytes and adverse events at day 7.Results From February 2019 to March 2022, a total of 92 patients were randomized, 48 to the Probiotic and 44 to Placebo group. When comparing with placebo, those in the Probiotics did not observe a higher KFR (HR 0.93, 0.52–1.68, p = 0.81), nor was there a benefit in mortality at 6 months (95% CI 0.32–1.04, p = 0.06). With probiotics, urea values decreased significantly, an event not observed with placebo (from 154 to 80 mg/dl, p = 0.04 and from 130 to 109 mg/dl, p = 0.09, respectively). Urinary volume, need for KRT, electrolyte abnormalities, and adverse events were similar between groups. (ClinicalTrial.gov NCT03877081) (registered 03/15/2019).Conclusion In AKI related to sepsis, probiotics for 7 consecutive days did not increase the probability of KFR, nor did other variables related to clinical improvement, although they were safe.

We propose a method for fitting transition intensities to a sufficiently large set of trajectories of a continuous-time non-homogeneous Markov chain with a finite state space. Starting with simulated data computed with Gompertz–Makeham transition intensities, we apply the proposed method to fit piecewise linear intensities and then compare the transition probabilities corresponding to both the Gompertz–Makeham transition intensities and the fitted piecewise linear intensities; the main comparison result is that the order of magnitude of the average fitting error per unit time—chosen as a year—is always less than 1%, thus validating the methodology proposed.

The search for alternative and effective therapies to fight cancer is one of the main goals of the pharmaceutical industry. Recently, ionic liquids (ILs) have emerged as potential therapeutic agents with antitumor properties. The goal of this study was to synthesize and evaluate the bioactivity of different ILs coupled with the active pharmaceutical ingredient (API) valproate (VPA) as an antitumor agent. The toxicity of the prepared ionic liquids was evaluated by the MTT cell metabolic assay in human neuroblastoma SH-SY5Y and human primary Gingival Fibroblast (GF) cell lines, in which they showed inhibitory effects during the study period. In addition, low cytotoxicity against GF cell lines was observed, suggesting that these compounds are not toxic to human cell lines. [C2OHDMiM][VPA] demonstrated an outstanding antitumor activity against SH-SY5Y and lower activity against the non-neoplastic GF line. The herein assessed compounds played an important role in the modulation of the signaling pathways involved in the cellular behavior. This work also highlights the potential of these ILs-API as possible antitumor agents.

Abstract Primates are very selective in the foods they include in their diets with foraging strategies that respond to spatial and temporal changes in resource availability, distribution and quality. Colombian woolly monkeys (Lagothrix lagotricha lugens), one of the largest primate species in the Americas, feed mainly on fruits, but they also eat a high percentage of arthropods. This differs from closely related Atelid species that supplement their diet with leaves. In an 11 month study, we investigated the foraging strategies of this endemic monkey and assessed how resource availability affects dietary selection. Using behavioural, phenological, arthropod sampling and metabarcoding methods, we recorded respectively foraging time, forest productivity, arthropod availability in the forest and arthropod consumption. Scat samples and capturing canopy substrates (i.e. moss, bromeliads, aerial insects) were used for assigning arthropod taxonomy. The most important resource in the diet was fruits (54%), followed by arthropods (28%). Resource availability predicted feeding time for arthropods but not for fruits. Further, there was a positive relationship between feeding time on fruits and arthropods, suggesting that eating both resources during the same periods might work as an optimal strategy to maximize nutrient intake. Woolly monkeys preferred and avoided some fruit and arthropod items available in their home range, choosing a wide variety of arthropods. Geometrid moths (Lepidoptera) were the most important and consistent insects eaten over time. We found no differences in the type of arthropods adults and juveniles ate, but adults invested more time foraging for this resource, especially in moss. Although woolly monkeys are generalist foragers, they do not select their food items randomly or opportunistically.

Introdução: A qualidade dos medicamentos tem sido inaceitável em muitas regiões do mundo, especificamente em países subdesenvolvidos, devido à escassez ou ausência total de laboratórios de controlo de qualidade de medicamentos (Devall, 2013). De facto, medicamentos falsificados ou de baixa qualidade constituem uma séria preocupação para a saúde pública, particularmente em países onde os sistemas de vigilância são fracos e ineficientes. Países como Índia, China, Vietname, Indonésia, Paquistão ou Filipinas têm sido identificados como os principais produtores de medicamentos falsificados; ao passo que, China (Hong Kong), Emirados Árabes Unidos, Egipto, Camarões e Turquia parecem ser os principais pontos de trânsito destes produtos farmacêuticos falsificados enviados para o resto do mundo (OCDE, 2020). Objetivo: Avaliação de vários métodos empregados para analisar a qualidade de Medicamentos. Material e Métodos: Foram coletados comprimidos com fármacos anti- inflamatórios não esteroides (AINEs) e antimaláricos, tais como, Zibufeno (Ibuprofeno 400mg), Diclomex 100 (Diclofenac sódico), Amidol® (paracetamol 500 mg), Quini PLUS®-500 (Quinino Sulfato) e Quini PLUS®-300 (Quinino Sulfato), obtidos de vendedores no mercado da Retranca, localizado no município de Cacuaco, província de Luanda, Angola e analisados por Calorimetria Diferencial de Varrimento (DSC), Espectroscopia de Infravermelho com Transformada de Fourier (FTIR) e Difração de Raios-X em Pó (XRPD) (Vueba et al., 2013). Resultados: Confirmou-se a presença da substância ativa como Zibufen e Amidol por DSC, FTIR e XRPD nos comprimidos; enquanto o Diclomex 100 não permitiu a identificação do diclofenac sódico no comprimido. Além disso, o sulfato de quinino no Quini Plus 500 mg e 300 mg só foi identificado por FTIR e XRPD. A análise das substâncias estudadas mostrou que durante a análise térmica podem ocorrer fenómenos como desidratação e (ou) fusão, e transformação cristalina. Conclusões: O estudo demonstrou a aplicação bem-sucedida dos métodos analíticos para avaliar a qualidade dos medicamentos. Os resultados desta investigação vão permitir à monitorização contínua da qualidade dos medicamentos comercializados para garantir a segurança e eficácia destes produtos no tratamento de muitas doenças em Angola.

Tenacibaculum maritimum, the etiological agent of tenacibaculosis in marine fish, constitutively secretes extracellular products (ECPs) in which protein content has not been yet comprehensively studied. In this work, the prevalence of extracellular proteolytic and lipolytic activities related to virulence was analyzed in 64 T. maritimum strains belonging to the O1–O4 serotypes. The results showed the existence of a great intra-specific heterogeneity in the enzymatic capacity, particularly within serotype O4. Thus, the secretome of a strain belonging to this serotype was characterized by analyzing the protein content of ECPs and the possible production of outer membrane vesicles (OMVs). Notably, the ECPs of T. maritimum SP9.1 contain a large amount of OMVs that were characterized by electron microscopy and purified. Thus, ECPs were divided into soluble (S-ECPs) and insoluble fractions (OMVs), and their protein content was analyzed by a high-throughput proteomic approach. A total of 641 proteins were identified in ECPs including some virulence-related factors, which were mainly found in one of the fractions, either OMVs or S-ECPs. Outer membrane proteins such as TonB-dependent siderophore transporters and the type IX secretion system (T9SS)-related proteins PorP, PorT, and SprA appeared to be mainly associated with OMVs. By contrast, putative virulence factors such as sialidase SiaA, chondroitinase CslA, sphingomyelinase Sph, ceramidase Cer, and collagenase Col were found only in the S-ECPs. These findings clearly demonstrate that T. maritimum releases, through surface blebbing, OMVs specifically enriched in TonB-dependent transporters and T9SS proteins. Interestingly, in vitro and in vivo assays also showed that OMVs could play a key role in virulence by promoting surface adhesion and biofilm formation and maximizing the cytotoxic effects of the ECPs. The characterization of T. maritimum secretome provides insights into ECP function and can constitute the basis for future studies aimed to elucidate the full role of OMVs in the pathogenesis of fish tenacibaculosis.

Portugal is the most fire-prone country in Southern Europe. Time series of satellite imagery have great potential to improve fire mapping and explore the spatiotemporal trends of burned areas. Thus, the objectives of this work were to disaggregate the Portuguese Annual Fire Atlas burned area patches into individual events according to their date of occurrence estimated from Landsat temporal series, and to assign them the closest date (day and month) of the detected change. From the resulting Monthly Fire Atlas, we assessed intra-annual fire variability in Portugal. Our analysis was performed from 1984 to 2021 for the entire mainland Portugal. We selected the closest fire date based on the index of the lowest ΔNBR in the time series. Historically, most of the large fires were concentrated in the summer season. However, when daily mean areas are analyzed, peaks can be identified due to fire events that occurred at a time of the year when burned areas are typically much lower. The results were validated using MODIS and VIIRS active fires. Accuracies of individual years fluctuated according to the satellite and cloudiness of each year. For the entire 37 analyzed years, when considering 16 and 32 days of time gap, the Monthly Fire Atlas achieved 84% and 91% of accuracy, respectively.

In this work, we present a rigorous development of a model for the Price–Volume relationship of transactions introduced in 2009. For this development, we rely on the precise formulation of diffusion auto-induced regime-switching models presented in our previous work of 2020. The auto-induced regime-switching models referred to may be based on a finite set of stochastic differential equations (SDE)—all defined on the same bounded time interval—and a sequence of interlacing stopping times defined by the hitting threshold times of the trajectories of the solutions of the SDE. The coupling between price and volume—which we take as a proxy of liquidity—is assumed to be the following: the regime switching in the price variable occurs at the stopping times for which there is a change of region—in the product state space of price and liquidity—for the liquidity variable (and vice versa). The regimes may be defined parametrically—that is, the SDE coefficients keep the same functional form but with varying parameters—or the functional form of the SDE coefficients may change with each regime. By using the same noise source for both the price and the liquidity regime-switching models—volume (liquidity), which, in general, is not a tradable asset—we ensure that despite incorporating information on liquidity, the price part of the coupled model can be assumed to be arbitrage free and complete, allowing the pricing and hedging of derivatives in a simple way.

Abstract Rationale Transbronchial cryobiopsy has been increasingly used to diagnose interstitial lung diseases. However, there is uncertainty regarding its accuracy and risks, mainly due to a paucity of prospective or randomized trials comparing cryobiopsy to surgical biopsy. Objectives To evaluate the diagnostic yield and complications of cryobiopsy in patients selected by multidisciplinary discussion. Methods This was a prospective cohort from 2017 to 2019. We included consecutive patients with suspected interstitial lung diseases being considered for lung biopsy presented at our multidisciplinary meeting. Measurements and main results Of 112 patients, we recommended no biopsy in 31, transbronchial forceps biopsy in 16, cryobiopsy in 54 and surgical biopsy in 11. By the end of the study, 34 patients had had cryobiopsy and 24 patients, surgical biopsy. Overall pathologic and multidisciplinary diagnostic yield of cryobiopsy was 47.1% and 61.8%, respectively. The yield increased over time for both pathologic (year 1: 28.6%, year 2: 54.5%, year 3: 66.7%, p = 0.161) and multidisciplinary (year 1: 50%, year 2: 63.6%, year 3: 77.8%, p = 0.412) diagnosis. Overall rate of grade 4 bleeding after cryobiopsy was 11.8%. Cryobiopsy required less chest tube placement (11.8% vs 100%, p

Five New World mammarenaviruses (NWMs) enter cells via binding to human transferrin receptor 1 (hTfR1). Here, Hickerson et al. show that hTfR1 targeting antibodies partially protect hTfR1-transgenic mice from lethal NWM challenge via competition of anti-hTfR1 antibody and viral glycoprotein for hTfR1.

Multiple myeloma (MM) is an incurable malignancy of plasma cells and the second most common hematologic malignancy in the United States. Although antibodies in clinical cancer therapy are generally of the IgG class, antibodies of the IgE class have attractive properties as cancer therapeutics, such as their high affinity for Fc receptors (FcεRs), the low serum levels of endogenous IgE allowing for less competition for FcR occupancy, and the lack of inhibitory FcRs. Importantly, the FcεRs are expressed on immune cells that elicit antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and/or antigen presentation such as mast cells, eosinophils, macrophages, and dendritic cells. We now report the development of a fully human IgE targeting human CD38 as a potential MM therapy. We targeted CD38 given its high and uniform expression on MM cells. The novel anti-CD38 IgE, expressed in mammalian cells, is properly assembled and secreted, exhibits the correct molecular weight, binds antigen and the high affinity FcεRI, and induces degranulation of FcεRI expressing cells in vitro and also in vivo in transgenic BALB/c mice expressing human FcεRIα. Moreover, the anti-CD38 IgE induces ADCC and ADCP mediated by monocytes/macrophages against human MM cells (MM.1S). Importantly, the anti-CD38 IgE also prolongs survival in a preclinical disseminated xenograft mouse model using SCID-Beige mice and human MM.1S cells when administered with human peripheral blood mononuclear cells (PBMCs) as a source of monocyte effector cells. Our results suggest that anti-CD38 IgE may be effective in humans bearing MM and other malignancies expressing CD38.

Abstract Background Oral squamous cell carcinoma (OSCC) has poor survival rates. There is a pressing need to develop more precise risk assessment methods to tailor clinical treatment. Epigenome-wide association studies in OSCC have not produced a viable biomarker. These studies have relied on methylation array platforms, which are limited in their ability to profile the methylome. In this study, we use MethylCap-Seq (MC-Seq), a comprehensive methylation quantification technique, and brush swab samples, to develop a noninvasive, readily translatable approach to profile the methylome in OSCC patients. Methods Three OSCC patients underwent collection of cancer and contralateral normal tissue and brush swab biopsies, totaling 4 samples for each patient. Epigenome-wide DNA methylation quantification was performed using the SureSelectXT Methyl-Seq platform. DNA quality and methylation site resolution were compared between brush swab and tissue samples. Correlation and methylation value difference were determined for brush swabs vs. tissues for each respective patient and site (i.e., cancer or normal). Correlations were calculated between cancer and normal tissues and brush swab samples for each patient to determine the robustness of DNA methylation marks using brush swabs in clinical biomarker studies. Results There were no significant differences in DNA yield between tissue and brush swab samples. Mapping efficiency exceeded 90% across all samples, with no differences between tissue and brush swabs. The average number of CpG sites with at least 10x depth of coverage was 2,716,674 for brush swabs and 2,903,261 for tissues. Matched tissue and brush swabs had excellent correlation (r = 0.913 for cancer samples and r = 0.951 for normal samples). The methylation profile of the top 1000 CpGs was significantly different between cancer and normal samples (mean p-value = 0.00021) but not different between tissues and brush swabs (mean p-value = 0.11). Conclusions Our results demonstrate that MC-Seq is an efficient platform for epigenome profiling in cancer biomarker studies, with broader methylome coverage than array-based platforms. Brush swab biopsy provides adequate DNA yield for MC-Seq, and taken together, our findings set the stage for development of a non-invasive methylome quantification technique for oral cancer with high translational potential.

Aeromonas salmonicida subsp. salmonicida (A. salmonicida), a Gram-negative bacterium causing furunculosis in fish, produces the siderophores acinetobactin and amonabactins in order to extract iron from its hosts. While the synthesis and transport of both systems is well understood, the regulation pathways and conditions necessary for the production of each one of these siderophores are not clear. The acinetobactin gene cluster carries a gene (asbI) encoding a putative sigma factor belonging to group 4 σ factors, or, the ExtraCytoplasmic Function (ECF) group. By generating a null asbI mutant, we demonstrate that AsbI is a key regulator that controls acinetobactin acquisition in A. salmonicida, since it directly regulates the expression of the outer membrane transporter gene and other genes necessary for Fe-acinetobactin transport. Furthermore, AsbI regulatory functions are interconnected with other iron-dependent regulators, such as the Fur protein, as well as with other sigma factors in a complex regulatory network.

The structure of the random matrices introduced in this work is given by deterministic matrices—the skeletons of the random matrices—built with an algorithm of matrix substitutions with entries in a finite field of integers modulo some prime number, akin to the algorithm of one dimensional automatic sequences. A random matrix has the structure of a given skeleton if to the same number of an entry of the skeleton, in the finite field, it corresponds a random variable having, at least, as its expected value the correspondent value of the number in the finite field. Affine matrix substitutions are introduced and fixed point theorems are proven that allow the consideration of steady states of the structure which are essential for an efficient observation. For some more restricted classes of structured random matrices the parameter estimation of the entries is addressed, as well as the convergence in law and also some aspects of the spectral analysis of the random operators associated with the random matrix. Finally, aiming at possible applications, it is shown that there is a procedure to associate a canonical random surface to every random structured matrix of a certain class.

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn’s disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.

We present an analysis on variability Bitcoin characteristics that help to quantitatively differentiate Bitcoin from the state-owned traditional currencies and the asset Gold. We provide a detailed study on returns of exchange rates—against the Swiss Franc—of several traditional currencies together with Bitcoin and Gold; for that purpose, we define a distance between currencies by means of the spectral densities of the ARMA models of the returns of the exchange rates, and we present the computed matrix of the distances between the chosen currencies. A statistical analysis of these matrix distances is further proposed, which shows that the distance between Bitcoin and any other currency or Gold is not comparable to any of the distances between currencies or between currencies and Gold and not involving Bitcoin. This result shows that Bitcoin is essentially different from the traditional currencies and from Gold, at least in what concerns the structure of its variance and auto-covariances.

Transferrin receptor 1 (TfR1), also known as CD71, is a transmembrane protein involved in the cellular uptake of iron and the regulation of cell growth. This receptor is expressed at low levels on a variety of normal cells, but is upregulated on cells with a high rate of proliferation, including malignant cells and activated immune cells. Infection with the human immunodeficiency virus (HIV) leads to the chronic activation of B cells, resulting in high expression of TfR1, B-cell dysfunction, and ultimately the development of acquired immunodeficiency syndrome-related B-cell non-Hodgkin lymphoma (AIDS-NHL). Importantly, TfR1 expression is correlated with the stage and prognosis of NHL. Thus, it is a meaningful target for antibody-based NHL therapy. We previously developed a mouse/human chimeric IgG3 specific for TfR1 (ch128.1/IgG3) and showed that this antibody exhibits antitumor activity in an in vivo model of AIDS-NHL using NOD-SCID mice challenged intraperitoneally with 2F7 human Burkitt lymphoma (BL) cells that harbor the Epstein-Barr virus (EBV). We have also developed an IgG1 version of ch128.1 that shows significant antitumor activity in SCID-Beige mouse models of disseminated multiple myeloma, another B-cell malignancy. Here, we aim to explore the utility of ch128.1/IgG1 and its humanized version (hu128.1) in mouse models of AIDS-NHL. To accomplish this goal, we used the 2F7 cell line variant 2F7-BR44, which is more aggressive than the parental cell line and forms metastases in the brain of mice after systemic (intravenous) administration. We also used the human BL cell line JB, which in contrast to 2F7, is EBV-negative, allowing us to study both EBV-infected and non-infected NHL tumors. Treatment with ch128.1/IgG1 or hu128.1 of SCID-Beige mice challenged locally (subcutaneously) with 2F7-BR44 or JB cells results in significant antitumor activity against different stages of disease. Treatment of mice challenged systemically (intravenously) with either 2F7-BR44 or JB cells also showed significant antitumor activity, including long-term survival. Taken together, our results suggest that targeting TfR1 with antibodies, such as ch128.1/IgG1 or hu128.1, has potential as an effective therapy for AIDS-NHL.

Circulating tumor cells (CTCs), and particularly circulating cancer stem cells (cCSC), are prognostic biomarkers for different malignancies and may be detected using liquid biopsies. The ex vivo culture of cCSCs would provide valuable information regarding biological aggressiveness and would allow monitoring the adaptive changes acquired by the tumor in real time. In this prospective pilot study, we analyzed the presence of EpCAM+ CTCs using the IsoFlux system in the peripheral blood of 37 patients with hepatocellular carcinoma undergoing transarterial chemoembolization (TACE). The average patient age was 63.5 ± 7.9 years and 91.9% of the patients were men. All patients had detectable CTCs at baseline and 20 patients (54.1%) showed CTC aggregates or clusters in their peripheral blood. The increased total tumor diameter (OR: 2.5 (95% CI: 1.3–4.8), p = 0.006) and the absence of clusters of CTCs at baseline (OR: 0.2 (95% CI: 0.0–1.0), p = 0.049) were independent predictors of a diminished response to TACE. Culture of cCSC was successful in five out of thirty-three patients, mostly using negative enrichment of CD45− cells, ultra-low adherence, high glucose, and a short period of hypoxia followed by normoxia. In conclusion, the identification of clusters of CTCs before TACE and the implementation of standardized approaches for cCSC culture could aid to predict outcomes and to define the optimal adjuvant therapeutic strategy for a true personalized medicine in hepatocellular carcinoma.

Abstract Rationale Despite the availability of multi-“omics” strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. Objective To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). Methods Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. Results Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. Conclusion These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.

Abstract Preclinical and early clinical studies suggest that angiotensin‐converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin‐converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi‐center, open‐label, exploratory, single‐dose, dose‐escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin‐angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy (N = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1–7) and angiotensin (1–5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined.

La compactación del suelo es una limitante de la producción de caña de azúcar en Cuba y su origen se vincula al tráfico de la maquinaria y al contenido de humedad del suelo durante la cosecha mecanizada. El objetivo del trabajo fue diseñar una metodología para diagnosticar la compactación en áreas de cosecha mecanizada, basado en impactos críticos del penetrómetro en los suelos Pardo Mullido Carbonatado, Gley Vértico y Ferralítico Rojo. Se evaluaron los tres suelos en condiciones perturbadas por el tráfico de los equipos de cosecha mecanizada en humedad variable y también, en ambientes no perturbados por la actividad humana o el pisoteo de animales y con 5 años o más con cubierta vegetal permanente. La resistencia a la penetración se midió con un penetrómetro de impacto que, para el límite crítico de 3 MPa y humedad en capacidad de campo, tiene como constante de penetración 0.029 m impacto-1 del mazo y 7.0 y 3.5 impactos en los perfiles 0-20 y 20-30 cm de profundidad, respectivamente. El efecto del tráfico sobre la resistencia a la penetración en humedad variable, permitió determinar los rangos de humedad por suelo donde el tráfico disminuyó o aumentó la resistencia y asumir dichos rangos como categorías de humedad baja, media y alta. En los suelos no perturbados se estudió la variación de la resistencia en función de la humedad, se obtuvieron ecuaciones exponenciales patrones para estimar impactos (y) vs humedad (x), que permitieron calcular los ∆ impactos (∆I) atribuible al efecto de la humedad sobre la resistencia del suelo. Si las constantes de impactos para 0-20 cm (7.0) y 20-30 cm (3.5) y los ∆I promedio de las categorías de humedad baja, media y alta, se suman se obtienen valores de impactos críticos según suelo y contenido de humedad

Shelly Wen,1,2 Lucy Manuel,1,2 Moira Doolan,1,2 Justin Westhuyzen,1 Thomas P Shakespeare,1,2 Noel J Aherne1,2 1Department of Radiation Oncology, Mid North Coast Cancer Institute, Coffs Harbour, New South Wales, Australia; 2University of New South Wales, Sydney, New South Wales, AustraliaCorrespondence: Noel J AherneDepartment of Radiation Oncology, Mid North Coast Cancer Institute, Coffs Harbour NSW 2450, AustraliaTel +61-2-6656-7000Fax +61-2-6656-5330Email noel.aherne@health.nsw.gov.auPurpose: Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases and is associated with a poor prognosis. In this retrospective study of patients undergoing radiation therapy as part of their treatment, disease-free survival (DFS) and overall survival (OS) of TNBC patients were examined in relation to clinical and treatment-related factors.Patients and Methods: The electronic records of 214 consecutive TNBC patients treated with surgery followed by radiotherapy at the Mid North Coast Cancer Institute between 2006 and 2016 were reviewed. Overall survival and DFS times were analyzed using the Kaplan-Meier method; multivariate Cox proportional hazard regression modelling was used to assess the significance of prognostic factors.Results: The majority of tumors were T1 (51.9%), followed by T2 (39.2%) and T3 (6.1%). For the whole group, mean DFS was 106.4 (SD 48.7) months; OS 109.4 (SD 52.1) months. Radiotherapy technique, fractionation protocol and laterality were not significant factors for DFS or OS (p> 0.05). However, compared to breast conservation, mastectomy was associated with poorer DFS (mean 114.2 vs 65.2 months; p< 0.0001) and poorer OS (mean 115.5 vs 80.5 months; p=0.0015). The mastectomy group had fewer patients with tumor size T1 (p=0.001) and higher proportions of T3 (p=0.001) and T4 (p=0.02). On multivariate analysis, tumor size T3/T4 and nodal status N2/N3 were significant factors for reduced DFS (p=0.023 and p=0.0003 respectively). Tumor size T3/T4 was the only significant prognostic factor for reduced OS (p=0.019).Conclusion: Advanced disease exhibited by tumor size > 5cm and positive nodal status is associated with poorer DFS in TNBC patients. Radiotherapy technique or fractionation protocol were not associated with differences in DFS or OS in our patient cohort.Keywords: dose fractionation, mastectomy, radiotherapy, survival analysis, triple negative breast neoplasms

En el Mundial del 78 –Mundial de Argentina– la selección albiceleste triunfó con la ayuda del «Matador» Kempes. No obstante, entre 1976 y 1983 se produjeron violaciones aberrantes de los derechos humanos, incluso durante los momentos de excitación futbolística. Tras la Dictadura se juzgó a los responsables de las atrocidades acaecidas. Mientras tanto, al otro lado del Atlántico, en España, en 1978 volvía a instaurarse un régimen democrático, con la promulgación de la Constitución española. Atrás quedaron los hechos sucedidos durante la Guerra Civil española y la Dictadura franquista. Nada se investigó, nada se juzgó… Y todo quedó en el olvido.

Abstract Background Low skeletal muscle index (SMI) in metastatic colorectal cancer (mCRC) patients is associated with poor outcomes. The prognostic impact of SMI changes during consecutive palliative systemic treatments is unknown. Methods This is a retrospective analysis of the phase 3 CAIRO3 study. The CAIRO3 study randomized 557 patients between maintenance capecitabine + bevacizumab (CAP‐B) or observation, after six cycles capecitabine + oxaliplatin + bevacizumab (CAPOX‐B). Upon first disease progression (PD1), CAPOX‐B was reintroduced until second progression (PD2). SMI was assessed by computed tomography (CT) (total 1355 scans). SMI and body mass index (BMI) changes were analyzed for three time‐periods; p1: during initial CAPOX‐B, p2: randomization to PD1, and p3: PD1 to PD2. The association between absolute and change in SMI and BMI (both per 1 standard deviation) during p1‐p3, with PD1, PD2, and survival was studied by Cox regression models. Results This analysis included 450 of the 557 patients randomized in the CAIRO3 study. Mean SMI decreased during p1: mean −0.6 SMI units [95% CI −1.07;‐0.26] and p3: −2.2 units [−2.7;‐1.8], whereas during p2, SMI increased + 1.2 units [0.8‐1.6]. BMI changes did not reflect changes in SMI. SMI loss during p2 and p3 was significantly associated with shorter survival (HR 1.19 [1.09‐1.35]; 1.54 [1.31‐1.79], respectively). Sarcopenia at PD1 was significantly associated with early PD2 (HR 1.40 [1.10‐1.70]). BMI loss independent of SMI loss was only associated with shorter overall survival during p3 (HR 1.35 [1.14‐1.63]). Conclusions In mCRC patients, SMI loss during palliative systemic treatment was related with early disease progression and reduced survival. BMI did not reflect changes in SMI and could not identify patients at risk of poor outcome during early treatment lines.

The high-pathogenicity island irp-HPI is widespread among Vibrionaceae encoding the piscibactin siderophore system. The expression of piscibactin genes in the fish pathogen Vibrio anguillarum is favored by low temperatures. However, information about the regulatory mechanism behind irp-HPI gene expression is scarce. In this work, in-frame deletion mutants of V. anguillarum defective in the putative regulators AraC1 and AraC2, encoded by irp-HPI, and in the global regulators H-NS and ToxRS, were constructed and their effect on irp-HPI gene expression was analyzed at 15 and 25°C. The results proved that only AraC1 (renamed as PbtA) is required for the expression of piscibactin biosynthesis and transport genes. PbtA inactivation led to an inability to grow under iron restriction, a loss of the outer membrane piscibactin transporter FrpA, and a significant decrease in virulence for fish. Inactivation of the global repressor H-NS, which is involved in silencing of horizontally acquired genes, also resulted in a lower transcriptional activity of the frpA promoter. Deletion of toxR-S, however, did not have a relevant effect on the expression of the irp-HPI genes. Therefore, while irp-HPI would not be part of the ToxR regulon, H-NS must exert an indirect effect on piscibactin gene expression. Thus, the temperature-dependent expression of the piscibactin-encoding pathogenicity island described in V. anguillarum is the result of the combined effect of the AraC-like transcriptional activator PbtA, harbored in the island, and other not yet defined regulator(s) encoded by the genome. Furthermore, different expression patterns were detected within different irp-HPI evolutionary lineages, which supports a long-term evolution of the irp-HPI genomic island within Vibrionaceae. The mechanism that modulates piscibactin gene expression could also be involved in global regulation of virulence factors in response to temperature changes.

Vibrio neptunius is an inhabitant of mollusc microbiota and an opportunistic pathogen causing disease outbreaks in marine bivalve mollusc species including oysters and clams. Virulence of mollusc pathogenic vibrios is mainly associated with the production of extracellular products. However, siderophore production is a common feature in pathogenic marine bacteria but its role in fitness and virulence of mollusc pathogens remains unknown. We previously found that V. neptunius produces amphibactin, one of the most abundant siderophores in marine microbes. In this work, synthesis of the siderophore piscibactin was identified as the second siderophore produced by V. neptunius. Single and double mutants in biosynthetic genes of each siderophore system, piscibactin and amphibactin, were constructed in V. neptunius and their role in growth ability and virulence was characterized. Although the High Pathogenicity Island encoding piscibactin is a major virulence factor in vibrios pathogenic for fish, the V. neptunius wild type did not cause mortality in turbot. The results showed that amphibactin contributes more than piscibactin to bacterial fitness in vitro. However, infection challenges showed that each siderophore system contributes equally to virulence for molluscs. The V. neptunius strain unable to produce any siderophore was severely impaired to cause vibriosis in clams. Although the inactivation of one of the two siderophore systems (either amphibactin or piscibactin) significantly reduced virulence compared to the wild type strain, the ability to produce both siderophores simultaneously maximised the degree of virulence. Evaluation of the gene expression pattern of each siderophore system showed that they are simultaneously expressed when V. neptunius is cultivated under low iron availability in vitro and ex vivo. Finally, the analysis of the distribution of siderophore systems in genomes of Vibrio spp. pathogenic for molluscs showed that the gene clusters encoding amphibactin and piscibactin are widespread in the Coralliilyticus clade. Thus, siderophore production would constitute a key virulence factor for bivalve molluscs pathogenic vibrios.

Nowadays, organic salts and ionic liquids (OSILs) containing active pharmaceutical ingredients (APIs) are being explored as drug delivery systems in modern therapies (OSILs-API). In that sense, this work is focused on the development of novel OSILs-API based on amphotericin B through an innovative procedure and the evaluation of the respective biological activity against Leishmania infantum. Several ammonium, methylimidazolium, pyridinium and phosphonium organic cations combined with amphotericin B as anion were synthesized in moderate to high yields and high purities by the water-reduced buffer neutralization method. All prepared compounds were characterized to confirm the desired chemical structure and the specific optical rotation ([α]D25) was also determined. The biological assays performed on L. infantum promastigotes showed increased activity against this parasitic disease when compared with the starting chloride forms and amphotericin B alone, highlighting [P6,6,6,14][AmB] as the most promising formulation. Possible synergism in the antiprotozoal activity was also evaluated for [P6,6,6,14][AmB], since it was proven to be the compound with the highest toxicity. This work reported a simple synthetic method, which can be applied to prepare other organic salts based on molecules containing fragile chemical groups, demonstrating the potential of these OSILs-AmB as possible agents against leishmaniasis.

Ante los desafíos del mundo globalizado, investigaciones recientes sugieren que la identificación con la humanidad tiene bases socio-afectivas y es impulsada con la celebración de rituales colectivos que promueven la benevolencia y universalismo. Este trabajo analiza la relación de una emoción de auto-trascendencia (Awe) vivida en encuentros colectivos locales con la identidad humana. Los resultados de ecuaciones estructurales a partir de un estudio transversal realizado en México y el País Vasco (N = 656) muestra que estas emociones incrementan la identificación con la humanidad, el bienestar (directamente) y también la conducta prosocial (de manera indirecta). Además, la intensidad de esta emoción también predice positivamente la percepción de sincronía emocional aun controlando por tendencias más estables de personalidad. En línea con la teorización de Durkheim, los procesos emocionales vividos en eventos colectivos fomentan el desarrollo de identidades compartidas y la promoción del bien común, a través de experiencias de auto-trascendencia, la cual puede resultar de gran importancia para la coordinación de esfuerzos comunes ante problemas sociales de gran envergadura.

Piscibactin is a widespread siderophore system present in many different bacteria, especially within the Vibrionaceae family. Previous works showed that most functions required for biosynthesis and transport of this siderophore are encoded by the high-pathogenicity island irp-HPI. In the present work, using Vibrio anguillarum as a model, we could identify additional key functions encoded by irp-HPI that are necessary for piscibactin production and transport and that have remained unknown. Allelic exchange mutagenesis, combined with cross-feeding bioassays and LC-MS analysis, were used to demonstrate that Irp4 protein is an essential component for piscibactin synthesis since it is the thioesterase required for nascent piscibactin be released from the NRPS Irp1. We also show that Irp8 is a MFS-type protein essential for piscibactin secretion. In addition, after passage through the outer membrane transporter FrpA, the completion of ferri-piscibactin internalization through the inner membrane would be achieved by the ABC-type transporter FrpBC. The expression of this transporter is coordinated with the expression of FrpA and with the genes encoding biosynthetic functions. Since piscibactin is a major virulence factor of some pathogenic vibrios, the elements of biosynthesis and transport described here could be additional interesting targets for the design of novel antimicrobials against these bacterial pathogens.

Abstract Brain glioma treatment with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross blood–brain barrier (BBB). Here we describe targeted nanoscale immunoconjugates (NICs) on natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) results in an increase of CD8+ T cells, NK cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with NIC combination is significantly longer compared to animals treated with single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of tumor-targeted polymer-conjugated checkpoint inhibitors as an effective GBM treatment via activation of both systemic and local privileged brain tumor immune response.

In recent years, the thienopyrazole moiety has emerged as a pharmacologically active scaffold with antitumoral and kinase inhibitory activity. In this study, high-throughput screening of 2000 small molecules obtained from the ChemBridge DIVERset library revealed a unique thieno[2,3-c]pyrazole derivative (Tpz-1) with potent and selective cytotoxic effects on cancer cells. Compound Tpz-1 consistently induced cell death at low micromolar concentrations (0.19 μM to 2.99 μM) against a panel of 17 human cancer cell lines after 24 h, 48 h, or 72 h of exposure. Furthermore, an in vitro investigation of Tpz-1’s mechanism of action revealed that Tpz-1 interfered with cell cycle progression, reduced phosphorylation of p38, CREB, Akt, and STAT3 kinases, induced hyperphosphorylation of Fgr, Hck, and ERK 1/2 kinases, and disrupted microtubules and mitotic spindle formation. These findings support the continued exploration of Tpz-1 and other thieno[2,3-c]pyrazole-based compounds as potential small-molecule anticancer agents.

In pursuit of a noncommutative spectrum functor, we argue that the Heyneman-Sweedler finite dual coalgebra can be viewed as a quantization of the maximal spectrum of a commutative affine algebra, integrating prior perspectives of Takeuchi, Batchelor, Kontsevich-Soibelman, and Le Bruyn. We introduce fully residually finite-dimensional algebras A as those with enough finite-dimensional representations to let A∘ act as an appropriate depiction of the noncommutative maximal spectrum of A; importantly, this class includes affine noetherian PI algebras. In the case of prime affine algebras that are module-finite over their center, we describe how the Azumaya locus is represented in the finite dual. This is used to describe the finite dual of quantum planes at roots of unity as an endeavor to visualize the noncommutative space on which these algebras act as functions. Finally, we discuss how a similar analysis can be carried out for other maximal orders over surfaces.

The transferrin receptor 1 (TfR1), also known as cluster of differentiation 71 (CD71), is a type II transmembrane glycoprotein that binds transferrin (Tf) and performs a critical role in cellular iron uptake through the interaction with iron-bound Tf. Iron is required for multiple cellular processes and is essential for DNA synthesis and, thus, cellular proliferation. Due to its central role in cancer cell pathology, malignant cells often overexpress TfR1 and this increased expression can be associated with poor prognosis in different types of cancer. The elevated levels of TfR1 expression on malignant cells, together with its extracellular accessibility, ability to internalize, and central role in cancer cell pathology make this receptor an attractive target for antibody-mediated therapy. The TfR1 can be targeted by antibodies for cancer therapy in two distinct ways: (1) indirectly through the use of antibodies conjugated to anti-cancer agents that are internalized by receptor-mediated endocytosis or (2) directly through the use of antibodies that disrupt the function of the receptor and/or induce Fc effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Although TfR1 has been used extensively as a target for antibody-mediated cancer therapy over the years, interest continues to increase for both targeting the receptor for delivery purposes and for its use as direct anti-cancer agents. This review focuses on the developments in the use of antibodies targeting TfR1 as direct anti-tumor agents.

El artículo analiza la evolución del castigo a lo largo de la historia, pasando de una primacía en la utilización de las penas corporales a la utilización casi masiva de la pena de prisión –que continúa siendo la principal sanción penal de los sistemas de penas en los ordenamientos penales del mundo-. Sin embargo, la propia prisión se fue transformando de acuerdo a las necesidades que debía cumplir como centro de reclusión, convirtiéndose en el paradigma más palmario de sociedad de control. A partir de ahí la institución penitenciaria se bifurcó en dos vías diversas, las cuales verdaderamente convergen en sí, puesto que el ordenamiento penal actual es esclavo del orden y el control, lo que terminado instaurando la inocuización de los individuos, tanto en los establecimientos penales, como en la propia sociedad.

Regular physical activity (PA) is associated with improved overall survival (OS) in stage I–III colorectal cancer (CRC) patients. This association is less defined in patients with metastatic CRC (mCRC). We therefore conducted a study in mCRC patients participating in the Prospective Dutch Colorectal Cancer cohort. PA was assessed with the validated SQUASH questionnaire, filled-in within a maximum of 60 days after diagnosis of mCRC. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week. American College of Sports and Medicine (ACSM) PA guideline adherence, tertiles of moderate to vigorous PA (MVPA), and sport and leisure time MVPA (MVPA-SL) were assessed as well. Vital status was obtained from the municipal population registry. Cox proportional-hazards models were used to study the association between PA determinants and all-cause mortality adjusted for prognostic patient and treatment-related factors. In total, 293 mCRC patients (mean age 62.9 ± 10.6 years, 67% male) were included in the analysis. Compared to low levels, moderate and high levels of MET-hours were significantly associated with longer OS (fully adjusted hazard ratios: 0.491, (95% CI 0.299–0.807, p value = 0.005) and 0.485 (95% CI 0.303–0.778, p value = 0.003), respectively), as were high levels of MVPA (0.476 (95% CI 0.278–0.816, p value = 0.007)) and MVPA-SL (0.389 (95% CI 0.224–0.677, p value < 0.001)), and adherence to ACSM PA guidelines compared to non-adherence (0.629 (95% CI 0.412–0.961, p value = 0.032)). The present study provides evidence that higher PA levels at diagnosis of mCRC are associated with longer OS.

Junín virus (JUNV) is one of five New World mammarenaviruses (NWMs) that causes fatal hemorrhagic disease in humans and is the etiological agent of Argentine hemorrhagic fever (AHF). The pathogenesis underlying AHF is poorly understood; however, a prolonged, elevated interferon-α (IFN-α) response is associated with a negative disease outcome. A feature of all NWMs that cause viral hemorrhagic fever is the use of human transferrin receptor 1 (hTfR1) for cellular entry. Here, we show that mice expressing hTfR1 develop a lethal disease course marked by an increase in serum IFN-α concentration when challenged with JUNV. Further, we provide evidence that the type I IFN response is central to the development of severe JUNV disease in hTfR1 mice. Our findings identify hTfR1-mediated entry and the type I IFN response as key factors in the pathogenesis of JUNV infection in mice.

Therapeutic blockade of PD-1/PD-L1 signaling with monoclonal antibodies (mAbs) has shown clinical success and activity across a broad set of cancer subtypes. However, monotherapy with PD-1/PD-L1 inhibitors are only effective in a subset of patients and ongoing studies show efficacy of treatment depends on a combinatorial approach. Contrary to mAbs chimeric B-cell cancer vaccines incorporating a “promiscuous” T-cell epitope have the advantage of producing a polyclonal B-cell antibody that can potentially induce memory B- and T-cell responses, while reducing immune evasion and suppression. Here, we describe a novel PD-1 B-cell peptide epitope vaccine (amino acid 92–110; PD1-Vaxx) linked to a measles virus fusion peptide (MVF) amino acid 288–302 via a four amino acid residue (GPSL) emulsified in Montanide ISA 720VG that aims to induce the production of polyclonal antibodies that block PD-1 signaling and thus trigger anticancer effects similar to nivolumab. In preclinical studies, the PD1-Vaxx outperformed the standard anti-mouse PD-1 antibody (mAb 29F.1A12) in a mouse model of human HER-2 expressing colon carcinoma. Furthermore, the combination of PD1-Vaxx with combo HER-2 peptide vaccine (B-Vaxx) showed enhanced inhibition of tumor growth in colon carcinoma BALB/c model challenged with CT26/HER-2 cells. The PD-1 or combined vaccines were safe with no evidence of toxicity or autoimmunity.

# Background Bacterial meningitis (BM) is a significant cause of mortality in children; with deaths from BM in children aged \

Vibrio anguillarum causes a hemorrhagic septicemia that affects cold- and warm-water adapted fish species. The main goal of this work was to determine the temperature-dependent changes in the virulence factors that could explain the virulence properties of V. anguillarum for fish cultivated at different temperatures. We have found that although the optimal growth temperature is around 25°C, the degree of virulence of V. anguillarum RV22 is higher at 15°C. To explain this result, an RNA-Seq analysis was performed to compare the whole transcriptome profile of V. anguillarum RV22 cultured under low-iron availability at either 25 or 15°C, which would mimic the conditions that V. anguillarum finds during colonization of fish cultivated at warm- or cold-water temperatures. The comparative analysis of transcriptomes at high- and low-iron conditions showed profound metabolic adaptations to grow under low iron. These changes were characterized by a down-regulation of the energetic metabolism and the induction of virulence-related factors like biosynthesis of LPS, production of hemolysins and lysozyme, membrane transport, heme uptake, or production of siderophores. However, the expression pattern of virulence factors under iron limitation showed interesting differences at warm and cold temperatures. Chemotaxis, motility, as well as the T6SS1 genes are expressed at higher levels at 25°C than at 15°C. By contrast, hemolysin RTX pore-forming toxin, T6SS2, and the genes associated with exopolysaccharides synthesis were preferentially expressed at 15°C. Notably, at this temperature, the siderophore piscibactin system was strongly up-regulated. In contrast, at 25°C, piscibactin genes were down-regulated and the vanchrobactin siderophore system seems to supply all the necessary iron to the cell. The results showed that V. anguillarum adjusts the expression of virulence factors responding to two environmental signals, iron levels and temperature. Thus, the relative relevance of each virulence factor for each fish species could vary depending on the water temperature. The results give clues about the physiological adaptations that allow V. anguillarum to cause infections in different fishes and could be relevant for vaccine development against fish vibriosis.

We study—with existence and unicity results—a variant of the SIR model for an infectious disease incorporating both the possibility of a death outcome—in a short period of time—and a regime switch that can account for the mitigation measures used to control the spreading of the infections, such as a total lockdown. This model is parametrised by three parameters: the basic reproduction number, the mortality rate of the infected, and the duration of the disease. We discuss a particular example of application to Portuguese COVID-19 data in two short periods just after the start of the epidemic in 4 March 2020, with the first two cases dated that day. We propose a simple and effective method for the estimation of the main parameters of the disease, namely, the basic reproduction number and the mortality rate of the infected. We correct these estimated values to take into account the asymptomatic non-diagnosed members of the population. We compare the outcome of the model in the cases of the existence, or not, of a regime switch, and under three different scenarios, with a remarkable agreement between model and data deaths in the case of our basis scenario. In a final short remark, we deal with the existence of symmetries for the proposed model.

Bismuth is a heavy metal with antibacterial properties that has a long history of medicinal use. The results reported here suggest that bismuth(III) (chelated with deferiprone) could be used in aquaculture systems to treat bacterial disease outbreaks, greatly reducing antibiotic use. We tested bismuth susceptibility in a collection of aquaculture bacterial pathogens. In the presence of bismuth concentrations ranging from 1.3 to 13 µM, most bacteria started showing a drastic decrease in their growth ability, although with high inter- and intraspecific variability. The minimal inhibitory concentrations of bismuth ranged from 13 to more than 780 µM, depending on bacterial species and strain. The results of in vivo assays suggest that low concentrations of bismuth could be especially effective to treat vibriosis caused by Vibrio anguillarum, since bismuth greatly reduced mortality in experimentally infected fish without any observable side effects. A bismuth therapy, alone or combined with other antimicrobials, could contribute to reduce the use of antibiotics in aquaculture.