Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells.

Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to perturb their biological functions. The Elongin BC heterodimer (ELOB/C) binds to a BC-box motif and is essential for cancer cell growth. Here, we report a peptide that mimics the high-affinity BC-box of the PRC2-associated protein EPOP. This peptide tightly binds to the ELOB/C dimer (kD = 0.46 ± 0.02 nM) and blocks the association of ELOB/C with its interaction partners, both in vitro and in the cellular environment. Cancer cells treated with our peptide inhibitor showed decreased cell viability, increased apoptosis, and perturbed gene expression. Therefore, our work proposes that blocking the BC-box-binding pocket of ELOB/C is a feasible strategy to impair its function and inhibit cancer cell growth. Our peptide inhibitor promises novel mechanistic insights into the biological function of the ELOB/C dimer and offers a starting point for therapeutics linked to ELOB/C dysfunction.

[Cost-effectiveness of universal childhood vaccination against hepatitis A in Spain: a dynamic approach]. / Coste-efectividad de la vacunación universal infantil frente a la hepatitis A en España: un enfoque dinámico.

OBJECTIVE: To evaluate the cost-effectiveness of infant universal vaccination against hepatitis A in Spain. METHOD: Using a dynamic model and decision tree model, a cost-effectiveness analysis was performed to compare three vaccination strategies against hepatitis A: non-vaccination strategy versus universal childhood vaccination of hepatitis A with one or two doses. The perspective of the study was that of the National Health System (NHS) and a lifetime horizon was considered. Both costs and effects were discounted at 3% per year. Health outcomes were measured in terms of quality adjusted life years (QALY) and the cost-effectiveness measure used was the incremental cost-effectiveness ratio (ICER). In addition, deterministic sensitivity analysis by scenarios was performed. RESULTS: In the particular case of Spain, with low endemicity for hepatitis A, the difference in health outcomes between vaccination strategies (with 1 or 2 doses) and non-vaccination are practically non-existent, terms of QALY. In addition, the ICER obtained is high, exceeding the limits of willingness to pay from Spain (€22,000-25,000/QALY). The deterministic sensitivity analysis showed that the results are sensitive to the variations of the key parameters, although in no case the vaccination strategies are cost-effective. CONCLUSIONS: Universal infant vaccination strategy against hepatitis A would not be a cost-effective option from the NHS perspective in Spain.

The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain.

The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.

Coste-efectividad de la vacunación universal infantil frente a la hepatitis A en España: un enfoque dinámico / Cost-effectiveness of universal childhood vaccination against hepatitis A in Spain: a dynamic approach

Objetivo: Evaluar el coste-efectividad de diferentes estrategias de vacunación universal infantil frente a la hepatitis A en España. Método: A partir de un modelo dinámico y un árbol de decisión, se realizó un análisis de coste-efectividad para comparar tres estrategias de vacunación frente a la hepatitis A: no vacunación y vacunación universal infantil con una y dos dosis. La perspectiva del estudio escogida fue la del Sistema Nacional de Salud (SNS) y se consideró como horizonte temporal toda la vida del paciente. Tanto los costes como los efectos se descontaron al 3% anual. Los resultados en salud se midieron en años de vida ajustados por calidad (AVAC) y la medida de coste-efectividad utilizada es la razón de coste-efectividad incremental (RCEI). Además, se llevaron a cabo análisis de sensibilidad determinísticos por escenarios. Resultados: En el caso particular de España, con baja endemicidad de hepatitis A, las diferencias en resultados en salud entre las distintas estrategias de vacunación (con una o dos dosis) y la no vacunación son prácticamente inexistentes, en términos de AVAC. Además, las RCEI obtenidas son elevadas, superando los límites establecidos de disposición a pagar obtenidos en España (22.000-25.000 €/AVAC). El análisis de sensibilidad determinístico muestra que los resultados son sensibles a las variaciones de los parámetros clave, aunque en ningún caso resultan coste-efectivos. Conclusiones: La vacunación universal infantil frente a la hepatitis A no sería una opción coste-efectiva desde la perspectiva del SNS en España en la actualidad. (AU)

Objective: To evaluate the cost-effectiveness of infant universal vaccination against hepatitis A in Spain. Method: Using a dynamic model and decision tree model, a cost-effectiveness analysis was performed to compare three vaccination strategies against hepatitis A: non-vaccination strategy versus universal childhood vaccination of hepatitis A with one or two doses. The perspective of the study was that of the National Health System (NHS) and a lifetime horizon was considered. Both costs and effects were discounted at 3% per year. Health outcomes were measured in terms of quality adjusted life years (QALY) and the cost-effectiveness measure used was the incremental cost-effectiveness ratio (ICER). In addition, deterministic sensitivity analysis by scenarios was performed. Results: In the particular case of Spain, with low endemicity for hepatitis A, the difference in health outcomes between vaccination strategies (with 1 or 2 doses) and non-vaccination are practically non-existent, terms of QALY. In addition, the ICER obtained is high, exceeding the limits of willingness to pay from Spain (€22,000–25,000/QALY). The deterministic sensitivity analysis showed that the results are sensitive to the variations of the key parameters, although in no case the vaccination strategies are cost-effective. Conclusions: Universal infant vaccination strategy against hepatitis A would not be a cost-effective option from the NHS perspective in Spain. (AU)

Applications of Ulva Biomass and Strategies to Improve Its Yield and Composition: A Perspective for Ulva Aquaculture.

Sea lettuce (Ulva spp.), with its worldwide distribution and remarkable ability to grow rapidly under various conditions, represents an important natural resource that is still under-exploited. Its biomass can be used for a wide range of applications in the food/feed, pharmaceutical, nutraceutical, biofuel, and bioremediation industries. However, knowledge of the factors affecting Ulva biomass yield and composition is far from complete. Indeed, the respective contributions of the microbiome, natural genetic variation in Ulva species, environmental conditions and importantly, the interactions between these three factors on the Ulva biomass, have been only partially elucidated. Further investigation is important for the implementation of large-scale Ulva aquaculture, which requires stable and controlled biomass composition and yields. In this review, we document Ulva biomass composition, describe the uses of Ulva biomass and we propose different strategies for developing a sustainable and profitable Ulva aquaculture industry.

Modified SIQR model for the COVID-19 outbreak in several countries.

In this paper, we propose a modified Susceptible-Infected-Quarantine-Recovered (mSIQR) model, for the COVID-19 pandemic. We start by proving the well-posedness of the model and then compute its reproduction number and the corresponding sensitivity indices. We discuss the values of these indices for epidemiological relevant parameters, namely, the contact rate, the proportion of unknown infectious, and the recovering rate. The mSIQR model is simulated, and the outputs are fit to COVID-19 pandemic data from several countries, including France, US, UK, and Portugal. We discuss the epidemiological relevance of the results and provide insights on future patterns, subjected to health policies.

The CpG Island-Binding Protein SAMD1 Contributes to an Unfavorable Gene Signature in HepG2 Hepatocellular Carcinoma Cells.

The unmethylated CpG island-binding protein SAMD1 is upregulated in many human cancer types, but its cancer-related role has not yet been investigated. Here, we used the hepatocellular carcinoma cell line HepG2 as a cancer model and investigated the cellular and transcriptional roles of SAMD1 using ChIP-Seq and RNA-Seq. SAMD1 targets several thousand gene promoters, where it acts predominantly as a transcriptional repressor. HepG2 cells with SAMD1 deletion showed slightly reduced proliferation, but strongly impaired clonogenicity. This phenotype was accompanied by the decreased expression of pro-proliferative genes, including MYC target genes. Consistently, we observed a decrease in the active H3K4me2 histone mark at most promoters, irrespective of SAMD1 binding. Conversely, we noticed an increase in interferon response pathways and a gain of H3K4me2 at a subset of enhancers that were enriched for IFN-stimulated response elements (ISREs). We identified key transcription factor genes, such as IRF1, STAT2, and FOSL2, that were directly repressed by SAMD1. Moreover, SAMD1 deletion also led to the derepression of the PI3K-inhibitor PIK3IP1, contributing to diminished mTOR signaling and ribosome biogenesis pathways. Our work suggests that SAMD1 is involved in establishing a pro-proliferative setting in hepatocellular carcinoma cells. Inhibiting SAMD1's function in liver cancer cells may therefore lead to a more favorable gene signature.

Viscoelastic Effects on the Response of Electroelastic Materials.

Electroelastic materials, as for example, 3M VHB 4910, are attracting attention as actuators or generators in some developments and applications. This is due to their capacity of being deformed when submitted to an electric field. Some models of their actuation are available, but recently, viscoelastic models have been proposed to give an account of the dissipative behaviour of these materials. Their response to an external mechanical or electrical force field implies a relaxation process towards a new state of thermodynamic equilibrium, which can be described by a relaxation time. However, it is well known that viscoelastic and dielectric materials, as for example, polymers, exhibit a distribution of relaxation times instead of a single relaxation time. In the present approach, a continuous distribution of relaxation times is proposed via the introduction of fractional derivatives of the stress and strain, which gives a better account of the material behaviour. The application of fractional derivatives is described and a comparison with former results is made. Then, a double generalisation is carried out: the first one is referred to the viscoelastic or dielectric models and is addressed to obtain a nonsymmetric spectrum of relaxation times, and the second one is the adoption of the more realistic Mooney-Rivlin equation for the stress-strain relationship of the elastomeric material. A modified Mooney-Rivlin model for the free energy density of a hyperelastic material, VHB 4910 has been used based on experimental results of previous authors. This last proposal ensures the appearance of the bifurcation phenomena which is analysed for equibiaxial dead loads; time-dependent bifurcation phenomena are predicted by the extended Mooney-Rivlin equations.

Making fundamental scientific discoveries by combining information from literature, databases, and computational tools - An example.

In recent years, the amount of available literature, data and computational tools has increased exponentially, providing opportunities and challenges to make use of this vast amount of material. Here, we describe how we utilized publicly available information to identify the previously hardly characterized protein SAMD1 (SAM domain-containing protein 1) as a novel unmethylated CpG island-binding protein. This discovery is an example, how the richness of material and tools on the internet can be used to make scientific breakthroughs, but also the hurdles that may occur. Specifically, we discuss how the misrepresentation of SAMD1 in literature and databases may have prevented an earlier characterization of this protein and we address what can be learned from this example.

The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands.

CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. The absence of SAMD1 impairs ES cell differentiation processes, leading to misregulation of key biological pathways. Together, our work establishes SAMD1 as a newly identified chromatin regulator acting at unmethylated CGIs.

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells.

Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells and its deletion leads to impaired proliferation in those cells. Consistently, high IRF8 expression is associated with poorer patients' prognoses. Combining gene expression changes upon IRF8 deletion and the genome-wide localization of IRF8 in the AML cell line MV4-11, we demonstrate that IRF8 directly regulates key signaling molecules, such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5, and the cell cycle regulator Cyclin D1. IRF8 loss impairs AML-driving signaling pathways, including the WNT, Chemokine, and VEGF signaling pathways. Additionally, many members of the focal adhesion pathway showed reduced expression, providing a putative link between high IRF8 expression and poor prognosis. Thus, this study suggests that IRF8 could serve as a biomarker and potential molecular target in a subset of human AMLs.

Vascular clinical anatomy of the submandibular gland.

OBJECTIVE: The aim of this study is to describe in depth the precise anatomy of the vascular supply of the submandibular gland, trying to determine the existence of patterns of glandular vascularization. Knowledge of these patterns could facilitate surgical management of the gland and the submandibular gland flap. MATERIAL AND METHODS: Neck dissections of formaldehyde preserved human cadavers were performed. Submandibular and transmandibular approaches were used during the dissections. All the vascular branches found were registered and classified into 2groups: main or accessory branches. The anatomical data analyzed was: The diameter and length of the main and accessory branches, as well as the most important measurements of the submandibular gland flap pedicle. RESULTS: 33 glands were dissected to study the arterial supply of the submandibular gland (17 right, 16 left; 17 males, 16 females) and 29 were dissected to study the venous supply (15 left, 14 right; 15 males,14 females). A total of 123 arterial branches were found reaching the 33 submandibular glands (47 main and 76 accessories) and 116 venous branches were found draining the 29 submandibular glands (47 main branches and 69 accessory branches). A constant main venous branch that ran parallel to the Wharton duct and drained in the sublingual vein was found in all of cases (Concomitant Wharton Duct Vein or CWDV). CONCLUSION: The CWDV is a constant venous branch for the drainage of the gland and should be considered as venous pedicle during the dissection of submandibular gland flaps.

Morphological changes of the pancreas after pancreaticoduodenectomy.

The aim of this retrospective study was thus to evaluate postoperative morphological changes in the remnant pancreas after pancreaticoduodenectomy (PD) associated with postoperative pancreatic fistula (POPF). Fifty-one patients subjected to PD were enrolled in the study and allocated into 2 groups according to the presence (n = 16) or absence of POPF (n = 35). A morphological evaluation of the pancreas was conducted for up to a 20 months follow-up on CT scans and compared between groups. No significant differences were observed in morphology between the groups at the different preoperative and PO intervals, regardless of the clinical relevance of the POPF or POPF grade. However, in the overall patient analysis we observed a significant reduction of the entire pancreas over time. In fact, thickness decreased 0.4 mm/month, length 1.2 mm/month and volume 1.17 cm3/month over the PO. The impact of age, POPF, type of anastomosis, surgical technique and PO follow-up (time) was evaluated in a multivariate analysis using the general linear model, but only PO follow-up had a significant influence on the final model (p < 0.001). A significant reduction on pancreatic parenchyma (thickness, length and volume) occurs after PD with no significant differences between patients with or without POPF.

Anatomical variations of the renal arteries: Cadaveric and radiologic study, review of the literature, and proposal of a new classification of clinical interest.

PURPOSE: To analyse the variations of the renal arteries in two samples, cadaveric and computerized tomographic (CT) images, as well as to propose a simple classification of such variations based on the obtained results and an extensive review of the literature on the topic. MATERIAL AND METHODS: Sixty human dissected kidneys and their vessels, and 583 abdominal CT were studied. RESULTS: A total of 86 arteries were described in the cadaveric sample, whereas 1223 were analysed in the radiological one. Five types (a-e) and patterns (I-V) have been stablished in the classification. Type a, aortic hilar artery, incidences were 79% in cadavers and 95% in CT; Type b, hilar upper polar artery, incidences were 10% in cadavers and 2% in CT; Type c, aortic upper polar artery, incidences were 5% in cadavers and 2% in CT; Type d, aortic lower polar artery, incidences were 3% in cadavers and 1% in CT; Type e, hilar lower polar artery, incidences were 2% in cadaver and less than 0.1% in CT. The pattern represents the number of arteries reaching one kidney. Patterns I-IV were found in cadavers (I: 78%; II: 19%; III and IV: 2%); in CT sample only patterns I (88%) and II (12%). Pattern V was added because it has been described in the reviewed literature. CONCLUSIONS: Type a and pattern I are the most prevalent, both in the cadaveric and the CT samples. Also in the consulted literature. There are no differences in the types and pattern incidences by side or sex. A simple, comprehensive and useful classification is proposed.

Morphometry of the suprascapular nerve in the supraspinous fossa

We describe the supraescapular region’s anatomy providing distances between osseous landmarks (supraglenoid tubercle, suprascapular notch, glenoid rim, scapular spine) and measuring the total length of the suprascapular nerve (ssn), to determine ideal places or safe zones for shoulder surgery. Fifty shoulders from cadavers belonging to the Human Anatomy and Embryology donated under consent of the Spanish law were studied. The course of the nerve in each shoulder has been defined by measuring the distances from the supraglenoid tubercle to the suprascapular notch and to the scapular spine, the distance from the midpoint of the posterior glenoid rim to the base of the scapular spine, and finally the total length of the nerve. After leaving the suprascapular notch, the ssn courses posteriorly and laterally deep to the supraspinatus muscle to reach the base of the scapular spine. The distance from the supraglenoid tubercle to the notch averaged 3.54 cm (range 3 - 4.1 cm) and the distance to the base of the spine averaged 2.51 cm (range 1.9 - 3 cm). The distance from the midline of the posterior glenoid rim to the scapular base ranged from average 2.42 (range1.9 - 3.1 cm). The total length of the nerve along the supraspinous fossa averaged 4.22 cm (range 3.6 - 5 cm). A surgical safe zone could be established taking into account these measurements

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The secondary metabolism glycosyltransferases UGT73B3 and UGT73B5 are components of redox status in resistance of Arabidopsis to Pseudomonas syringae pv. tomato.

Secondary metabolism plant glycosyltransferases (UGTs) ensure conjugation of sugar moieties to secondary metabolites (SMs) and glycosylation contributes to the great diversity, reactivity and regulation of SMs. UGT73B3 and UGT73B5, two UGTs of Arabidopsis thaliana (Arabidopsis), are involved in the hypersensitive response (HR) to the avirulent bacteria Pseudomonas syringae pv. tomato (Pst-AvrRpm1), but their function in planta is unknown. Here, we report that ugt73b3, ugt73b5 and ugt73b3 ugt73b5 T-DNA insertion mutants exhibited an accumulation of reactive oxygen species (ROS), an enhanced cell death during the HR to Pst-AvrRpm1, whereas glutathione levels increased in the single mutants. In silico analyses indicate that UGT73B3 and UGT73B5 belong to the early salicylic acid (SA)-induced genes whose pathogen-induced expression is co-regulated with genes related to cellular redox homeostasis and general detoxification. Analyses of metabolic alterations in ugt mutants reveal modification of SA and scopoletin contents which correlate with redox perturbation, and indicate quantitative modifications in the pattern of tryptophan-derived SM accumulation after Pst-AvrRpm1 inoculation. Our data suggest that UGT73B3 and UGT73B5 participate in regulation of redox status and general detoxification of ROS-reactive SMs during the HR to Pst-AvrRpm1, and that decreased resistance to Pst-AvrRpm1 in ugt mutants is tightly linked to redox perturbation.

The differential spatial distribution of secondary metabolites in Arabidopsis leaves reacting hypersensitively to Pseudomonas syringae pv. tomato is dependent on the oxidative burst.

Secondary metabolites (SMs) play key roles in pathogen responses, although knowledge of their precise functions is limited by insufficient characterization of their spatial response. The present study addressed this issue in Arabidopsis leaves by non-targeted and targeted metabolite profiling of Pseudomonas syringae pv. tomato (Pst-AvrRpm1) infected and adjacent uninfected leaf tissues. While overlap was observed between infected and uninfected areas, the non-targeted metabolite profiles of these regions differed quantitatively and clustering analysis underscores a differential distribution of SMs within distinct metabolic pathways. Targeted metabolite profiling revealed that infected tissues accumulate more salicylic acid and the characteristic phytoalexin of Arabidopsis, camalexin, than uninfected adjacent areas. On the contrary, the antioxidant coumarin derivative, scopoletin, was induced in infected tissues while its glucoside scopolin predominated in adjacent tissues. To elucidate the still unclear relationship between the accumulation of SMs and reactive oxygen species (ROS) accumulation and signalling, a catalase-deficient line (cat2) in which ROS signalling is up-regulated, was used. Metabolic analysis of cat2 suggests that some SMs have important interactions with ROS in redox homeostasis during the hypersensitive response to Pst-AvrRpm1. Overall, the study demonstrates that ROS availability influences both the amount and the pattern of infection-induced SM accumulation.

Microbial siderophores exert a subtle role in Arabidopsis during infection by manipulating the immune response and the iron status.

Siderophores (ferric ion chelators) are secreted by organisms in response to iron deficiency. The pathogenic enterobacterium Erwinia chrysanthemi produces two siderophores, achromobactin and chrysobactin (CB), which are required for systemic dissemination in host plants. Previous studies have shown that CB is produced in planta and can trigger the up-regulation of the plant ferritin gene AtFER1. To further investigate the function of CB during pathogenesis, we analyzed its effect in Arabidopsis (Arabidopsis thaliana) plants following leaf infiltration. CB activates the salicylic acid (SA)-mediated signaling pathway, while the CB ferric complex is ineffective, suggesting that the elicitor activity of this siderophore is due to its iron-binding property. We confirmed this hypothesis by testing the effect of siderophores structurally unrelated to CB, including deferrioxamine. There was no activation of SA-dependent defense in plants grown under iron deficiency before CB treatment. Transcriptional analysis of the genes encoding the root ferrous ion transporter and ferric chelate reductase, and determination of the activity of this enzyme in response to CB or deferrioxamine, showed that these compounds induce a leaf-to-root iron deficiency signal. This root response as well as ferritin gene up-regulation in the leaf were not compromised in a SA-deficient mutant line. Using the Arabidopsis-E. chrysanthemi pathosystem, we have shown that CB promotes bacterial growth in planta and can modulate plant defenses through an antagonistic mechanism between SA and jasmonic acid signaling cascades. Collectively, these data reveal a new link between two processes mediated by SA and iron in response to microbial siderophores.