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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.

Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to interfere with their biological functions. The Elongin BC heterodimer (ELOB/C) is involved in transcription elongation and protein turnover by PPIs that involve the so-called BC-box. ELOB and ELOC are commonly upregulated in cancer and essential for cancer cell growth, making them attractive drug targets. However, no strategy has been established to inhibit their functions in cells, so far. Here, we report a peptide that mimics a high-affinity BC-box and tightly binds to the ELOB/C dimer (kD= 0.45 ± 0.03 nM). Our peptide blocks the association of ELOB/C with its interaction partners, both in vitro and in the cellular environment. Cancer cells treated with this peptide inhibitor show decreased cell viability, altered cell cycle and increased apoptosis. Therefore, our work proposes that blocking the BC-box binding pocket of ELOB/C is a feasible strategy to impair the function of the ELOB/C heterodimer 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.

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Purpose Lumbar discogenic diffuse pain is still not understood. Authors describe the sinuvertebral nerve (SVN) as one possible cause. Body-donor studies are rare and controversial. Therefore, the aim was to revisit the origin, course and distribution in a body-donor study. Methods Six lumbar blocks (3 female, 3 male) aged between 59 and 94 years were dissected. After removal of the back muscles, lamina, dura mater and cauda equina, the anterior vertebral venous plexus, spinal artery and SVN were exposed and evaluated. Results 43 nerves out of 48 levels could be evaluated. The origin of the SVN was constituted by two roots: a somatic and a sympathetic branch arising from the rami communicantes. In 4/48 intervertebral canals studied (8.3%), we found two SVN at the same level. In 35/48 cases, one SVN was found. In 9/48 cases, no SVN was found. The SVN had a recurrent course below the inferior vertebral notch; in the vertebral canal it showed different patterns: ascending branch (31/43, 72.1%), common branch diverging into two branches (10/43, 23.3%), double ascending branch (1/43, 2.3%) finalizing two levels above and a descending branch (1/43, 2.3%). In 12/43 cases (27.9%) the SVN had ipsilateral connections with another SVN. The distribution ended in the middle of the vertebral body supplying adjacent structures. Conclusion A thorough understanding of the anatomy of the SVN might lead to significant benefits in therapy of discogenic low back pain. We suggest blocking the SVN at the level of the inferior vertebral notch of two adjacent segments. Level of evidence I Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding

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.

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.

This paper aims to both fit and predict crop biophysical variables with a SAR image series by performing a factorial experiment and estimating time series models using a combination of forecasts. Two plots of barley grown under rainfed conditions in Spain were monitored during the growing cycle of 2015 (February to June). The dataset included nine field estimations of agronomic parameters, 20 RADARSAT-2 images, and daily weather records. Ten polarimetric observables were retrieved and integrated to derive the six agronomic and monitoring variables, including the height, biomass, fraction of vegetation cover, leaf area index, water content, and soil moisture. The statistical methods applied, namely double smoothing, ARIMAX, and robust regression, allowed the adjustment and modelling of these field variables. The model equations showed a positive contribution of meteorological variables and a strong temporal component in the crop’s development, as occurs in natural conditions. After combining different models, the results showed the best efficiency in terms of forecasting and the influence of several weather variables. The existence of a cointegration relationship between the data series of the same crop in different fields allows for adjusting and predicting the results in other fields with similar crops without re-modelling.

Forecasting the energy consumption of heating, ventilating, and air conditioning systems is important for the energy efficiency and sustainability of buildings. In fact, conventional models present limitations in these systems due to their complexity and unpredictability. To overcome this, the long short-term memory-based model is employed in this work. Our objective is to develop and evaluate a model to forecast the daily energy consumption of heating, ventilating, and air conditioning systems in buildings. For this purpose, we apply a comprehensive methodology that allows us to obtain a robust, generalizable, and reliable model by tuning different parameters. The results show that the proposed model achieves a significant improvement in the coefficient of variation of root mean square error of 9.5% compared to that proposed by international agencies. We conclude that these results provide an encouraging outlook for its implementation as an intelligent service for decision making, capable of overcoming the problems of other noise-sensitive models affected by data variations and disturbances without the need for expert knowledge in the domain.

SAMD1 is a newly identified repressive CpG island regulator., 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.

Simple Summary Despite progress, acute myeloid leukemia (AML) remains one of the deadliest cancer diseases. The identification of novel molecular targets may allow developing innovative and alternative treatment options for AML. Using public data from genome-edited cancer cells, we identified factors that are specifically essential for AML cell growth. We validated the critical role of the transcription factor IRF8 and demonstrated that it modulates the function of the cells by regulating important signaling molecules. These results support that IRF8 may be a suitable molecular target for the treatment of AML. Abstract 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.

From 1970 to nowadays, breeders have improved oilseed rape (Brassica napus) in many ways: creation of double low varieties (free of erucic acid and with a low content in glucosinolates), increase of the seed yield and quality of seeds and improvement of resistance to diseases. All this work helped oilseed rape to become one of the most produced oilseed crop in the world. However, this intensive breeding on quality has reduced the genetic diversity of winter oilseed rape. In this study, a group of four breeding companies (RAGT, Limagrain, Syngenta, Euralis) called “GIE Colza” has been working with INRAE (National Research Institute for Agriculture, Food and Environment, France) on the FSRSO project “Printiver”. This project aimed at enlarging the genetic variability available in winter-type oilseed rape through crossing with spring-type materials to create lines with a winter-type behavior (need of vernalization) and a genetic background that has introgressed spring-type genetic diversity. Two pools have been created and selected for their need of vernalization, date of flowering, yield and other agronomic traits. The Group tested these two pools in multilocal trials. The results show interestingper sevalue and combining ability.

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.

O objetivo deste projeto de pesquisa foi de avaliar, por meio de um estudo transversal observacional, as associações entre características de saúde e psicossociais de adolescentes e o rendimento escolar. Participaram da pesquisa, 250 adolescentes na faixa etária de 14 a 18 anos, de ambos os sexos, provenientes de 5 escolas públicas do ensino médio do município de Piracicaba, SP. Foram aplicados, em semanas distintas, os seguintes questionários: características sociodemográficas (sexo, idade, moradia etc.), autopercepção do rendimento escolar e autopercepção da saúde bucal; senso de coerência; resiliência; bullying e letramento em saúde bucal. Verificou-se que as indivíduos do sexo masculino, que autoreferiram um estado de saúde geral ruim, que foram ao dentista pela última vez devido a problemas odontológicos e que apresentavam baixo letramento em saúde bucal apresentaram maior chance de apresentarem um baixo rendimento escolar (p

The superior mesenteric artery (SMA) supplies irrigation to the small intestine, ascending and a variable area of the transverse colon. Although medical imaging and surgical procedures have been widely developed in the last decades, the anatomy of the SMA using advanced imaging technology remains to be elucidated. Previous studies have used small sample sizes of cadaveric or radiological samples to propose a number of classifications for the SMA. In this study, we aimed to provide a more detailed description and useful classification of the SMA and its main branches [middle colic artery (MCA), right colic artery (RCA), and ileocolic artery (ICA)]. Samples (n = 50, 28 males and 22 females) were obtained from the repository of human cadavers located at the Department of Human Anatomy and Embryology, Complutense University of Madrid. This sample was dissected by preclinical medical students and completed by two of the authors (Gamo and Jiménez). A second set of samples was obtained from a bank of computerized tomography (CT) (560 CTs, 399 males and 161 females) collected by the Radiology Department at the Clínico San Carlos Hospital, Spain. Based on the results obtained from these studies, we propose a new classification of four patterns for the SMA anatomy. Pattern I as the independent origin of the three main branches of the SMA (cadaveric 40 %; CT 73.69 %); Pattern II is subdivided in three sub-patterns based on the common trunks of origin: Pattern IIa, common trunk between RCA and MCA (cadaveric 20 %, CT 4.28 %); Pattern IIb, common trunk between RCA and ICA (cadaveric 32 %, CT 15 %); Pattern IIc, common trunk for the three main branches (cadaveric 0 %, CT 0.35 %); Pattern III, as the absence of RCA (cadaveric 8 %; CT 2.32 %) and Pattern IV, based on presence of accessory arteries (not found in any of the samples). Although the independent origin of the three colic arteries have been classically described as the most frequent, the right colic artery is responsible of major variations.

Scabbardfishes are a group of deep-water fishes from the family Trichiuridae that form the basis of an important longline fishery in the Madeira archipelago, in the southern part of the Northeast Atlantic. Two closely related and morphologically similar species occur in this area: the black scabbardfish, Aphanopus carbo, and the intermediate scabbardfish, A. intermedius. In this study, 112 scabbardfish specimens captured in Madeira, Canary Islands, and nearby seamounts were examined for the presence of anisakid nematodes. Infection levels were extremely high in both species. A generalised linear model was applied to anisakid abundance, using fishing location and several host parameters as predictors. Fish length had a strong positive effect, and A. carbo was more heavily infected than A. intermedius, whereas fishing location had no effect. The microhabitat distribution of anisakid larvae within the fish followed a gradient from the stomach to other visceral organs; however, infection levels in the muscle were not negligible, which raises safety issues for consumers. It is strongly recommended that scabbardfish should never be eaten raw or undercooked, unless frozen prior to consumption.

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.

This paper analyzes productivity growth, technical progress, and efficiency change in a sample of 34 Spanish university libraries between 2003 and 2007. Data envelopment analysis and a Malmquist index are combined with a bootstrap method to provide statistical inference estimators of individual productivity, technical progress, pure efficiency, and scale efficiency scores. To calculate productivity, a three-stage service model has been developed, examining productivity changes in the relationships between the libraries' basic inputs, intermediate outputs, and final outputs. The results indicate a growth in the productivity of the libraries (relationship between basic inputs and intermediate outputs) and in the productivity of the service (relationship between basic inputs and final outputs). The growth in productivity in both relationships is due to technical progress. If the variable representing the use of electronic information resources is removed from the final output, the result is a significant reduction in productivity.

In this paper we address the problem of batching orders in a warehouse, with the objective of minimizing the total travel time. Order batching is an NP-hard optimization problem that is very difficult to solve exactly in practice. Thus, most implemented solutions are based on elementary heuristic methods that perform a relatively limited exploration of the solution space. As an alternative, we propose a heuristic based on variable neighborhood search, where the emphasis is placed on performing an intensive exploration of the most promising regions of the solution space. Simulations are conducted to study the performance of the method with different warehouse configurations, and an exhaustive comparative analysis, which considers all the best known heuristics, is carried out. The results obtained show that the proposed heuristic is competitive and that it provides a suitable method which can be used in practice. Additionally, since the performance of the algorithms depends heavily on factors such as storage policy, routing strategies, or the structure of the orders, we have developed an ANOVA in order to consider the effect of all the above factors on the different methods tested.

The celiac trunk (CT) is a vascular structure of the upper abdomen which gives off the left gastric artery (LGA), the splenic artery and the common hepatic artery. This study aims to compare the vascular patterns of the CT of two different samples (cadaveric and radiological) and to propose a simple classification of CT variations based on previous studies and our results. To perform this study we examined 43 adult cadavers, 24 males and 19 females, ages ranged from 69 to 92. In addition, we analysed 596 MDCT (multidetector computed tomographic) angiography examinations of 430 males and 166 females, ages ranged from 42 to 82. According to the classification proposed, results were divided into Type I or complete CT (578/639 cases, 90.5 %), Type II or incomplete CT (61/639 cases, 9.5 %), Type III or absence of CT and Type IV or celiacomesenteric trunk with no cases reported. Type I was divided into Type Ia or bifurcated trunk with LGA arising first (368/639 cases, 57.6 %), Type Ib or trifurcated trunk (205/639 cases, 32.1 %) and Type Ic or tetrafurcated trunk with an extra branch (5/639 cases, 0.8 %). Type II included hepatosplenic (29/639 cases, 4.5 %), gastroplenic (32/639, 5 %) and hepatogastric trunks (0/639, 0 %) which represented Types IIa, IIb and IIc respectively. No significant differences were found between the cadaveric and radiological samples. Gender did not appear to be related to any variability of the structures either. A new, simple and complete classification of the anatomical variations of the CT is proposed.

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.

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.

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.