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The “premonitory symptoms” of eclampsia can be interpreted as actual symptoms of cerebral involvement within the posterior reversible leukoencephalopathy syndrome, and eclampsia as a severe symptom of the same syndrome. Objective: To review the characteristics of women with eclampsia in a national hospital, with emphasis on the associated neurological manifestations. Design: Case series. Institution: Hospital Nacional Daniel Alcides Carrion (HNDAC), Lima, Peru. Patients: Women with eclampsia. Methodology: Study of all patients with eclampsia over a period of 5 years and 6 months. Eclampsia cases that occurred outside the institution or with insufficient data were excluded. Main outcome measures: General characteristics, associated symptoms, complications and laboratory values in eclamptic patients. Results: Thirty-nine cases were reported. The incidence of eclampsia in pregnant women was 0.19%. The mean age was 21 years; 75.8% of the women were primiparous and 44.4% were less than 34 weeks pregnant. 69.7% of them were diagnosed before delivery; 51.5% had blood pressure above 160/110 mmHg and 12.1% had no hypertension. 93.9% presented symptoms, mainly headache (87.9%), as well as visual (27.2%) and auditory (12.1%) disturbances. Two patients had headache and normal blood pressure, and 2 cases were asymptomatic. Complications were: sensory alterations, abruptio placentae (15.2%), HELLP syndrome (15.2%) and difficult-to-control hypertension (39.4%). There were neither maternal nor perinatal deaths. Conclusions: The neurological manifestations that precede eclampsia are variable and do not have a constant correlation with the severity of maternal hypertension. Los ‘síntomas premonitorios’ de la eclampsia se pueden ver englobados como verdaderos síntomas de afectación cerebral dentro del síndrome de leucoencefalopatía posterior reversible, y la eclampsia como un síntoma severo. Objetivo. Revisar las características epidemiológicas de los casos con eclampsia, enfatizando el análisis de las manifestaciones neurológicas asociadas, en un hospital nacional. Diseño. Serie de casos. Institución. Hospital Nacional Daniel A. Carrión (HNDAC), Lima, Perú. Pacientes. Mujeres con eclampsia. Metodología. Estudio de todas las pacientes con eclampsia en un periodo de 5 años y 6 meses. Se excluyó aquellas con eclampsia extrainstitucional o con datos insuficientes. Principales medidas de resultados. Características generales, síntomas asociados, complicaciones y valores laboratoriales en pacientes eclámpticas. Resultados. Se halló 39 casos. La incidencia fue 0,19% del total de gestantes. La edad media fue 21 años, 75,8% fueron primíparas, 44,4% por debajo de las 34 semanas y en 69,7% ocurrió antes del parto; 51,5% tuvo presión arterial mayor a 160/110 mmHg y 12,1% no presentó hipertensión arterial; 93,9% tuvo síntomas, siendo los más frecuentes cefalea (87,9%), alteraciones visuales (27,2%) y auditivas (12,1%). Hubo dos casos de pacientes con cefalea y presión arterial normal, y 2 casos sin sintomatología. Las complicaciones fueron trastorno de sensorio, desprendimiento prematuro de placenta (15,2%), síndrome HELLP (15,2%) e HTA de difícil control (39,4%). No hubo casos de mortalidad materno perinatal. Conclusiones. La sintomatología neurológica que antecede a la eclampsia en la gestante con preeclampsia es muy variable y su correlación con la severidad de la hipertensión arterial materna no es constante.

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can cause arrhythmias, heart failure, and cardiac death. Here, we functionally characterized the motor domains of five DCM-causing mutations in human β-cardiac myosin. Kinetic analyses of the individual events in the ATPase cycle revealed that each mutation alters different steps in this cycle. For example, different mutations gave enhanced or reduced rate constants of ATP binding, ATP hydrolysis, or ADP release or exhibited altered ATP, ADP, or actin affinity. Local effects dominated, no common pattern accounted for the similar mutant phenotype, and there was no distinct set of changes that distinguished DCM mutations from previously analyzed HCM myosin mutations. That said, using our data to model the complete ATPase contraction cycle revealed additional critical insights. Four of the DCM mutations lowered the duty ratio (the ATPase cycle portion when myosin strongly binds actin) because of reduced occupancy of the force-holding A·M·D complex in the steady state. Under load, the A·M·D state is predicted to increase owing to a reduced rate constant for ADP release, and this effect was blunted for all five DCM mutations. We observed the opposite effects for two HCM mutations, namely R403Q and R453C. Moreover, the analysis predicted more economical use of ATP by the DCM mutants than by WT and the HCM mutants. Our findings indicate that DCM mutants have a deficit in force generation and force-holding capacity due to the reduced occupancy of the force-holding state.

Simultaneous synthesis and purification (SSP) of galacto-oligosaccharides (GOS) from lactose was conducted using a combi-biocatalyst formed by crosslinked enzyme aggregates of Aspergillus oryzae β-galactosidase and Saccharomyces cerevisiae cells co-immobilized by entrapment in calcium alginate gel particles. Product yield obtained with the combi-biocatalyst was similar than obtained with the soluble enzyme (23.3%), having a final purity of 25.7%. During the simultaneous process, ethyl-β-galactoside was produced from the ethanol generated as a metabolic product of yeast cells, but ethyl-β-galactoside was considerably decreased at high aeration (4 vvm). The combi-biocatalyst can be recovered and reused but its performance is limited by the reduction of the metabolic capacity of the cells. In this way, a process was developed for the SSP of GOS from lactose, obtaining a comparable product yield and higher specific productivity than in a conventional synthesis.

OI is a clinically and genetically heterogeneous disorder characterized by bone fragility. More than 90% of patients are heterozygous for mutations in type I collagen genes, COL1A1 and COL1A2, and a common mutation is substitution for an obligatory glycine in the triple helical Gly-X-Y repeats. Few non-glycine substitutions in the triple helical domain have been reported; most result in Y-position substitutions of arginine by cysteine. Here, we investigated leucine and cysteine substitutions for one Y-position arginine, p.Arg958 (Arg780 in the triple helical domain) of proα1(I) chains that cause mild OI. We compared their effects with two substitutions for glycine located in close proximity. Like substitutions for glycine, those for arginine reduced the denaturation temperature of the whole molecule and caused asymmetric posttranslational overmodification of the chains. Circular dichroism and increased susceptibility to cleavage by MMP1, MMP2 and catalytic domain of MMP1 revealed significant destabilization of the triple helix near the collagenase cleavage site. On a cellular level, we observed slower triple helix folding and intracellular collagen retention, which disturbed the Endoplasmic Reticulum function and affected matrix deposition. Molecular dynamic modeling suggested that Arg780 substitutions disrupt the triple helix structure and folding by eliminating hydrogen bonds of arginine side chains, in addition to preventing HSP47 binding. The pathogenic effects of these non-glycine substitutions in bone are probably caused mostly by procollagen misfolding and its downstream effects.

Enzymes are important industrial catalysts whose use has evolved from simple degradation processes—conducted mostly with hydrolases dissolved in the aqueous reaction medium—to processes of organic synthesis in which different classes of enzymes catalyze more complex reactions in different catalyst formats and reaction media. Extending the use of enzymes from the former low added-value processes to ones in which added-value is considerable is an exciting opportunity for biocatalysis; however, converting these remarkable physiological catalysts into robust process catalysts represents a complex technological challenge. Impressive advances both in enzyme production and enzyme molecular (re)design has opened a whole new field of enzyme use that projects into the fine chemicals and pharmaceutical industries where the outstanding properties of enzymes in terms of molecular precision are highly appreciated. Enzyme processes are compliant with green chemistry principles representing another important asset of biocatalysis. This chapter describes the evolution of enzyme catalysis, its present status and future prospects. Special emphasis is made on its impact on processes of organic synthesis and in non-conventional reaction media. Advances in the field related to the use of enzymes as industrial catalysts as well as the present and future challenges are analyzed in a hopefully unbiased perspective.

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This study is an overview of the state of research on the process of neolithisation of the northwesterncorner of Morocco. Particularly noteworthy are the recentfindings of a Spanish-Moroccan team in theframework of the AGRIWESTMED project carried out between 2011 and 2013 for the most part at thecaves of Magharat el-Khil (Tangier), Kaf Taht el-Ghar (Tetouan) and Ifri n'Amr or Moussa (Khemisset).These excavations brought to light occupations from the Moroccan Early Neolithic Impressed-Cardialware complex, levels that correspond to the earliest horizon of agricultural and animal husbandrypractices in the northwestern corner of Africa.

[EN] The period comprising the end of the Early Neolithic and the Middle Neolithic, dated broadly within the fifth millennium cal BC, corresponds to an interval that remains largely unknown in the extreme northwestern tip of Africa. This situation contrasts with that of the Early Neolithic, a period characterised by the earliest evidence of the diffusion of a productive economy, cultivated plants and domestic animals. The paucity of data for these later phases can be explained in part by the lack of secure contexts and sequences based on radiocarbon datings of short-lived samples. The current study presents the results of the excavations of ElKhil Caves B and C that yield materials allowing reevaluation of the chronology of a type of ceramic known as Ashakar ware. The study also identifies two traditions in the northern Moroccan Middle Neolithic. The first is heir to the so-called Impressa Mediterranean ware and rooted in the Cardial Neolithic, while the second is characterised by roulette cord impressions, red slip and tunnel lugs and probably rooted in the region of the Sahara, and has no technological precedents in the study area., [FR] La fin du Néolithique ancien et le Néolithique moyen, correspondant au Ve millénaire av. n. è. (dates calibrées), demeure largement méconnue à l’extrême nord-ouest de l’Afrique. Cette situation contraste avec le Néolithique ancien qui est marqué par les premiers indices de la diffusion d’une économie de production basée sur la culture des plantes et la domestication. Le manque de données pour ces phases plus récentes peut notamment s’expliquer par l’absence de contextes sûrs ainsi que la rareté des datations radiocarbones d’échantillons organiques de courte durée de vie. Cette étude présente les données issues des fouilles des grottes El-Khil B et C (Maroc) qui ont livré des assemblages mobiliers qui permettent de revoir la chronologie de la céramique de type Achakar. L’étude met également en évidence deux traditions dans le nord du Maroc au cours du Néolithique moyen. La première découle de la tradition de la céramique imprimée et est enracinée dans le néolithique Cardial connu dans le monde méditerranéen. La seconde est caractérisée par des céramiques décorées à roulette de cordelette enroulée, un engobe rouge et des anses « funiculaires ». Ces influences seraient probablement originaires de la région saharienne et sont sans précédents technologiques dans la zone d’étude, The research was jointly funded by the Ministry of Foreign Affairs with a grant awarded for the call for Excavations Abroad 2011 by the AGRIWESTMED ERC-EdG project of the European Research Council as well as through the project BOrígenes y expansión de la agricultura en el sur peninsular y norte de Marruecos: aportaciones desde la arqueobotánica y la genética (HAR 2008-01920 HIST)^ coordinated by Leonor PeñaChocarro (Peña-Chocarro et al. 2013). RMMS work has been funded by the CSIC PIE 201510E015 BPrimeras comunidades campesinas en el norte de África^ (2015) and by the Junta de Andalucía research project of excellence BHUM-1510: Dieta y movilidad en la Prehistoria Reciente Andaluza^ (2016-2017). The GPJ research was carried out within the postdoctoral contract FPDI-2013-16034 and IJCI-2015-25082 funded by the Spanish Ministerio de Economía y Competitividad. SPG was supported by University of Valencia (subprograma Atracció de Talent - Contractes Postdoctorals). The radiocarbon dating Beta424638 was carried out in the framework of the project BMolecular Archaeology: Carbon Isotope Analysis of Amino Acids as a Means to Investigate Diets, Physiology, Metabolism and Palaeoenvironment^ coordinated by Dr. Colin Smith and funded by the ARC Future Fellowship (FT 0992258) 2010-2014

Summary Introduction What is the current status of photodynamic therapy (PDT) with regard to treating malignant brain tumors? Despite several decades of effort, PDT has yet to achieve standard of care. Purpose The questions we wish to answer are: where are we clinically with PDT, why is it not standard of care, and what is being done in clinical trials to get us there. Method Rather than a meta-analysis or comprehensive review, our review focuses on who the major research groups are, what their approaches to the problem are, and how their results compare to standard of care. Secondary questions include what the effective depth of light penetration is, and how deep can we expect to kill tumor cells. Current results A measurable degree of necrosis is seen to a depth of about 5 mm. Cavitary PDT with hematoporphyrin derivative (HpD) results are encouraging, but need an adequate Phase III trial. Talaporfin with cavitary light application appears promising, although only a small case series has been reported. Foscan for fluorescence guided resection (FGR) plus intraoperative cavitary PDT results were improved over controls, but are poor compared to other groups. 5-Aminolevulinic acid-FGR plus postop cavitary HpD PDT show improvement over controls, but the comparison to standard of care is still poor. Conclusion Continued research in PDT will determine whether the advances shown will mitigate morbidity and mortality, but certainly the potential for this modality to revolutionize the treatment of brain tumors remains. The various uses for PDT in clinical practice should be pursued.

Lactulose and galacto-oligosaccharides (GOS) are well recognized prebiotics derived from lactose. In the synthesis of lactulose with β-galactosidases GOS are also produced, but the ratio of lactulose and GOS in the product can be tuned at will, depending on the operation conditions, so to obtain an optimal product distribution in terms of prebiotic potential. The selectivity of fermentation of each carbohydrate alone as well as mixtures of both was determined using pH-controlled anaerobic batch cultures with faecal inoculum. Within the experimental range considered, lactulose/GOS molar ratio of 4 resulted in the highest selectivity for Bifidobacterium and Lactobacillus/Enterococcus, so this ratio was selected as the target for the synthesis of lactulose from fructose and lactose with Aspergillus oryzae β-galactosidase. Synthesis was optimized using response surface methodology, considering temperature, initial concentrations of acceptor sugars and fructose/lactose molar ratio as key variables, with the aim of maximizing lactulose yield at the optimal product distribution in terms of prebiotic potential (lactulose/GOS molar ratio of 4). Under optimal conditions (50°C, 50%w/w total initial concentrations of sugars and fructose/lactose molar ratio of 6.44), lactulose yield of 0.26g of lactulose produced per g of initial lactose was obtained at the optimal product distribution.

The development and survival of male germ cells depend on the antioxidant capacity of the seminiferous tubule. Glutathione (GSH) plays an important role in the antioxidant defenses of the spermatogenic epithelium. Autophagy can act as a pro-survival response during oxidative stress or nutrient deficiency. In this work, we evaluated whether autophagy is involved in spermatogonia-type germ cell survival during severe GSH deficiency. We showed that the disruption of GSH metabolism with l-buthionine-(S,R)-sulfoximine (BSO) decreased reduced (GSH), oxidized (GSSG) glutathione content, and GSH/GSSG ratio in germ cells, without altering reactive oxygen species production and cell viability, evaluated by 2',7'-dichlorodihydrofluorescein (DCF) fluorescence and exclusion of propidium iodide assays, respectively. Autophagy was assessed by processing the endogenous protein LC3I and observing its sub-cellular distribution. Immunoblot and immunofluorescence analysis showed a consistent increase in LC3II and accumulation of autophagic vesicles under GSH-depletion conditions. This condition did not show changes in the level of phosphorylation of AMP-activated protein kinase (AMPK) or the ATP content. A loss in S-glutathionylated protein pattern was also observed. However, inhibition of autophagy resulted in decreased ATP content and increased caspase-3/7 activity in GSH-depleted germ cells. These findings suggest that GSH deficiency triggers an AMPK-independent induction of autophagy in germ cells as an adaptive stress response.

Ruptura Prematura de Membranas - Etiopatogenia, Uso de antibióticos, Manejo en pretérmino, Manejo a término, Cuidados del recién nacido.

Ascorbic acid is transported into cells by the sodium-coupled vitamin C transporters (SVCTs). Recently, we obtained evidence of differential regulation of SVCT expression in response to acute oxidative stress in cells from species that differ in their capacity to synthesize vitamin C, with a marked decrease in SVCT1 mRNA and protein levels in rat hepatoma cells that was not observed in human hepatoma cells. To better understand the regulatory aspects involved, we performed a structural and functional analysis of the proximal promoter of the SVCT1 rat gene. We cloned a 1476-bp segment containing the proximal promoter of the rat SVCT1 gene and generated deletion-derived truncated promoters of decreasing sizes and mutant promoters by modification of consensus binding sites for transcription factors by site-directed mutagenesis. We next analyzed their capacity to direct the transcription of a reporter gene after transfection into rat H4IIE and human HepG2 hepatoma cells, in experiments involving the coexpression of transcription factors whose consensus binding sequences are present in the SVCT1 promoter. This analysis revealed the presence of two critical cis-regulatory elements of the transcriptional activity of the rat SVCT1 gene promoter, sites containing consensus sequences for the binding of the transcription factors Bach1 and HNF4 that are not present in equivalent locations in the human SVCT1 gene promoter. Moreover, a consensus site for HNF1 that is crucial for the regulation of the human SVCT1 promoter is present in the SVCT1 rat promoter but has no effect on its transcriptional activity. These findings imply that regulation of vitamin C metabolism in the rat, a species with the capacity to synthesize large amounts of ascorbic acid, may differ from that of humans, a species that must obtain ascorbic acid from the diet through a transport mechanism that depends on proper SVCT1 expression.

Parto Prematuro 28-38 semanas - Epidemiología, Rol de la infección bacteriana, Vías del parto, Manejo del recién nacido.

β-Galactosidases exhibit both hydrolytic and transgalactosylation activities; the former has been used traditionally for the production of delactosed milk and dairies, while the latter is being increasingly used for the synthesis of lactose-derived oligosaccharides: balance between both activities was highly dependent on the enzyme origin: β-galactosidases from Aspegillus oryzae and Bacillus circulans exhibited high transgalactosylation activity, while those from one from Kluyveromyces exhibited high hydrolytic activity but quite low transgalactosylation activity. Also the affinity for the donors (lactose or lactulose) and the acceptors (lactose, lactulose or fructose) of transgalactosylated galactose was dependent on the enzyme origin, as reflected by the Michaelis constants obtained in the synthesis of galacto-oligosaccharides, fructosyl-galacto-oligosaccharides and lactulose. Finally, the balance between transgalactosylation and hydrolytic activities of β-galactosidases could be tuned by changing the concentration of galactose donor.

Presentamos un avance al analisis estratigrafico y contextual de quince estructuras negativas espacialmente relacionadas y asociables en tres grupos, datables en el III milenio cal. a.C.. Ello nos ha permitido establecer una diversificacion funcional de los contextos desde estructuras de habitacion y de almacenamiento hasta usos funerarios, simbolicos, de produccion, consumo y desecho en el interior del poblado.

Recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase pathway inhibitors, anticytotoxic T lymphocyte-associated antigen-4, and programmed cell death protein 1/programmed cell death ligand 1 (PD-L1) pathway-blocking antibodies, as well as combination strategies, all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with melanoma. One promising new treatment modality is based on the use of immunomodulatory monoclonal antibodies that enhance the function of components of the antitumor immune response such as T cells or block immunologic checkpoints that restrain effective antitumor immunity. Program death-1 receptor and its ligand, PD-L1, is a major mechanism by which a tumor suppresses T cell-mediated antitumor immune responses. Studies in mice have shown that GK-1, an 18 amino acid peptide from Taenia crassiceps cisticerci, has the potential to be used as a primary or adjuvant component for the treatment of cancers by stimulating proinflammatory cytokines. The authors hypothesized that treatment with GK-1 in combination with anti-PD-L1 will increase survival in mice bearing melanoma tumors. C57BL/6 mice were injected with B16-F10-luc2 cells and separated into four groups: control, GK-1, anti-PD-L1, and GK-1/anti-PD-L1. The tumor sizes were measured and monitored using calipers and bioluminescence. The GK-1 peptide in combination with anti-PD-L1 showed significantly longer survival (34 days) compared with the other groups (23-27 days). This means an increase; survival increased 47.82% in the mice treated with GK-1+anti-PD-L1, 21.7% in mice treated with GK-1 alone, and 6.08% in those mice treated with anti-PD-L1 only. Blood samples were collected at days 0, 14, and at euthanization or end of the experiment and monitored for cytokines using mouse-specific V-PLEX Proinflammatory Panel. A decrease in TNF-α, IL-4, IL-5, IL-6, and IL-10 serum levels was observed in the GK-1/anti-PD-L1 combination group that may explain the beneficial effects of the combination treatment in prolonging the life of mice bearing melanoma. The data indicate that GK-1/anti-PD-L1 combined therapy affectively increases survival and warrants further clinical investigations.

ResumenAntecedentesEl primer caso de perforación intestinal por metástasis de cáncer pulmonar, fue reportado en 1957. Las metástasis intestinales se reportan hasta en el 1.8% de los casos. La presentación clínica más frecuente es la obstrucción intestinal.Caso clínicoPaciente masculino de 89 años de edad, con antecedente de carcinoma mucoepidermoide de pulmón de alto grado, de 2 meses de diagnóstico. Acude al hospital con cuadro clínico de 3 días de evolución, con dolor abdominal de tipo cólico, difuso, de moderada a severa intensidad, acompañado de náuseas y vómito de contenido gastrobiliar y evacuaciones melénicas en 2 ocasiones. A la exploración física se encuentra: taquicárdico, taquipneico y con datos de abdomen agudo. Reporte de laboratorio: leucocitos 24,900 células por mm3, neutrófilos 87%. Se realizó laparotomía exploradora, encontrándose tumor perforado a 15cm del ángulo de Treitz. Se realizó resección intestinal y anastomosis primaria. Reporte histopatológico de carcinoma mucoepidermoide de alto grado, intestino delgado y mesenterio con límites quirúrgicos sin neoplasia. El paciente tuvo mala evolución por desarrollar neumonía nosocomial, lo que resultó en su fallecimiento.ConclusiónSon pocos los casos de metástasis intestinal reportados a nivel mundial; en México este es el primer caso reportado. Clínicamente se manifestó con sangrado de tubo digestivo y perforación intestinal que requirió cirugía de urgencia, en la que se realizó resección intestinal con anastomosis primaria. Finalmente, el paciente falleció por neumonía nosocomial.AbstractBackgroundThe first reported case of intestinal perforation secondary to metastatic lung carcinoma was reported in 1957. Intestinal metastases are present in up to 1.8% of the cases, with small bowel obstruction as the most common clinical presentation.Clinical caseAn 89 year-old male, who was diagnosed with a high-grade pulmonary mucoepidermoid tumour 2 months previously. The patient was admitted to the hospital for 3 days due to diffuse colic abdominal pain of moderate to severe intensity, accompanied by nausea and gastric vomiting, as well as 2 episodes of bloody bowel movements. On physical examination, the patient was noted to have tachycardia and tachypnoea, as well as clinical signs of acute abdomen. He had white cells of 24,900 per mm3, and 87% neutrophils. Exploratory laparotomy was performed, which showed a bowel perforation associated with a tumour mass 15cm beyond the angle of Treitz. Bowel resection and primary anastomosis were performed. The histopathological analysis reported the diagnosis of a high-grade mucoepidermoid tumour with small bowel and mesentery with disease-free surgical margins. Unfortunately the patient had a fatal outcome secondary to hospital-acquired pneumonia.ConclusionThe cases of metastases to small bowel are extremely rare, and to our knowledge this is first case reported in Mexico. The patient described went to the emergency room with gastrointestinal bleed and intestinal perforation that required urgent surgical intervention with small bowel resection and primary anastomosis. Unfortunately the patient died secondary to hospital acquired pneumonia.

Significance The gene pool of modern Europeans was shaped through prehistoric migrations that reached the Western Mediterranean last. Obtaining biomolecular data has been challenging due to poor preservation related to adverse climatic conditions in this region. Here, we study the impact of prehistoric (Neolithic–Bronze Age) migrations in Iberia by analyzing genomic and dietary data, demonstrating that farming practices were introduced by a population genetically distinct from the first farmers in central and northern Europe. After recovering from a founder bottleneck, these first farmers mixed with local hunter-gatherers. Finally, post-Neolithic migrations had a much smaller impact on the Iberian gene pool than they had in other parts of Europe. Stable isotope analysis reveals a homogenous terrestrial diet throughout this period., Population genomic studies of ancient human remains have shown how modern-day European population structure has been shaped by a number of prehistoric migrations. The Neolithization of Europe has been associated with large-scale migrations from Anatolia, which was followed by migrations of herders from the Pontic steppe at the onset of the Bronze Age. Southwestern Europe was one of the last parts of the continent reached by these migrations, and modern-day populations from this region show intriguing similarities to the initial Neolithic migrants. Partly due to climatic conditions that are unfavorable for DNA preservation, regional studies on the Mediterranean remain challenging. Here, we present genome-wide sequence data from 13 individuals combined with stable isotope analysis from the north and south of Iberia covering a four-millennial temporal transect (7,500–3,500 BP). Early Iberian farmers and Early Central European farmers exhibit significant genetic differences, suggesting two independent fronts of the Neolithic expansion. The first Neolithic migrants that arrived in Iberia had low levels of genetic diversity, potentially reflecting a small number of individuals; this diversity gradually increased over time from mixing with local hunter-gatherers and potential population expansion. The impact of post-Neolithic migrations on Iberia was much smaller than for the rest of the continent, showing little external influence from the Neolithic to the Bronze Age. Paleodietary reconstruction shows that these populations have a remarkable degree of dietary homogeneity across space and time, suggesting a strong reliance on terrestrial food resources despite changing culture and genetic make-up.

The use of seashells for the decoration of pottery from the sixth millennium cal BC is well known in the western Mediterranean, with the emergence of so-called Cardial Pottery. Actually, the most discussed issue up until now has been the use of bivalves for impressed decoration. However, the experimental approach followed in the present study provides for the first time clear evidence for the utilization of a very specific group of shells as tools for the decoration of some of the early pottery productions in northwest Africa. In particular, we propose the use of cowry, a gastropod family with a well-known ideological and symbolic role in many human cultures around the world. Also, it is suggested that cowry was used for making impressed wares on the opposite European shore. The implications for reconstruction of Neolithic diffusion along both the European and African coasts of the Mediterranean are of great significance., This study was carried out within the framework of the AGRIWESTMED project (Origins and spread of agriculture in the south-western Mediterranean region) funded by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007e2013/ERC Grant Agreement 230561) coordinated by Leonor Peña-Chocarro. Rafael M. Martínez Sánchez’s work has been funded by the Consejo Superior de Investigaciones Científicas Proyecto Intramural Especial (201510E015 “Primeras comunidades campesinas en el norte de África”). Guillem Pérez Jordà’s work has been carried out within the postdoctoral contract (FPDI-2013-16034) funded by the Ministerio de Economía y Competitividad of the Spanish government.

Despite the fundamental importance of the redox metabolism of mitochondria under normal and pathological conditions, our knowledge regarding the transport of vitamin C across mitochondrial membranes remains far from complete. We report here that human HEK-293 cells express a mitochondrial low-affinity ascorbic acid transporter that molecularly corresponds to SVCT2, a member of the sodium-coupled ascorbic acid transporter family 2. The transporter SVCT1 is absent from HEK-293 cells. Confocal colocalization experiments with anti-SVCT2 and anti-organelle protein markers revealed that most of the SVCT2 immunoreactivity was associated with mitochondria, with minor colocalization at the endoplasmic reticulum and very low immunoreactivity at the plasma membrane. Immunoblotting of proteins extracted from highly purified mitochondrial fractions confirmed that SVCT2 protein was associated with mitochondria, and transport analysis revealed a sigmoidal ascorbic acid concentration curve with an apparent ascorbic acid transport Km of 0.6mM. Use of SVCT2 siRNA for silencing SVCT2 expression produced a major decrease in mitochondrial SVCT2 immunoreactivity, and immunoblotting revealed decreased SVCT2 protein expression by approximately 75%. Most importantly, the decreased protein expression was accompanied by a concomitant decrease in the mitochondrial ascorbic acid transport rate. Further studies using HEK-293 cells overexpressing SVCT2 at the plasma membrane revealed that the altered kinetic properties of mitochondrial SVCT2 are due to the ionic intracellular microenvironment (low in sodium and high in potassium), with potassium acting as a concentration-dependent inhibitor of SVCT2. We discarded the participation of two glucose transporters previously described as mitochondrial dehydroascorbic acid transporters; GLUT1 is absent from mitochondria and GLUT10 is not expressed in HEK-293 cells. Overall, our data indicate that intracellular SVCT2 is localized in mitochondria, is sensitive to an intracellular microenvironment low in sodium and high in potassium, and functions as a low-affinity ascorbic acid transporter. We propose that the mitochondrial localization of SVCT2 is a property shared across cells, tissues, and species.

e comparan los pastizales en una finca ganadera y cuartones con diferentes por cientos de leguminosas, en cuanto al tiempo de reposo, su calidad nutricional y la producción de leche con vacas en pastoreo en la seca. Se utilizaron cuatro cuartones de 0,45 ha/tratamiento de composición botánica del pasto, como réplicas de pastizales de Cynodon nlemfuensis, Vanderysty Panicum máximum, Jacq y, asociadas a ellos, leguminosas de los géneros Centrosema, Desmodium, Macroptilium y Teramnuz. La carga fue de 1,09 vacas/ha y los animales recibieron 16 % de PB a razón de 0,46 kg a partir del tercer kilogramo producido y forraje cortado en comedero. El diseño fue completamente aleatorio y se realizó análisis de varianza simple para el procesamiento estadístico de los datos. Las poblaciones incrementadas de leguminosas influyeron en el tiempo de reposo (P < 0,05) a favor de acelerar el tiempo adecuado para la ocupación del cuartón y mejoraron la calidad y respuesta láctea de las vacas en el período. El factor presencia de las leguminosas en el pastizal influyó parcialmente en la calidad, consumo y respuesta animal en rendimiento lechero, a favor de mayor presencia de leguminosas (37 %) con 9,1 kg/vaca/día.

Lactulose synthesis was done in repeated-batch mode with Aspergillus oryzae β-galactosidase immobilized in glyoxyl-agarose (GA-βG), amino-glyoxyl-agarose (Am-GA-βG) and chelate-glyoxyl-agarose (Che-GA-βG), at fructose/lactose molar ratios of 4, 12 and 20. Highest yields of lactulose in batch were obtained with Che-GA-βG (0.21, 0.29 and 0.32g·g-1) for 4, 12 and 20 fructose/lactose molar ratios respectively; when operating in 10 repeated batches highest product to biocatalyst mass ratios were obtained with Am-GA-βG (1.82, 2.52 and 2.7g·mg-1), while the lowest were obtained with Che-GA-βG (0.25, 0.33 and 0.39g·mg-1). Operational stability of Am-GA-βG was higher than GA-βG and Che-GA-βG and much higher than that of the free enzyme, at all fructose/lactose molar ratios evaluated. Efficiency of biocatalyst use for GA-βG were 64.4, 35.5 and 18.4kglactulose/gprotein, for fructose/lactose molar ratios of 4, 12 and 20 respectively, while for Che-GA-βG were 1.46, 1.05 and 0.96kglactulose/gprotein.

HIGHLIGHTS Short-term incubation with insulin increases the L-arginine transport in HUVECs. Short-term incubation with insulin increases the NO synthesis in HUVECs. Insulin induces relaxation in human placental vascular bed. Insulin attenuates the constriction induced by hydrogen peroxide in human placenta. The relaxation induced by insulin is dependent on BKCa channels activity in human placenta. Insulin induces relaxation in umbilical veins, increasing the expression of human amino acid transporter 1 (hCAT-1) and nitric oxide synthesis (NO) in human umbilical vein endothelial cells (HUVECs). Short-term effects of insulin on vasculature have been reported in healthy subjects and cell cultures; however, its mechanisms remain unknown. The aim of this study was to characterize the effect of acute incubation with insulin on the regulation of vascular tone of placental vasculature. HUVECs and chorionic vein rings were isolated from normal pregnancies. The effect of insulin on NO synthesis, L-arginine transport, and hCAT-1 abundance was measured in HUVECs. Isometric tension induced by U46619 (thromboxane A2 analog) or hydrogen peroxide (H2O2) were measured in vessels previously incubated 30 min with insulin and/or the following pharmacological inhibitors: tetraethylammonium (KCa channels), iberiotoxin (BKCa channels), genistein (tyrosine kinases), and wortmannin (phosphatidylinositol 3-kinase). Insulin increases L-arginine transport and NO synthesis in HUVECs. In the placenta, this hormone caused relaxation of the chorionic vein, and reduced perfusion pressure in placental cotyledons. In vessels pre-incubated with insulin, the constriction evoked by H2O2 and U46619 was attenuated and the effect on H2O2-induced constriction was blocked with tetraethylammonium and iberiotoxin, but not with genistein, or wortmannin. Insulin rapidly dilates the placental vasculature through a mechanism involving activity of BKCa channels and L-arginine/NO pathway in endothelial cells. This phenomenon is related to quick increases of hCAT-1 abundance and higher capacity of endothelial cells to take up L-arginine and generate NO.

La investigación tuvo coma objetivo determinar el grado de influencia de Técnicas de Asepsia y Antisepsia en la recuperación del RN en el servicio de Neonatología.Materiales y métodos: Se realizó un estudio descriptivo, cualitativo de corte transversal en el Servicio de neonatología del Hospital Marco Vinicio Iza durante el cuarto trimestre del 2010. Se evaluó al personal a través de técnicas como la encuesta y la observación, las cuales estuvieron encaminadas a obtener información sobre sus conocimientos, practicas, y actitud sobre las técnicas de Asepsia y Antisepsia; seguido de esto se realizó el análisis e interpretación de datos.Resultados: Con la información recopilada se llegó a deducir que el personal que labora en este servicio no cuenta con la calidad apropiada de conocimientos sobre las técnicas de Asepsia y Antisepsia influyendo en la recuperación del neonato negativamente, debido a que no son aplicadas en su totalidad, ya sea por no contar con el material adecuado, o por descuido del mismo personal.Con el propósito de dar vigilancia al cumplimiento de las técnicas básicas de Asepsia y Antisepsia en el servicio de Neonatología, y la prevención de las enfermedades intrahospitalarias favoreciendo la recuperación del neonato, se realizó un ciclo rápido de capacitación iniciando con cursos de preparación y evaluación periódica al personal del área en estudio.

Background: R453C is a mutation in human cardiac myosin and is associated with a high incidence of sudden cardiac death. Results: R453C alters few kinetic parameters, except for the conformational changes associated with ATP binding and hydrolysis. Conclusion: The closure of switch-2 on ATP is disrupted by R453C. Significance: This is the first detailed kinetic analysis of the motor domain of the human β-cardiac myosin carrying the R453C mutation., The human hypertrophic cardiomyopathy mutation R453C results in one of the more severe forms of the myopathy. Arg-453 is found in a conserved surface loop of the upper 50-kDa domain of the myosin motor domain and lies between the nucleotide binding pocket and the actin binding site. It connects to the cardiomyopathy loop via a long α-helix, helix O, and to Switch-2 via the fifth strand of the central β-sheet. The mutation is, therefore, in a position to perturb a wide range of myosin molecular activities. We report here the first detailed biochemical kinetic analysis of the motor domain of the human β-cardiac myosin carrying the R453C mutation. A recent report of the same mutation (Sommese, R. F., Sung, J., Nag, S., Sutton, S., Deacon, J. C., Choe, E., Leinwand, L. A., Ruppel, K., and Spudich, J. A. (2013) Proc. Natl. Acad. Sci. U.S.A. 110, 12607–12612) found reduced ATPase and in vitro motility but increased force production using an optical trap. Surprisingly, our results show that the mutation alters few biochemical kinetic parameters significantly. The exceptions are the rate constants for ATP binding to the motor domain (reduced by 35%) and the ATP hydrolysis step/recovery stroke (slowed 3-fold), which could be the rate-limiting step for the ATPase cycle. Effects of the mutation on the recovery stroke are consistent with a perturbation of Switch-2 closure, which is required for the recovery stroke and the subsequent ATP hydrolysis.

Fed-batch synthesis of galacto-oligosaccharides (GOS) from lactose with β-galactosidase from Aspergillus oryzae was evaluated experimentally and reaction yield was maximized via optimal control technique. The optimal lactose and enzyme feed flow rate profiles were determined using a model for GOS synthesis previously reported by the authors. Experimentally it was found that fed-batch synthesis allowed an increase on the maximum total GOS concentration from 115 (batch synthesis) to 218 g L−1 as consequence of the increase in total sugars concentration from 40 to 58% w/w. Such high concentration of total sugars was not attainable in batch operation because of the low solubility of lactose at the reaction temperature (40°C). Simulations predicted a GOS yield of 32.5 g g−1 in fed-batch synthesis under optimal conditions, while experimentally the same yield as in batch synthesis was obtained (28 g g−1). Besides, an enrichment of total oligosaccharides in GOS with a high polymerization degree (GOS-5 and GOS-6) was observed in the fed-batch synthesis. Experimental profiles for all sugars were similar to the ones predicted by simulation, which supports the use of this methodology for the optimization of GOS synthesis. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 30:59–67, 2014

The therapeutic efficacy of a synthetic parasite-derived peptide GK1, an immune response booster, was evaluated in a mouse melanoma model. This melanoma model correlates with human stage IIb melanoma, which is treated with wide surgical excision; a parallel study employing a surgical treatment was carried out as an instructive goal.C57BL/6 mice were injected subcutaneously in the flank with 2×10(5) B16-F10 murine melanoma cells. When the tumors reached 20 mm3, mice were separated into two different groups; the GK1 group, treated weekly with peritumoral injections of GK1 (10 μg/100 μL of sterile saline solution) and the control group, treated weekly with an antiseptic peritumoral injection of 100 μL of sterile saline solution without further intervention. All mice were monitored daily for clinical appearance, tumor size, and survival. Surgical treatment was performed in parallel when the tumor size was 20 mm3 (group A), 500 mm3 (group B), and500 mm3 (group C).The GK1 peptide effectively increased the mean survival time by 9.05 days, corresponding to an increase of 42.58%, and significantly delayed tumor growth from day 3 to 12 of treatment. In addition, tumor necrosis was significantly increased (p0.05) in the treated mice. The overall survival rates obtained with surgical treatment at 6 months were 83.33% for group A, 40% for group B, and 0% for group C, with significant differences (p0.05) among the groups.The GK1 peptide demonstrated therapeutic properties in a mouse melanoma model, as treatment resulted in a significant increase in the mean survival time of the treated animals (42.58%). The potential for GK1 to be used as a primary or adjuvant component of chemotherapeutic cocktails for the treatment of experimental and human cancers remains to be determined, and surgical removal remains a challenge for any new experimental treatment of melanoma in mouse models.

Batch synthesis of fructosyl-galacto-oligosaccharides from lactulose was performed with commercial β-galactosidase preparations from Aspergillus oryzae, Kluyveromyces lactis and Bacillus circulans. The enzyme from A. oryzae produced the highest yield and specific productivity of synthesis, being selected for further studies. Optimization of fructosyl-galacto-oligosaccharides synthesis was carried out using response surface methodology, considering temperature and initial sugar concentration as variables and yield and specific productivity as response parameters. Maximum yield of 0.41 g g−1 fructosyl-galacto-oligosaccharides was obtained at 70 °C and 60% w/w lactulose concentration, while maximum specific productivity of 1.2 g h−1 mg−1 was obtained at 70 °C and 40% w/w lactulose concentration.

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We combine the six high-resolution Aquarius dark matter simulations with a semi-analytic galaxy formation model to investigate the properties of the satellites of Milky Way-like galaxies. We find good correspondence with the observed luminosity function, luminosity-metallicity relation and radial distribution of the Milky Way satellites. The star formation histories of the dwarf galaxies in our model vary widely, in accordance with what is seen observationally. Ram-pressure stripping of hot gas from the satellites leaves a clear imprint of the environment on the characteristics of a dwarf galaxy. We find that the fraction of satellites dominated by old populations of stars matches observations well. However, the internal metallicity distributions of the model satellites appear to be narrower than observed. This may indicate limitations in our treatment of chemical enrichment, which is based on the instantaneous recycling approximation. Our model works best if the dark matter halo of the Milky Way has a mass of ~8 x 10^11 Msun, in agreement with the lower estimates from observations. The galaxy that resembles the Milky Way the most also has the best matching satellite luminosity function, although it does not contain an object as bright as the SMC or LMC. Compared to other semi-analytic models and abundance matching relations we find that central galaxies reside in less massive haloes, but the halo mass-stellar mass relation in our model is consistent both with hydrodynamical simulations and with recent observations., Comment: 20 pages, 16 figures. MNRAS in press. Minor changes in this version to match the version in press

This work studies the ambulance location problem for the Red Cross in Tijuana, Baja California , Mexico. The solution to the ambulance location problem is to optimally locate all available ambulances within the city such that coverage of the city population is maximized and a quick response to any emergency is ensured. The problem is posed using three different coverage models; namely the Location Set Covering Model (LSCM), the Maximal Covering Location Problem (MCLP) and the Double Standard Model (DSM), also we proposed robust versions of each model, where the goal was to find a single solution that might provide optima coverage in several different scenarios. Using real-world data collected from over 44,000 emergency calls received by the Red Cross of Tijuana, several scenarios were generated that provide different perspectives of the demand throughout the city, considering such factors as the time of day, work and off-days, geographical organization and call priority. These scenarios are solved using Integer Linear Programming and the solutions are compared with the current locations used by the Red Cross. Results show that demand coverage and response times can be substantially improved without additional resources.

Lactose-derived non-digestible oligosaccharides are prominent components of functional foods. Among them, galacto-oligosaccharides (GOS) outstand for being prebiotics whose health-promoting effects are supported on strong scientific evidences, having unique properties as substitutes of human milk oligosaccharides in formulas for newborns and infants. GOS are currently produced enzymatically in a kinetically-controlled reaction of lactose transgalactosylation catalyzed by β-galactosidases from different microbial strains. The enzymatic synthesis of GOS, although being an established technology, still offers many technological challenges and opportunities for further development that has to be considered within the framework of functional foods which is the most rapidly expanding market within the food sector. This paper presents the current technological status of GOS production, its main achievements and challenges. Most of the problems yet to be solved refer to the rather low GOS yields attainable that rarely exceed 40 %, corresponding to lactose conversions around 60 %. This means that the product or reaction (raw GOS) contains significant amounts of residual lactose and monosaccharides (glucose and galactose). Efforts to increase such yields have been for the most part unsuccessful, even though improvements by genetic and protein engineering strategies are to be expected in the near future. Low yields impose a burden on downstream processing to obtain a GOS product of the required purity. Different strategies for raw GOS purification are reviewed and their technological significance is appraised.

© The Author(s) 2016. To increase environmental health literacy (EHL) and leadership skills in Latino youth in Salinas, CA., we worked from 2012-2015 with 15 members of the CHAMACOS Youth Community Council (YCC), an outreach arm of a longitudinal study of impacts of environmental chemicals on children’s health. The YCC program provided hands-on research experiences related to Endocrine Disrupting Chemicals (EDCs) in cosmetics and their possible health effects. We use participatory research principles and Bloom’s Taxonomy of Educational Objectives to describe the development of EHC and leadership in the youth co-researchers. Using data from multiple qualitative sources, we explore the youths’ engagement in a wide range of research and action processes. Promising outcomes, including perceptions of improved youth self-esteem, EHL, leadership, and career orientation are discussed, as are challenges, such as time constraints and high priority youth concerns not addressed by the study. Implications for other youth-engaged participatory science and leadership programs are presented.

The liver has an extraordinary regenerative capacity in response to partial hepatectomy (PHx), which develops with neither tissue inflammation response nor alterations in the whole organism. This process is highly coordinated and it has been associated with changes in glutathione (GSH) metabolism. However, there are no reports indicating ascorbic acid (AA) levels after partial hepatectomy. AA and GSH act integrally as an antioxidant system that protects cells and tissues from oxidative damage and imbalance observed in a variety of diseases that affect the liver. Although rat hepatocytes are able to synthesize AA and GSH, which are the providers of AA for the whole organism, they also acquire AA from extracellular sources through the sodium-coupled ascorbic acid transporter-1 (SVCT1). Here, we show that hepatocytes from rat livers subjected to PHx increase their GSH and AA levels from 1 to 7 days post hepatectomy, whose peaks precede the peak in cell proliferation observed at 3 days post-hepatectomy. The increase in both antioxidants was associated with higher expression of the enzymes involved in their synthesis, such as the modifier subunit of enzyme glutamine cysteine ligase (GCLM), glutathione synthetase (GS), gulonolactonase (GLN) and gulonolactone oxidase (GULO). Importantly, rat hepatocytes, that normally exhibit kinetic evidence indicating only SVCT1-mediated transport of AA, lost more than 90% of their capacity to transport it at day 1 after PHx without evidence of recovery at day 7. This observation was in agreement with loss of SVCT1 protein expression, which was undetectable in hepatocytes as early as 2 h after PHx, with partial recovery at day 7, when the regenerated liver weight returns to normal. We conclude that after PHx, rat hepatocytes enhance their antioxidant capacity by increasing GSH and AA levels prior to the proliferative peak. GSH and AA are increased by de novo synthesis, however paradoxically hepatocytes from rat subjected to PHx also suppress their capacity to acquire AA from extracellular sources through SVCT1.

Background: Brain tumors represent a group of neoplasms arising from brain tissue, each with their own unique biology, prognosis, and treatment. Included in this group are neoplasms not arising from brain parenchyma, which encompass meningiomas, lymphomas, and metastatic disease from other primary sources (often referred to as secondary brain tumors). Despite the diverse group of neoplasms represented, most intracranial tumors follow similar clinical presentations and diagnostic workups. Methods: This review focuses on primary and secondary brain tumor epidemiology, imaging, and treatment modalities. In addition, we will highlight molecular genetic advances in the field that will help shape future treatment approaches. Results: Although tumors affecting the Central Nervous System (CNS) are relatively uncommon, they are often very difficult to treat and cause disproportionate morbidity and mortality. Many of these neoplasms are universally fatal and our ability to treat both benign and malignant tumors is still in its infancy. Our lack of effective treatment leaves many of our patients with few options. Conclusions: The combination of poor prognosis and lack of therapeutic options make further innovation and investigation a priority to improve clinical outcomes for patients suffering from CNS malignancies.

La necrópolis tardoantigua de época visigoda de La Orden-Seminario (Huelva) se encuentra entre los vestigios arqueológicos que han puesto de manifiesto la gran importancia de este yacimiento, y constituye una de las escasisimas evidencias sobre necrópolis rurales de esta clase con que contamos a nivel local y regional. Su hallazgo es de capital relevancia para el mejor conocimiento del ceremonial funerario establecido durante la Antigüedad tardía, un período histórico que hasta la fecha aún no ha sido bien definido y sobre el que existe un cierto vacío teórico, Late-Ancient Visigothic Era cemetery of La Orden-Seminario (Huelva) is found between archeological remains that revealed this archeological site great significance. This means this is one of the scarcest evidences of rural necropolis in this class we posses both on local and regional level. This finding is a key point for the best understanding of funerary ceremonies established during Late Antique Age, a historic period that until the date has not been well defined and in which exists a certain theoretical emptiness

Galactooligosaccharides (GOS) are the most relevant prebiotics synthesized from lactose. During the last decades, a number of processes have been reported for its industrial production using β-galactosidase as catalyst. However, economic and technical analyses are seldom published. This chapter analyzes a number of processes for GOS production considering two sources of β-galactosidase and several purification strategies from a technical and economic point of view. Among the purification alternatives, simulated moving bed chromatography and removal of unwanted mono and disaccharides by bioconversion with yeast are included. Process alternatives are compared within a common price framework using the minimum product selling price. Results show that the calculated minimum selling prices are well below the market prices for GOS, thus leaving room for marketing and distribution costs. Furthermore, the integration of GOS production to an existing dairy industry is analyzed focusing in plant capacity, installed equipment and market lactose and whey prices.