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El riesgo sanitario de los triatominos como vectores de Trypanosoma cruzi está relacionado con la domiciliación de especies originalmente selváticas que logran adaptarse a hábitats humanos, encontrando variadas fuentes de alimento y refugio. Para el control de estos insectos se utiliza la fumigación residual con insecticidas piretroides, pero debido a la resistencia de los triatominos a insecticidas químicos y altos costos de fumigaciones permanentes, alternativamente se ha probado con éxito el potencial de algunos hongos entomopatógenos como controladores biológicos. Sin embargo, se desconoce el efecto de dosis sub letales sobre parámetros reproductivos, siendo estos factores muy importantes en el crecimiento poblacional y colonización de nuevos hábitats. En este trabajo probamos el efecto de una concentración de conidios baja de Beauveria. bassiana (1 x 10⁸ conidios/ml) en los parámetros reproductivos de hembras de Meccus pallipennis inoculadas en el estadio adulto, contabilizando diariamente el número de huevos puestos y eclosionados en un periodo de 44 días. No se registró inhibición de la oviposición, todas las hembras pusieron huevos, pero la infección fúngica redujo un 63% la fertilidad de las hembras tratadas. El rendimiento reproductivo de las hembras control fue de 56.7 ± 3.8 huevos /hembra/vida mientras que el rendimiento de las hembras infectadas fue de 20.8 ± 2.9 huevos /hembra/vida encontrando diferencias significativas entre las medias de los grupos. (p

Acknowledgements: A.D-G. thanks the Fundacion Alfonso Martin Escudero for his postdoctoral fellowship. We thank Dr. Brooke Howitt for providing ovarian tissue. Figures 1, 3, and 4 were created using BioRender., Funder: BRCA Foundation, Funder: V Foundation for Cancer Research; doi: http://dx.doi.org/10.13039/100001368, Funder: Stanford Cancer Institute, Innovation Award 2019, Funder: Stanford Cancer Institute, Innovation Award 2021, Funder: CRUK CC (crukcambridgecentre.org.uk), Funder: Fundacion Alfonso Martin Escudero, High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. Its diagnosis at advanced stage compounded with its excessive genomic and cellular heterogeneity make curative treatment challenging. Two critical therapeutic challenges to overcome are carboplatin resistance and lack of response to immunotherapy. Carboplatin resistance results from diverse cell autonomous mechanisms which operate in different combinations within and across tumors. The lack of response to immunotherapy is highly likely to be related to an immunosuppressive HGSOC tumor microenvironment which overrides any clinical benefit. Results from a number of studies, mainly using transcriptomics, indicate that the immune tumor microenvironment (iTME) plays a role in carboplatin response. However, in patients receiving treatment, the exact mechanistic details are unclear. During the past decade, multiplex single-cell proteomic technologies have come to the forefront of biomedical research. Mass cytometry or cytometry by time-of-flight, measures up to 60 parameters in single cells that are in suspension. Multiplex cellular imaging technologies allow simultaneous measurement of up to 60 proteins in single cells with spatial resolution and interrogation of cell-cell interactions. This review suggests that functional interplay between cell autonomous responses to carboplatin and the HGSOC immune tumor microenvironment could be clarified through the application of multiplex single-cell proteomic technologies. We conclude that for better clinical care, multiplex single-cell proteomic technologies could be an integral component of multimodal biomarker development that also includes genomics and radiomics. Collection of matched samples from patients before and on treatment will be critical to the success of these efforts.

Barcoding and pooling cells for processing as a composite sample are critical to minimize technical variability in multiplex technologies. Fluorescent cell barcoding has been established as a standard method for multiplexing in flow cytometry analysis. In parallel, mass-tag barcoding is routinely used to label cells for mass cytometry. Barcode reagents currently used label intracellular proteins in fixed and permeabilized cells and, therefore, are not suitable for studies with live cells in long-term culture prior to analysis. In this study, we report the development of fluorescent palladium-based hybrid-tag nanotrackers to barcode live cells for flow and mass cytometry dual-modal readout. We describe the preparation, physicochemical characterization, efficiency of cell internalization, and durability of these nanotrackers in live cells cultured over time. In addition, we demonstrate their compatibility with standardized cytometry reagents and protocols. Finally, we validated these nanotrackers for drug response assays during a long-term coculture experiment with two barcoded cell lines. This method represents a new and widely applicable advance for fluorescent and mass-tag barcoding that is independent of protein expression levels and can be used to label cells before long-term drug studies.

There is a growing trend in using saliva for SARS-CoV-2 detection with reasonable accuracy. We have studied the responses of IgA, IgG, and IgM in human saliva by directly comparing disease with control analyzing two-trace two-dimensional correlation spectra (2T2D-COS) employing Fourier transform infrared (FTIR) spectra. The findings show the decrease of IgG and IgM salivary antibodies in the 50, 60, 65, and 75-years samples. Among the various COVID-19 populations studied, the female 30 years group reveal defence mechanisms exhibited by IgM and IgA. Lipids and fatty acids decrease, resulting in lipid oxidation due to the SARS-CoV-2 in the samples studied. Study shows salivary thiocyanate plays defence against SARS-CoV-2 in male population in 25 and 35 age groups. The receiver operation characteristics statistical method shows a sensitivity of 98% and specificity 94% for the samples studied. The measure of accuracy computed as F1 score and G score has a high value which supports the validation of our study. The 2T2D-COS analysis has the potential to monitor the progression of immunoglobulin’s response function of COVID-19 with good accuracy, which could help in diagnosing clinical trials.

Wastewater management and treatment are key points in maintaining the quality and the sustainability of water resources. To preserve receiving water environments, efforts are being conducted to improve the treatment efficiency. Soil infiltration can therefore be used as a nature-based solution tertiary treatment, in some areas without surface water available, or with supplementary water bodies’ protection regulations. Secondary wastewater effluents (SWE) infiltration surfaces mainly consist of infiltration trenches or flood-meadows. Among the main issues encountered with soil infiltration, two can be highlighted: the possible low hydraulic conductivity induced by soil clogging, on the one hand, and the use of non-renewable draining materials such as pebbles or gravel to ensure the distribution of water in trenches, on the other hand. In France, in order to overcome those issues, stakeholders are now considering the replacement of the gravel with woodchips, a renewable biodegradable material, also prone to biodiversity in soils. If there is no woodchip-filled soil infiltration surfaces downstream wastewater treatment plant in France, woodchips are however used for decentralized wastewater treatment, even though no study has quantified precisely their efficiency. The understanding of the flow processes and the risk of preferential flows in the woodchip-filled infiltration trenches is a prerequisite for a proper management of these works.Our study aims at investigating flow regimes in woodchip-filled infiltration trenches. Several woodchip-filled infiltration trenches were studied and analyzed with regards to their infiltration capacity in four decentralized wastewater treatment sites, located in South-West of France on silty-clay soil. Measurements of infiltration capacity of the soil below the woodchips-filled trenches were conducted with infiltration tests according to the Beerkan method (Braud et al., 2005). On each site, two tests were conducted on the bottom of the infiltration trenches after extracting woodchips and two others in the soil at a lateral distance of 1 m from the infiltration trench at the same soil depth, in order to sample the same type of soil. The soil hydraulic functions, i.e., water retention and hydraulic conductivity curves, below the woodchips and in the natural soil profiles were then calculated using the BEST method (Angulo-Jaramillo et al., 2019) and compared. Our findings showed that the use of woodchips locally maintains or even enhances the infiltration rate in the soil below. Moreover, the hydraulic conductivity was 5 to 14 times higher (up to 8600 mm.d-1) in soils under woodchip-filled infiltration trenches than in the reference soils. To explain such positive effects, several hypothesis were formulated and discussed against physical, biogeochemical and ecological factors (woodchips organic amendment, suitable moisture conditions, earthworm communities’ activity). Dye tracer experiment, soil pit, and soil samples (chemical tracings and analyses) revealed the presence of preferential pathways induced by macro fauna and roots plants. An earthworm count showed that the majority of earthworms in the woodchips were 10 times higher than in the natural soil profile. Experiments also showed an organic carbon enrichment in woodchip-filled infiltration trenches soils that could lead to an improvement and stabilization of soils structure.

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that causes coronavirus disease-2019 (COVID-19) has provoked a global pandemic, mainly affecting the respiratory tract; however, a percentage of infected individuals can develop gastrointestinal (GI) symptoms. Some studies describe the development of GI symptoms and how they affect the progression of COVID-19. In this review, we summarize the main mechanisms associated with gut damage during infection by SARS-CoV-2 as well as other organs such as the liver and pancreas. Not only are host factors associated with severe COVID-19 but intestinal microbiota dysbiosis is also observed in patients with severe disease.

Gastrointestinal adenocarcinomas are one of the world’s deadliest cancers. Cancer stem cells and the tissue microenvironment are highly regulated by cell and molecular mechanisms. Cancer stem cells are essential for maintenance and progression and are associated with resistance to conventional treatments. This article reviews the current knowledge of the role of the microenvironment during the primary establishment of gastrointestinal adenocarcinomas in the stomach, colon, and rectum and its relationship with cancer stem cells. We also describe novel developments in cancer therapeutics, such as targeted therapy, and discuss the advantages and disadvantages of different treatments for improving gastrointestinal cancer prognosis.

Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with properties, such as self-renewal, differentiation, and tumorigenicity. CSCs have been proposed as a plausible therapeutic target as they are responsible for tumor recurrence, metastasis, and conventional therapy resistance. Selectively targeting CSCs is a promising strategy to eliminate the propagation of tumor cells and impair overall tumor development. Recent research shows that several immune cells play a crucial role in regulating tumor cell proliferation by regulating different CSC maintenance or proliferation pathways. There have been great advances in cellular immunotherapy using T cells, natural killer (NK) cells, macrophages, or stem cells for the selective targeting of tumor cells or CSCs in colorectal cancer (CRC). This review summarizes the CRC molecular profiles that may benefit from said therapy and the main vehicles used in cell therapy against CSCs. We also discuss the challenges, limitations, and advantages of combining conventional and/or current targeted treatments in the late stages of CRC.

Natural apatites have previously shown a great capacity for phosphate retention from wastewater. However, its fine particle size distribution may lead to a premature clogging of the filter. Accordingly, a granulated apatite product was developed and manufactured in order to control the particle size distribution of the media. Experiments were conducted on laboratory columns to assess their phosphorus retention capacity, to identify the processes involved in phosphorus retention and to evaluate their kinetic rates. The results showed phosphorus retention capacities of 10.5 and 12.4 g PO4-P·kg−1 and kinetic rate coefficients in the range of 0.63 and 0.23 h−1 involving lower values than those found for natural apatites in previous studies. Scanning Electron Microscopy images showed that apatite particles in the granules were embedded in the binder and were not readily accessible to act as seeds for calcium phosphate precipitation. The retention processes differ depending on the supersaturation of the solution with respect to calcium phosphate phases: at low calcium concentrations (69.8 ± 3.9 mg·L−1), hydroxyapatite precipitates fill up the porosity of the binder up to a depth of 100–300 μm from the granule surface; at higher calcium concentrations (112.7 ± 7.4 mg·L−1) precipitation occurs at the granule surface, forming successive layers of hydroxyapatite and carbonated calcium phosphates.

Mass cytometry is a highly multiparametric proteomic technology that allows the measurement and quantification of nearly 50 markers with single-cell resolution. Mass cytometry reagents are probes tagged with metal isotopes of defined mass and act as reporters. Metals are detected using inductively coupled plasma time-of-flight mass spectrometry (ICP-TOF-MS). Many different types of mass-tag reagents have been developed to afford myriad applications. We have classified these compounds into polymer-based mass-tag reagents, nonpolymer-based mass-tag reagents, and inorganic nanoparticles. Metal-chelating polymers (MCPs) are widely used to profile and quantify cellular biomarkers; however, both the range of metals that can be detected and the metal signals have to be improved. Several strategies such as the inclusion of chelating agents or highly branched polymers may overcome these issues. Biocompatible materials such as polystyrene and inorganic nanoparticles are also of profound interest in mass cytometry. While polystyrene allows the inclusion of a wide variety of metals, the high metal content of inorganic nanoparticles offers an excellent opportunity to increase the signal from the metals to detect low-abundance biomarkers. Nonpolymer-based mass-tag reagents offer multiple applications: cell detection, cell cycle property determination, biomarker detection, and mass-tag cellular barcoding (MCB). Recent developments have been achieved in live cell barcoding by targeting proteins (CD45, b2m, and CD298), by using small and nonpolar probes or by ratiometric barcoding. From this perspective, the principal applications, strengths, and shortcomings of mass-tag reagents are highlighted, summarized, and discussed, with special emphasis on mass-tag reagents for MCB. Thereafter, the future perspectives of mass-tag reagents are discussed considering the current state-of-the-art technologies.

We evaluated cell markers of oligodendrocyte-like cells (OLC) and neuron-like cells (NLC) differentiation from human adipose tissue-derived mesenchymal stem cells (hADSCs) cocultured on decellularized sciatic nerves. OLC and NLC were incubated at a 10:1 ratio with decellularized rat nerves. We estimated the percentage of myelin basic protein (MBP)- and neurofilament protein (NFP)-positive cells. OLC and NLC cocultures showed an increase in positive cells for MBP and proteolipid protein (PLP) markers. Oligodendrocytes and neurons cocultured with sciatic nerve scaffolds promoted myelination by OLC within three days, which remained stable for at least 21 days. We propose a reproducible experimental strategy for promoting sciatic nerve myelination by coculturing hADSCs-derived OLC and NLC in nerve scaffolds., Scientific Letters, Vol. 1 No. 1 (2022)

Cardiovascular diseases are the leading cause of death worldwide. Cardiovascular diseases complication can give rise to myocardial infarction which produces cell death by blockage of blood flow, leading to loss of heart function. Current treatments directed at heart repair have several disadvantages such as the lack of donors for heart transplantation or the use of non-bioactive inert materials for replacement of the damage tissue. New treatment strategies involve stimulation of heart tissue regeneration with the use of bioactive materials like chitosan, in combination with cells and biochemical factors. Chitosan scaffolds have the necessary proprieties of biocompatibility, porosity, and biodegradation, that imitates the heart extracellular matrix. Chitosan scaffolds physical proprieties, such as electrical conductivity and mechanical proprieties, can be improved by different preparation techniques and by the functionalization with other materials.

Stand out contribution of pericytes and cancer stem cells (CSC) to progression of colorectal cancer (CRC). Reported that CSC are responsible for the initiation and spread of the tumor; however, the microenvironment in the tumor plays a decisive role in prognosis; CSC and pericytes interaction are capable of contributing to neovascularization and promoting metastasis. We reviewed the contribution of cellular communication between pericytes, endothelial cells, and CSC with focus vascular remodeling, metastasis, angiogenesis, and vasculogenesis. Also, we were analyzed concise microRNAs and approved therapeutic target with the potential anti-angiogenic as treatment of CRC. This work seeks to give an overview of pericytes in cancer and their role angiogenic with CSC in CRC.

Introduction: Gas gangrene, also known as clostridial myonecrosis, is an acute, potentially life-threatening infection of muscular and soft tissues caused by pathogens in the Clostridium genus. Clinical case: We present the case of spontaneous gas gangrene caused by C. Perfringens in a patient with no history of trauma. Discussion: The treatment of gas gangrene consists of prompt surgical debridement combined with antibiotic therapy. Emergency surgical debridement is especially important for patient survival, preserving the limb and preventing complications. If C. Perfringens is confirmed, the antibiotic therapy should consist of penicillin (3-4 million units intravenously every 4h) with clindamycin (900 mg intravenously every 8h) or tetracycline (500 mg intravenously every 6h). Even when we encounter a patient with no history of trauma, gastrointestinal pathology, neutropenia or immunodeficiencies, we should quickly suspect this diagnosis when there is extreme pain in a limb, with or without fever. This suspicion is important due to the need for rapid and aggressive treatment to save the limb and life of the patient and to prevent complications.

Additive Manufacturing (AM) offers remarkable advantages in relation to traditional methods used to obtain solid structures, such as the capability to obtain customized complex geometries adapted to individual requirements. The design of novel nanocomposites suitable for AM is an excellent strategy to widen the application field of these techniques. In this work, we report on the fabrication of metal/polymer nanocomposites with enhanced optical/electrical behaviour for stereolithography (SLA). In particular, we analyse the in situ generation of Ag nanoparticles (NPs) from Ag precursors (AgNO3 and AgClO4) within acrylic resins via SLA. Transmission electron microscopy (TEM) analysis confirmed the formation of Ag NPs smaller than 5 nm in all nanocomposites, providing optical activity to the materials. A high density of Ag NPs with a good distribution through the material for the larger concentration of AgClO4 precursor tested was observed, in contrast to the isolated agglomerations found when the precursor amount was reduced to 0.1%. A significant reduction in the electrical resistivity up to four orders of magnitude was found for this material compared to the unfilled resin. However, consumption of part of the photoinitiator in the formation process of the Ag NPs contributed to a reduction in the polymerization degree of the resin and, consequently, degraded the mechanical properties of the nanocomposites. Experiments with longer curing times showed that, for the higher AgClO4 concentrations tested, post-curing times of 300 min allowed an 80% degree of polymerization to be achieved. These conditions turned these materials into promising candidates to obtain solid structures with multifunctional properties.

Background: Cancer treatment has many side effects; therefore, more efficient treatments are needed. Mesenchymal stem cells (MSC) have immunoregulatory properties, tumor site migration and can be genetically modified. Some proteins, such as soluble TRAIL (sTRAIL) and interleukin-12 (IL-12), have shown antitumoral potential, thus its combination in solid tumors could increase their activity. Materials and Methods: Lentiviral transduction of bone marrow MSC with green fluorescent protein (GFP) and transgenes (sTRAIL and IL-12) was confirmed by fluorescence microscopy and Western blot. Soluble TRAIL levels were quantified by ELISA. Lymphoma L5178Y cells express a reporter gene (GFP/mCherry), and TRAIL receptor (DR5). Results: An in vivo model showed that combined treatment with MSC expressing sTRAIL+IL-12 or IL-12 alone significantly reduced tumor volume and increased survival in BALB/c mice (p < 0.05) with only one application. However, at the histological level, only MSC expressing IL-12 reduced tumor cell infiltration significantly in the right gastrocnemius compared with the control group (p < 0.05). It presented less tissue dysplasia confirmed by fluorescence and hematoxylin–eosin dye; nevertheless, treatment not inhibited hepatic metastasis. Conclusions: MSC expressing IL-12, is or combination with BM-MSC expressing sTRAIL represents an antitumor strategy for lymphoma tumors since they increase survival and reduce tumor development. However, the combination did not show significative additive effect. The localized application did not inhibit metastasis but reduced morphological alterations of tissue associated with liver metastasis.

Hepatocellular carcinoma (HCC) is the most common liver cancer. It is highly lethal and has high recurrence. Death among HCC patients occur mainly due to tumor progression, recurrence, metastasis, and chemoresistance. Cancer stem cells (CSCs) are cell subpopulations within the tumor that promote invasion, recurrence, metastasis, and drug resistance. Hepatic stellate cells (HSCs) are important components of the tumor microenvironment (TME) responsible for primary secretory ECM proteins during liver injury and inflammation. These cells promote fibrogenesis, infiltrate the tumor stroma, and contribute to HCC development. Interactions between HSC and CSC and their microenvironment help promote carcinogenesis through different mechanisms. This review summarizes the roles of CSCs and HSCs in establishing the TME in primary liver tumors and describes their involvement in HCC chemoresistance.

The infiltration of secondary treated effluent (STE) into the soil downstream of wastewater treatment plants is becoming increasingly common in a climate change context. In STE infiltration, STE is discharged onto the soil over a large surface allowing for a gradual infiltration of the water. This paper investigates a novel time-lapse electrical resistivity tomography strategy to evaluate the impact of STE infiltration on the water pathways of two planted loamy-soil trenches located in a Fluvisol region in southwestern France. The system has been monitored for 3 years using discontinuous monitoring of electrical resistivity tomography during four saline tracer tests. Results show that: 1) the new methodology has successfully highlighted the evolution of water pathways in the soil over time; 2) such evolution is in agreement with reeds root distribution in the trenches which seems to be affected by water quality i.e. sludge losses and TSS, for this study case. Indeed, for the infiltration trench receiving STE with lower pollution levels (2.2 mg TSS. L

Pancreatic cancer leads the most common lethal tumor in America. This lethality is related to limited treatment options. Conventional treatments involve a non-specific use of chemotherapeutical agents like 5-FU, capecitabine, gemcitabine, cisplatine, oxaliplatine, or irinotecan, that produce several side effects. This review we focus on the use of targeted nanoparticles as an alternative to the standard treatment for the pancreatic cancer. The principal objective of the use of nanoparticles is the reduction in side effects that conventional treatments produce, mostly because of their nonspecificity. Currently, several molecular markets of pancreatic cancer cells have been studied to target nanoparticles and improve the actual treatment. Therefore, properly functionalizated nanoparticles with specific aptamers or antibodies can be used to recognize pancreatic cancer cells and once cancer is recognized, these nanoparticles can attack the tumor by drug delivery, hyperthermia, or gene therapy.

SUMMARY Tubo-ovarian high-grade serous carcinoma (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we apply mass cytometry and uncover decidual-like natural killer (dl-NK) cell subpopulations (CD56+CD9+CXCR3+KIR+CD3−CD16−) in newly diagnosed HGSC samples that correlate with both tumor and transitioning epithelial-mesenchymal cell abundance. We show different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within three HGSC tumor compartments: epithelial (E), transitioning epithelial-mesenchymal (EV), and mesenchymal (vimentin expressing [V]), with a more inhibitory ligand phenotype in V cells. In cocultures, NK-92 natural killer cells acquire CD9 from HGSC tumor cells by trogocytosis, resulting in reduced anti-tumor cytokine production and cytotoxicity. Cytotoxicity in these cocultures is restored with a CD9-blocking antibody or CD9 CRISPR knockout, thereby identifying mechanisms of immune suppression in HGSC. CD9 is widely expressed in HGSC tumors and so represents an important new therapeutic target with immediate relevance for NK immunotherapy., Graphical Abstarct, In brief In their mass cytometry study of newly diagnosed tubo-ovarian HGSC, Gonzalez et al. identify decidual-like NK cells that correlate with tumor cell abundance. CD9 distinguishes decidual NK cells from other NK cell phenotypes. In coculture, CD9 trogocytosis from ovarian tumor to NK cells confers NK cells with immune-suppressive properties.

Colorectal cancer (CRC) is one of the main causes of mortality. Recent studies suggest that cancer stem cells (CSCs) can survive after chemotherapy and promote tumor invasiveness and aggression. According to a higher hierarchy complexity of CSC, different protocols for isolation, expansion, and characterization have been used; however, there are no available resistance biomarkers that allow predicting the clinical response of treatment 5-fluorouracil (5FU) and oxaliplatin. Therefore, the primary aim of the present study was to analyze the expression of gene resistance on tumors and CSC-derived isolates from patients CRC. In the present study, adenocarcinomas of the colon and rectum (CRAC) were classified based on an in vitro adenosine triphosphate-based chemotherapy response assay, as sensitive and resistant and the percentage of CD24 and CD44 markers are evaluated by immunohistochemistry. To isolate resistant colon-CSC, adenocarcinoma tissues resistant to 5FU and oxaliplatin were evaluated. Finally, all samples were sequenced using a custom assay with chemoresistance-associated genes to find a candidate gene on resistance colon-CSC. Results showed that 59% of the CRC tissue analyzed was resistant and had a higher percentage of CD44 and CD24 markers. An association was found in the expression of some genes between the tumor-resistant tissue and CSC. Overall, isolates of the CSC population CD44+ resistant to 5FU and oxaliplatin demonstrated different expression profiles; however, the present study was able to identify overexpression of the KRT-18 gene, in most of the isolates. In conclusion, the results of the present study showed overexpression of KRT-18 in CD44+ cells is associated with chemoresistance to 5FU and oxaliplatin in CRAC.

miRNAs are well known for being implicated in a myriad of biological situations, including those related to serious diseases. Amongst miRNAs, miRNA-21 has the spotlight as it is reported to be up-regulated in multiple severe pathological conditions, being its quantification a key point in medicine. To date, most of the techniques for miRNA quantification have shown to be less effective than expected; thus, we herein present a novel, rapid, cost-effective, robust and PCR-free approach, based on dynamic chemistry, for the identification and quantification of miRNA directly from tumour cells using both FACS and a fluorescent microplate. This dynamic chemistry novel application involves bead based reagents and allows quantifying the number of miR-21 molecules presented in MDA-MB-468 and H1975 tumour cells.

Q (1) What are the effects on the social and communication skills of a person with developmental disability when intervention is implemented by a family member? (2) Are differential effects of fami...

Articular cartilage is a highly organized tissue that provides remarkable load-bearing and low friction properties, allowing for smooth movement of diarthrodial joints; however, due to the avascular, aneural, and non-lymphatic characteristics of cartilage, joint cartilage has self-regeneration and repair limitations. Cartilage tissue engineering is a promising alternative for chondral defect repair. It proposes models that mimic natural tissue structure through the use of cells, scaffolds, and signaling factors to repair, replace, maintain, or improve the specific function of the tissue. In chondral tissue engineering, fibrin is a biocompatible biomaterial suitable for cell growth and differentiation with adequate properties to regenerate damaged cartilage. Additionally, its mechanical, biological, and physical properties can be enhanced by combining it with other materials or biological components. This review addresses the biological, physical, and mechanical properties of fibrin as a biomaterial for cartilage tissue engineering and as an element to enhance the regeneration or repair of chondral lesions.

Cardiovascular diseases are a leading cause of death worldwide. Current treatments directed at heart repair have several disadvantages, such as a lack of donors for heart transplantation or non-bioactive inert materials for replacing damaged tissue. Because of the natural lack of regeneration of cardiomyocytes, new treatment strategies involve stimulating heart tissue regeneration. The basic three elements of cardiac tissue engineering (cells, growth factors, and scaffolds) are described in this review, with a highlight on the role of artificial scaffolds. Scaffolds for cardiac tissue engineering are tridimensional porous structures that imitate the extracellular heart matrix, with the ability to promote cell adhesion, migration, differentiation, and proliferation. In the heart, there is an important requirement to provide scaffold cellular attachment, but scaffolds also need to permit mechanical contractility and electrical conductivity. For researchers working in cardiac tissue engineering, there is an important need to choose an adequate artificial scaffold biofabrication technique, as well as the ideal biocompatible biodegradable biomaterial for scaffold construction. Finally, there are many suitable options for researchers to obtain scaffolds that promote cell–electrical interactions and tissue repair, reaching the goal of cardiac tissue engineering.

The potential effect of intravenous administration of glutamate on the ovarian activity and the LH secretion pattern, considering the anestrous yearling goat as an animal model, were assessed. In late April, yearling goats (n = 20) were randomly assigned to either (1) Glutamate supplemented (GLUT; n = 10, Live Weight (LW) = 29.6 ± 1.02 kg, Body Condition (BCS) = 3.4 ± 0.2 units; i.v. supplemented with 7 mg GLUT kg−1 LW) or (2) Non-supplemented (CONT; n = 10; LW = 29.2 ± 1.07 kg, BCS = 3.5 ± 0.2 units; i.v. saline). The oats were estrus-synchronized; blood sampling (6 h × 15 min) was carried out for LH quantification. Response variables included pulsatility (PULSE), time to first pulse (TTFP), amplitude (AMPL), nadir (NAD), and area under the curve (AUC) of LH. Ovaries were ultra-sonographically scanned to assess ovulation rate (OR), number of antral follicles (AF), and total ovarian activity (TOA = OR + AF). LH-PULSE was quantified with the Munro algorithm; significant treatment x time interactions were evaluated across time. The variables LW and BCS did not differ (p > 0.05) between the experimental groups. Nevertheless, OR (1.77 vs. 0.87 ± 0.20 units), TOA (4.11 vs. 1.87 ± 0.47 units) and LH-PULSE (5.0 vs. 2.2 pulses 6 h-1) favored (p < 0.05) to the GLUT group. Our results reveal that targeted glutamate supplementation, the main central nervous system neurotransmitter, arose as an interesting strategy to enhance the hypothalamic–hypophyseal–ovarian response considering the anestrous-yearling goat as an animal model, with thought-provoking while promising translational applications.

Trogocytosis is an active transport mechanism by which one cell extracts a plasma membrane fragment with embedded molecules from an adjacent cell in a contact-dependent process leading to the acquisition of a new function. Our protocol, which has general applicability, consolidates and optimizes existing protocols while highlighting key experimental variables to demonstrate that natural killer (NK) cells acquire the tetraspanin CD9 by trogocytosis from ovarian tumor cells. For complete details on the use and execution of this protocol, please refer to Gonzalez et al. (2021).

Metastasis is the process of dissemination of a tumor, whereby cells from the primary site dislodge and find their way to other tissues where secondary tumors establish. Metastasis is the primary cause of death related to cancer. This process warrants changes in original tumoral cells and their microenvironment to establish a metastatic niche. Traditionally, cancer therapy has focused on metastasis prevention by systematic treatments or direct surgical re-sectioning. However, metastasis can still occur. More recently, new therapies direct their attention to targeting cancer stem cells. As they propose, these cells could be the orchestrators of the metastatic niche. In this review, we describe conventional and novel developments in cancer therapeutics for liver and lung metastasis. We further discuss the resistance mechanisms of targeted therapy, the advantages, and disadvantages of diverse treatment approaches, and future novel strategies to enhance cancer prognosis.

Summary Soil infiltration is regularly practised downstream of wastewater treatment plants, particularly in areas without surface water systems. In France, stakeholders are considering the use of biodegradable and renewable material such as woodchips. This material has two main advantages: it has a high capillarity, thus a great capacity for water retention, and it amends the soil with carbon improving its structure. Moreover, woodchips have been told to promote biodiversity in particular for bioturbating species like earthworms, which play a major role regarding soil structure and organic matter transport into the soil. Such macrofaune is expected to promote water infiltration for poorly infiltrating capacity soils and to limit soil clogging caused by the infiltration of treated wastewater. In this study, we evaluate the interaction between woodchips and loamy soils on woodchip-filled trenches operated for 2 to 6 years using a non-destructive geophysical approach: Electrical Resistivity Tomography (ERT) and Time Domain Induced Polarisation (TDIP). ERT provided information of the structure of the soil under the woodchip-filled trenches, but anything could be said about the impact of such system in the soil. By contrast, TDIP showed significant variations of the signal around the trenches which may result from the presence of organic matter.

Herein, we describe the synthesis and application of cross-linked polystyrene-based dual-function nano- and microparticles containing both fluorescent tags and metals. Despite containing a single dye, these particles exhibit a characteristic dual-band fluorescence emission. Moreover, these particles can be combined with different metal ions to obtain hybrid metallofluorescent particles. We demonstrate that these particles are easily nanofected into living cells, allowing them to be used for effective fingerprinting in multimodal fluorescence-based and mass spectrometry-based flow cytometry experiments. Likewise, the in situ reductions of the metal ions enable other potential uses of the particles as heterogeneous catalysts., This work was funded by the Consejeria de Economia, Innovacion, Ciencia y Empleo (Junta de Andalucia, grant BIO-1778), the Spanish Ministry of Economy and Competitiveness (grants BIO2016-80519-R and CTQ2014-56370-R) and the Fundación Ramón Areces. A.D.-G. acknowledges scholarships from the Spanish Ministry of Education (grant FPU14/02181) and the University of Granada, PhD programme in Biomedicine. T.V. thanks the Talentia Postdoc Fellowship Programme (grant 267226, co-funded by the Andalusian Knowledge Agency and the 7th Framework Program of the European Union). A.U.-B. is grateful to the EPSRC (EP/N021134/1) for funding. The authors thank the staff at the microscopy facility of the Centre for Integrative Biology (CIBIO) of the University of Trento (Italy), the staff at the electron microscopy facilities of the Centre for Scientific Instrumentation (CIC) of the University of Granada, and the staff at the Flow Cytometry unit at the Pfizer-University of Granada-Junta de Andalucia Centre for Genomics and Oncological Research (GENYO).

SummaryTubo-ovarian high-grade serous cancer (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we applied mass cytometry to uncover decidual-like (dl)-NK cell subpopulations (CD56+CD9+CXCR3+KIR+CD3-CD16-) in chemo-naïve HGSC tumors that correlated with both tumor and transitioning epithelial-mesenchymal cell abundance. We showed different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within the three HGSC tumor cell compartments; epithelial (E), transitioning epithelial-mesenchymal (EV) and mesenchymal (vimentin-expressing cells, V) with a more inhibitory ligand phenotype in V cells. When co-cultured with HGSC cell lines the NK-92 cell line acquired CD9 from tumor cells by trogocytosis with a resultant reduction in both anti-tumor cytokine production and cytotoxicity. Critically, a CD9 blocking antibody restored the killing activity of CD9+-NK-92 cells. These findings identify previously unrecognized mechanisms of immune suppression in HGSC. Furthermore, since CD9 is widely expressed in HGSC tumors it represents an important new therapeutic target with immediate relevance for NK immunotherapy.

Dissertation submitted in partial fulfilment of the requirements for the degree of Master of Science in Geospatial Technologies Nowadays, constant overpopulation and urban expansion in cities worldwide have led to several transport-related challenges. Traffic congestion, long commuting, parking difficulties, automobile dependence, high infrastructure maintenance costs, poor public transportation, and loss of public space are some of the problems that afflict major metropolitan areas. Trying to provide a solution for the future inner-city transportation, several companies have worked in recent years to design aircraft prototypes that base their technology on current UAVs. Therefore, vehicles with electrical Vertical Take-Off and Landing (eVTOL) technology are rapidly emerging so that they can be included in the Urban Air Mobility (UAM) system. For this to become a reality, space agencies, governments and academics are generating concepts and recommendations to be considered a safe means of transportation for citizens. However, one of the most relevant points for this future implementation is the suitable location of the potential UAM hubs within the metropolitan areas. Since although UAM vehicles can take advantage of infrastructure such as roofs of buildings to clear and land, several criteria must be considered to find the ideal location. As a solution, this thesis seeks to carry out an integral rooftop-place suitability analysis by involving both the essential variables of the urban ecosystem and the adequate rooftop surfaces for UAM operability. The study area selected for this research is Manhattan (New York, U.S), which is the most densely populated metropolitan area of one of the megacities in the world. The applied methodology has an unsupervised-data-driving and GIS-based approach, which is covered in three sections. The first part is responsible for analyzing the suitability of place when evaluating spatial patterns given by the application of Self-Organizing Maps on the urban ecosystem variables attached to the city census blocks. The second part is based on the development of an algorithm in Python for both the evaluation of the flatness of the roof surfaces and the definition of the UAM platform type suitable for its settlement. The final stage performs a combined analysis of the suitability indexes generated for the development of UAM hubs. Results reflect that 16% of the roofs in the study area have high integral suitability for the development of UAM hubs, where UAVs platforms and Vertistops (small size platforms) are the types that can be the most settled in Manhattan. The reproducibility self-assessment of this research when considering Nüst et al. [45] criteria (https://osf.io/j97zp/) is: 2, 1, 2, 1, 1 (input data, preprocessing, methods, computational environment, results). GitHub repository code is available in https://github.com/carlosjdelgadonovaims/rooftop-place_suitability_analysis_for_Urban_Air_Mobility_hubs

Pancreatic cancer is the most common lethal tumor in America. This lethality is related to limited treatment options. Conventional treatments involve the non-specific use of chemotherapeutical agents such as 5-FU, capecitabine, gemcitabine, paclitaxel, cisplatin, oxaliplatin, or irinotecan, which produce several side effects. This review focuses on the use of targeted nanoparticles, such as metallic nanoparticles, polymeric nanoparticles, liposomes, micelles, and carbon nanotubes as an alternative to standard treatment for pancreatic cancer. The principal objective of nanoparticles is reduction of the side effects that conventional treatments produce, mostly because of their non-specificity. Several molecular markers of pancreatic cancer cells have been studied to target nanoparticles and improve current treatment. Therefore, properly functionalized nanoparticles with specific aptamers or antibodies can be used to recognize pancreatic cancer cells. Once cancer is recognized, these nanoparticles can attack the tumor by drug delivery, gene therapy, or hyperthermia.

Wastewater treatment, a major issue at the European level, focuses on improving surface water and groundwater quality, preserving the receiving environment, and ensuring a sustainable use of water. Soil infiltration is increasingly practiced downstream of wastewater treatment plants, particularly in rural areas without surface water bodies, as is the use of soil as an additional buffer and treatment step. However, the design of infiltration areas on heterogeneous soils remains an extremely complex task due to the costly and time-consuming spatial measurement of saturated hydraulic conductivity (Ks). This article proposes integrating 2D electrical resistivity tomography and infiltration tests into a Bayesian Maximum Entropy method, yielding a vertical mapping of soil heterogeneities at a metric scale. This updated method will facilitate infiltration area design in a heterogeneous soil setting.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.

In this study, we sought to analyze the evaluation processes in the field of forensic psychology in Colombia, having as argumentative product a theoretical framework about the definition of forensic psychology (functions and role), its ethical problems, its application in different fields of law, and its most recurrent counter-flows as the type of instruments and interviews used by the psychologist. In accordance with the foregoing and taking into account the selection criteria of the experts for the tests, a structured interview was designed applied to a sample of forensic field psychologists at a national level performing a quantitative analysis on the experience of the forensic psychologist, their participation in the different types of expert works, the techniques and criteria used as support in any process, and finally, some conclusions about the position in which the forensic psychologist is in Colombia. En este estudio se buscó analizar los procesos de evaluación en el campo de la psicología forense en Colombia, teniendo como producto argumentativo un marco teórico acerca de la definición de la Psicología Forense (funciones y rol), sus problemas éticos, su aplicación en los diferentes campos del derecho, y sus contraflujos más recurrentes como el tipo de instrumentos y entrevistas que utiliza el psicólogo. De acuerdo con lo anterior y teniendo en cuenta los criterios de selección de los peritos para las pruebas, se diseñó una entrevista estructurada aplicada a una muestra de psicólogos del campo forense a nivel nacional realizando un análisis de corte cuantitativo sobre la experiencia del psicólogo forense, su participación en los diferentes clases de perito, las técnicas y criterios que usa como soporte en cualquier proceso, y por último, algunas conclusiones acerca del posicionamiento en que se encuentra el psicólogo forense en Colombia.

Resumen En este estudio se buscó analizar los procesos de evaluación en el campo de la psicología forense en Colombia, teniendo como producto argumentativo un marco teórico acerca de la definición de la Psicología Forense (funciones y rol), sus problemas éticos, su aplicación en los diferentes campos del derecho, y sus contraflujos más recurrentes como el tipo de instrumentos y entrevistas que utiliza el psicólogo. De acuerdo con lo anterior y teniendo en cuenta los criterios de selección de los peritos para las pruebas, se diseñó una entrevista estructurada aplicada a una muestra de psicólogos del campo forense a nivel nacional realizando un análisis de corte cuantitativo sobre la experiencia del psicólogo forense, su participación en los diferentes clases de perito, las técnicas y criterios que usa como soporte en cualquier proceso, y por último, algunas conclusiones acerca del posicionamiento en que se encuentra el psicólogo forense en Colombia. Abstract In this study, we sought to analyze the evaluation processes in the field of forensic psychology in Colombia, having as argumentative product a theoretical framework about the definition of forensic psychology (functions and role), its ethical problems, its application in different fields of law, and its most recurrent counter-flows as the type of instruments and interviews used by the psychologist. In accordance with the foregoing and taking into account the selection criteria of the experts for the tests, a structured interview was designed applied to a sample of forensic field psychologists at a national level performing a quantitative analysis on the experience of the forensic psychologist, their participation in the different types of expert works, the techniques and criteria used as support in any process, and finally, some conclusions about the position in which the forensic psychologist is in Colombia.

International audience; Results from laboratory columns of granulated apatite for phosphorus retention are presented. Different experimental conditions have been tested. Calcium addition leads to an enhacement on phosphorus retention and a calcium phosphate deposit has been identified onto the surface of the granule by SEM.

The study aimed to measure the correlation between the motivation to learn English as a foreign language and the achievement level in students in the first semester of the Bachelor’s degree in Primary Education at a higher education school “Escuela Normal Oficial de Irapuato” (ENOI). These future teachers of basic education are of interest due to the high impact they have on the education of future generations in Mexico. The present study comprised a quantitative non-experimental correlational research. Gardner´s attitude/motivation test battery (Gardner, 1985) was used to measure motivation and the Oxford on-line Placement Test scored the students’ English level achievement. The motivation results show the high motivation intensity these future teachers have to acquire English as a foreign language, both for integrative and instrumental reasons; the average is 5.79 points out of 7. The English achievement results showed that 67% of incoming students barely reached an A1 which is less than 20 points out of 120, even though, it did not include a speaking section which has been reported as one of the most difficult abilities. The Spearman’s rank correlation was calculated at 0.2430 using the results before mentioned. Based on these grounded findings, the authors propose focusing on specific learning areas that can better prepare these futures teachers to take advantage of their own students’ crucial period.

International audience; There are 20 full-scale Phosclean® filters for P removal being used together with treatment wetlands (TW) to treat wastewaters of small and medium-size communities, in France. Some of them are in operation for more than five years now, reason why some field experiences are being conducted under the project name of APPROVE (APatite for P Removal and Valorisation: an Evaluation) to assess the current performance and saturation conditions of full-scale filters. This paper will present fieldfeedback results from 4 different wastewater treatment plants (WWTP) with Phosclean® filters. WWTP A (filter A) has been monitored since its commission in 2017 to assess the effluent's pH evolution due to material dissolution in the very first stage of its life span. Three other WWTPs (B, C and D) with hydraulically different Phosclean® filters, in operation since 2012, are also monitored: vertical up-flow (filter B); vertical down-flow (filter C) and horizontal flow (filter D). Assessment of the treatment plants use regulatory surveys since the beginning of plants operations. As treatment plants have not the same capacity, the number of regulatory surveys is heterogeneous and not high enough to have a precise knowledge on saturation levels and retention kinetics. Consequently, additional measurement campaigns have been carried out over two years. Four-day campaigns have been carried out twice per year for each WWTP. In order to evaluate the P retention's performance, 24h-flow proportional samplings at the inlet and outlet of the Phosclean® filter were coupled to spotsamplings at different hydraulic retention times inside the filter to measure retention's kinetic. Online P-PO4 measurements at the outlet of the filter were also conducted to observe possible dynamic within a day. Mayor parameters as pH, conductivity, redox potential, TSS, BOD, COD, N, TP, P-PO4 3- as well as anions and cations were measured for these samples. For filter A, a flowmeter and an online pH probe at the outlet of the filter have been implemented for several months. To determine the nature of phosphate precipitates, SEM and DRX analyses were performed for solid samples taken at different points in the filters. Furthermore, fluorescein-tracer tests were carried out to precisely determine water retention times and possible short-circuiting, as well as dynamic penetrometer measurements to assess potential changes on the material density due to surface precipitation. Results of first campaigns show that P concentration at the outlet of filters C and D respect the maximal regulation limit for total phosphorous disposal after 5 years of operation. This is not the case for filter B, after 4 years of operation, which is over the regulation limit fixed at 2.5mgTP/L. Nevertheless, differences in the regulation limits, inlet P concentrations, hydraulic loads, operation and design, must be taken into consideration to analyze variations of filters performances. The evolution of TP concentrations along time will be presented for all filters according to saturation levels for comparison. Kinetics evolution as a function of saturation conditions will be also presented. Results show that filters B, C and D are at different saturation levels, being filter B the most saturated.

International audience; There are 20 full-scale Phosclean® filters for P removal being used together with treatment wetlands (TW) to treat wastewaters of small and medium-size communities, in France. Some of them are in operation for more than five years now, reason why some field experiences are being conducted under the project name of APPROVE (APatite for P Removal and Valorisation: an Evaluation) to assess the current performance and saturation conditions of full-scale filters. This paper will present fieldfeedback results from 4 different wastewater treatment plants (WWTP) with Phosclean® filters. WWTP A (filter A) has been monitored since its commission in 2017 to assess the effluent's pH evolution due to material dissolution in the very first stage of its life span. Three other WWTPs (B, C and D) with hydraulically different Phosclean® filters, in operation since 2012, are also monitored: vertical up-flow (filter B); vertical down-flow (filter C) and horizontal flow (filter D). Assessment of the treatment plants use regulatory surveys since the beginning of plants operations. As treatment plants have not the same capacity, the number of regulatory surveys is heterogeneous and not high enough to have a precise knowledge on saturation levels and retention kinetics. Consequently, additional measurement campaigns have been carried out over two years. Four-day campaigns have been carried out twice per year for each WWTP. In order to evaluate the P retention's performance, 24h-flow proportional samplings at the inlet and outlet of the Phosclean® filter were coupled to spotsamplings at different hydraulic retention times inside the filter to measure retention's kinetic. Online P-PO4 measurements at the outlet of the filter were also conducted to observe possible dynamic within a day. Mayor parameters as pH, conductivity, redox potential, TSS, BOD, COD, N, TP, P-PO4 3- as well as anions and cations were measured for these samples. For filter A, a flowmeter and an online pH probe at the outlet of the filter have been implemented for several months. To determine the nature of phosphate precipitates, SEM and DRX analyses were performed for solid samples taken at different points in the filters. Furthermore, fluorescein-tracer tests were carried out to precisely determine water retention times and possible short-circuiting, as well as dynamic penetrometer measurements to assess potential changes on the material density due to surface precipitation. Results of first campaigns show that P concentration at the outlet of filters C and D respect the maximal regulation limit for total phosphorous disposal after 5 years of operation. This is not the case for filter B, after 4 years of operation, which is over the regulation limit fixed at 2.5mgTP/L. Nevertheless, differences in the regulation limits, inlet P concentrations, hydraulic loads, operation and design, must be taken into consideration to analyze variations of filters performances. The evolution of TP concentrations along time will be presented for all filters according to saturation levels for comparison. Kinetics evolution as a function of saturation conditions will be also presented. Results show that filters B, C and D are at different saturation levels, being filter B the most saturated.

To determine in vitro, the efficacy and safety window of not-front-line and first-line anti-colorectal (CRC) drug combinations.The adenocarcinoma cell line Colo 320DM and normal human mesenchymal stem cells derived from adipose tissue were used respectively to determine the anti-CRC efficacy (% of Colo 320DM cell death [CD]) and safety window [SW] - % Colo 320DM percent cancer death (PCD)/% of mesenchymal stem cell's death) of drug combinations, using the adenosine triphosphate-based chemotherapy response assay (ATP-CRA).First-line anti-CRC drug combinations (5-fluorouracil [5FU]/oxaliplatin [oxa] and 5-FU/Oxa /leucovorin [Leuco]) produced 57.7% and 52.4% CD, and 1.38 and 2.44 SW, respectively. Combinations of 5-FU/Oxa and 1 to 3 non-front line drugs led to 56.3-99.8% CD and to 0.96-2.2 SW. The highest safety window corresponded to 5FU/Oxa/ carboplatin [Carbo] (93% CD and 1.4 SW) and to 5-FU/ Oxa/cisplatin [Cispl] (93.5% CD and 1.4 SW). In contrast, non-front line drugs led to 89.8-97.4% CD and to 1.1-78.2 SW. Outstandingly, those combinations containing Carbo/ Cispl/3,3'-diindolylmethane (DIM), aspirin (Asp), or 3,3'- DIM/ Asp showed a very high CD (91.9-96.9% [39.2-39.5 times higher than first-line-combined drugs]) and very wide SW (57.8-81.56 [66.6-40 times higher than the first-line drug combinations]).Human mesenchymal stem cells could be an excellent alternative to laboratory animals, when testing the safety profiles of drugs. The most promising combinations of non-frontline drugs to treat CRC are Carbo/Cispl/ Asp and Carbo/Cispl/DIM.

La vinculación entre conocimiento, innovación y competitividad en la economía y la empresa ha impulsado una importante actividad investigadora tendente a mejorar la comprensión del complejo proceso de la innovación y favorecer los resultados económicos y empresariales de una manera eficiente y sostenible en el marco actual de la economía global. El diseño de políticas de innovación requiere el desarrollo de instrumentos de medición y diagnostico de la situación económica, de los componentes que configuran el sistema de innovación y, especialmente, de la empresa innovadora como agente vertebrador del sistema. A pesar de ello, el estudio de este tipo de organizaciones carece aún de metodologías acordes con la complejidad y especificidad características del proceso innovador. El enfoque de investigación micro-nivel, o nivel empresa, es considerado como una esperanzadora vía de superación de las limitaciones existentes actualmente en la investigación empírica de la innovación a nivel agregado (Uyarra, 2010), en particular en contextos espaciales y sectoriales de menor intensidad tecnológica, donde la implantación de modelos únicos y las mejores prácticas contrastadas en contextos mas tecnológicos no conducen generalmente a los resultados deseados, como queda de manifiesto en la literatura (Todtling y Trippl, 2005). La Unión Europea ha realizado un notable esfuerzo en las últimas décadas para impulsar un nuevo modelo de desarrollo económico en la comunidad basado en la innovación y la competitividad. Esta orientación marcada inicialmente en la Estrategia de Lisboa (Council of the European Union, 2000) ha tenido su continuación en la Estrategia Europa 2020 (European Commission, 2010) que proyecta un crecimiento económico para la comunidad basado en el conocimiento y la innovación. Consecuencia de esta trayectoria política es el Programa Marco para la Competitividad y la Innovación 2007-2013 (European Commission, 2005), cuyos recursos han fomentado las actividades de innovacion, facilitando el acceso a la financiación e incentivado la implantación de nuevas TICs y la eficiencia energética en las empresas europeas, en particular entre las de pequeño y mediano tamaño. En el Séptimo Programa Marco 2014-2020, denominado Horizonte 2020 (Council of the European Union, 2013), se integran por primera vez todas las fases del proceso innovador, desde la investigación básica hasta las actividades mas próximas al mercado, ampliando la gama de actividades de apoyo para la innovación en las organizaciones. En esta misma línea se halla el Programa para la Competitividad de Empresas y PYMEs 2014- 2020 (European Commission, 2014a), cuyo propósito es reforzar la competitividad y favorecer el emprendimiento en la Unión Europea. Las diversas medidas de este completo programa abarcan el apoyo financiero para las pymes (capital riesgo, líneas de crédito, etc.), el asesoramiento para la expansión comercial de las empresas, dentro y fuera de la Unión Europea, otras iniciativas orientadas a facilitar las actividades de innovación y transferencia tecnológica en las empresas, así como la cooperación industrial internacional en I+D+i. Finalmente, el apoyo a emprendedores también es contemplado en este programa con actividades de apoyo a la creacion y el desarrollo de las empresas (European Commission, 2014a). En concreto, la mejora de políticas europeas para las pymes y el intercambio de buenas prácticas constituyen importantes desafíos de este capítulo del programa que requieren del impulso previo de la investigación empírica a nivel empresa en el ámbito europeo. Diversos programas internacionales de cooperación tecnológica bilateral y multilateral completan una amplia oferta dirigida a la generación y difusión del conocimiento tecnológico en el tejido empresarial a nivel europeo y nacional. Las diferencias de stock de capital tecnológico explican las divergencias en innovación tecnológica entre países (Chen y Guan, 2011; Guan y Chen, 2012), demostrándose que las zonas con mayores dotaciones tecnológicas obtienen normalmente mejores resultados innovadores que aquellas con menores infraestructuras de conocimiento al alcance de las empresas. La existencia de rendimientos crecientes en la generación y difusión del conocimiento tecnológico (Howells, 2005; Chen y Guan, 2011) explican estas diferencias en innovación y crecimiento económico entre economías y sustentan las políticas que buscan incrementar la dotación de capital tecnológico en las regiones europeas tecnológica y económicamente menos desarrolladas (Clarysse y Muldur, 2001; Rodriguez-Pose, 2001; Rodriguez-Pose y Crescenzi, 2008). Una amplia red de centros de investigación y transferencia tecnológica, así como múltiples incentivos y ayudas financieras, han sido creados en el ámbito nacional y regional con el fin de fomentar la innovación, facilitando el acceso a los recursos y capacidades necesarios para mejorar de procesos internos organizativos y la introducción sistemática de novedades en bienes y servicios en los mercados europeos e internacionales. Junto a esta red de infraestructuras de apoyo a la innovación, investigadores y autoridades destacan la importancia de la cooperación empresarial en el proceso de creación y difusión de conocimientos e innovaciones, especialmente entre las pymes que constituyen el armazón del tejido empresarial. Este cumulo de relaciones externas de carácter sistémico tienen el objetivo de apoyar la generación de las capacidades internas para innovar en las organizaciones, mostrando así la verdadera dimensión interactiva y compleja del fenómeno de la innovación en su concepción actual. Sin embargo, diversos informes comunitarios (European Commission, 2009 y 2014b) y otras investigaciones cientificas (Bilbao–Osorio y Rodriguez- Pose, 2004; Clarysse y Muldur, 2001; Fritsch, 2000) muestran divergencias en el crecimiento económico asociadas a las asimetrías en los resultados innovadores entre países europeos, así como la necesidad de comprender las fuentes y modalidades de actividad innovadora de las empresas para aumentar la eficacia de la acción política. Estas diferencias entre países han permitido clasificar a los estados miembros en cuatro categorías según sus resultados innovadores (innovadores modestos, moderados, seguidores y lideres), aunque con diferencias dentro de cada grupo (European Commission, 2015. Si bien la brecha entre los estados miembros se ha ido reduciendo lentamente en los últimos 8 años, la ultima Community Innovation Survey –CIS– muestra que los efectos de la crisis económica continúan afectando negativamente a las actividades de innovación de las empresas europeas (Comisión Europea, 2015). Así, España es un innovador moderado cuya brecha innovadora ha aumentado a pesar de haber mejorado sus resultados innovadores en 2006–2013, situándose por debajo de la media comunitaria en la mayoría de los indicadores en dicho periodo, siendo la caída en las actividades de innovación internas en las pymes uno de los factores cuyo descenso resulta más acusado y preocupante en nuestro país (Comisión Europea, 2015). El análisis de los resultados empíricos a nivel europeo deja de manifiesto las importantes implicaciones económicas que derivan del conocimiento del comportamiento innovador de las empresas y del diseño de políticas factibles y eficaces en la Unión Europea. “La comprensión de las fuentes y los patrones de la actividad innovadora en la economía es fundamental para desarrollar mejores políticas” (European Commission, 2009: 6), de forma que la eficacia de la acción política europea pasa por el diagnostico previo de la realidad a nivel empresa en el ámbito comunitario y nacional. La corriente evolucionista (Dosi y Nelson, 1994; Nelson y Winter, 1982) proporciona el enfoque necesario para el análisis cuantitativo del complejo fenómeno de la innovación. Una contribución fundamental del evolucionismo es el enfoque interactivo (Kline, 1985; Kline y Rosenberg, 1986; Lundvall, 1988), que concibe la generación de innovaciones como un complejo proceso de aprendizaje y difusión del conocimiento en todas las aéreas funcionales de la empresa, sujeto a decisiones especificas internas de la organización y dependiente de los factores contextuales (Martinez-Roman, Gamero y Tamayo, 2011). Estas premisas, contrarias a la visión clásica del enfoque lineal, analiza la innovación tecnológica y no tecnológica considerando las características institucionales, sectoriales y de las organizaciones cuya influencia en la actividad innovadora ha quedado patente en la literatura. La aplicación del modelo interactivo se convierte en una característica importante del enfoque evolucionista y, al mismo tiempo, constituye un reto importante su utilización en la investigación empírica a nivel agregado (Todtling y Trippl, 2005). A pesar del significativo avance logrado en el estudio empírico de la innovación, la literatura deja patente la existencia de importantes vacios de conocimiento en tres importantes bloques de la investigación: la generación de capacidad innovadora en las empresas, los determinantes y efectos de la cooperación entre los agentes del sistema de innovación y la influencia ambiental en los resultados innovadores. En primer lugar, hay que conocer el proceso innovador en las organizaciones del territorio para que las infraestructuras y medidas de soporte de la innovación contribuyan eficazmente a incrementar la capacidad innovadora de las empresas (Kaufmann y Todtling, 2002), especialmente entre las SMEs (Asheim, Isaksen, Nauwelaers y Todtling, 2003; Bougrain y Haudeville, 2002). Para avanzar en este campo, es preciso desarrollar nuevos modelos de carácter interactivo, más complejos y cercanos a la realidad (Howells, 2005), cuya capacidad explicativa permita la investigación incluso en contextos con menor intensidad tecnológica. A pesar del consenso suscitado en la literatura en torno a este objetivo, el avance logrado por la investigación empírica hasta el momento en este ámbito de estudio es calificado de insuficiente en la literatura (Romijn y Albaladejo, 2002; Todtling y Trippl, 2005; Martinez–Roman, Gamero y Tamayo, 2011). En segundo lugar, hay que seguir profundizando en el estudio de los vínculos de cooperación entre los diversos agentes del sistema de conocimiento para comprender los procesos de generación y difusión de conocimientos e innovaciones en el ámbito regional (Caloghirou, Kastelli y Tsakanikas, 2004; Lhuillery y Pfister, 2009; Yam, Lo, Tang y Lau, 2011), incluyendo las medidas de apoyo público a la innovación (Keizer, Dijkstra y Halman, 2002; Santamaría Barge- Gil y Modrego, 2010; Tassey, 2007). En este sentido, la literatura suele diferenciar la cooperación en el sistema de valor de la cooperación con Universidades, centros tecnológicos y de investigación y otros agentes del sistema de ciencia (Caniels y van den Bosch, H., 2011; Kaufmann y Todtling, 2000, 2001; Ronde y Hussler, 2005). A pesar de su influencia reciproca, ambos grupos mantienen intereses y comportamientos bien diferenciados, estableciéndose una relación entre la estructura de las redes de innovación y el nivel de innovación alcanzado por las empresas de un territorio (Kaufmann y Todtling, 2001). Así, los resultados muestran que la reducción del efecto spillover regional se produce cuando las SMEs no interactúan suficientemente con los agentes del sistema de ciencia local (Kaufmann y Todtling, 2002). Análogamente, puede ocurrir que las ayudas públicas de fomento a la innovación no cumplan su objetivo (Radas y Bozic, 2009) o que su utilidad este en función del tipo de proyecto de innovación que apoyen (Santamaría, Barge-Gil y Modrego, 2010) En tercer lugar, la investigación empírica ha centrado su atención en países y regiones industrializadas con alta actividad tecnológica dejando en un segundo plano a los países periféricos y a las regiones menos favorecidas, cuyas peculiares características estructurales requieren políticas de innovación especificas (Cooke, 2001; Fritsch, 2003). Los resultados empíricos demuestran que los modelos de innovación contrastados en aéreas geográficas y sectores con mayor intensidad tecnológica no tienen la misma eficacia en otro tipo de contextos económicos (Fritsch, 2000), mostrando la inexistencia de modelos únicos de innovación y mejores prácticas de carácter general (Asheim y Coenen, 2005; Todtling y Trippl, 2005) y generando un vacio de conocimiento en la literatura sobre el proceso innovador en estos casos (Doloreux, 2002; Fritsch, 2003). Para cubrir dicho gap hay que superar la limitación del enfoque centrado en las industrias más tecnológicas, ampliando la investigación a otros sectores como los servicios (Doloreux, 2002). En este sentido, recientes investigaciones demuestran la utilidad que ofrecen los modelos de innovación desarrollados en otros sectores para mejorar la comprensión de la innovación en los servicios (Clausen y Madsen, 2014; Gallouj y Savona, 2009; Martinez-Roman, Tamayo, Gamero y Romero, 2015), dando lugar a un enfoque de integración o de síntesis que facilitara la comprensión global del fenómeno de la innovación en la economía. Solo a través del desarrollo pleno del enfoque interactivo en la investigación empírica a nivel empresa podremos cubrir estos gaps y progresar en el conocimiento de la innovación. Sin embargo, la literatura señala la subsistencia del enfoque lineal de la innovación en la investigación empírica y la política económica por razones de orden práctico, lo que significa que una visión incompleta o simplificada del fenómeno vela la complejidad del proceso ante la mirada del científico y del responsable político, con graves consecuencias económicas (Howells, 2005). Ante estas evidencias, el desarrollo de nuevas técnicas cuantitativas que faciliten el análisis de la innovación en su complejidad adquieren sentido prioritario en la comunidad científica, destacando en este proceso tanto las singularidades del contexto que afectan al desempeño innovador como la especificidad interna de las organizaciones que innovan. El propósito que anima al presente proyecto de investigación es la posibilidad de contribuir en el orden práctico al desarrollo del enfoque interactivo de la innovación y mejorar el conocimiento de la empresa innovadora europea. Para ello, en este trabajo se modelizara el comportamiento innovador de las empresas con el fin de analizar las complementariedades entre elementos organizativos y factores del mercado e institucionales a nivel comunitario, nacional y sectorial. La aplicación de diversas técnicas de análisis cuantitativo sobre una amplia base de datos de empresas europeas permitirá detectar las singularidades y comunalidades de cada contexto y ofrecer una visión próxima a la realidad micro-nivel de la innovación, que favorezcan estudios analíticos para la investigación y las políticas de innovación en la Unión Europea. El impacto del nivel de innovación en los resultados empresariales también será analizado en el trabajo, estableciendo la relación entre la innovación y determinados resultados económicos de las empresas. Para alcanzar estos objetivos se ha elaborado un modelo explicativo bietapico, representado en la figura 1, a partir de la Community Innovation Survey –CIS– que coordina Eurostat en la U.E. En su primera etapa, el modelo propuesto explica el nivel de innovación en productos a partir de tres categorías básicas de variables explicativas de los apartados 1,5, 6,7 y 11 de dicha encuesta (ver Anexo). En la segunda etapa, el modelo describe el impacto de la innovación sobre la amplitud del mercado y el porcentaje de ventas por nuevos productos de las empresas, utilizando variables de los apartados 1 y 2 de la encuesta. El modelo ha demostrado su significatividad y capacidad explicativa global a nivel comunitario, por países y sectores productivos, facilitando en todos los casos los rasgos más relevantes de las empresas innovadoras. Estos resultados serán analizados para extraer información relevante para la toma de decisiones sobre la innovación por parte de los responsables políticos y los directivos de empresas europeas. Los factores internos relacionados con las actividades para la innovación, las fuentes internas de la innovación, la cooperación dentro del grupo empresarial y la orientación estratégica frente a la innovación aparecen reunidos en el modelo bajo una categoría común denominada “Empresa”, en virtud del rasgo compartido de impulsar la innovación desde el interior de las organizaciones que poseen estas variables explicativas. Por otra parte, los factores externos de la innovación quedan agrupados en dos categorías del modelo propuesto. La primera es el “Mercado”, formada por canales externos asociados al desempeño empresarial, como son la cooperación y la información obtenida de competidores y agentes de la cadena de valor. La segunda de ellas es el “Soporte Institucional”, que reúne factores explicativos institucionales referidos a las fuentes de innovación y cooperación con el sistema de ciencia, los intermediarios del conocimiento y las administraciones públicas, incluyendo la financiación publica en concepto de incentivos a la innovación en las empresas. Estructurar los factores internos y externos del comportamiento innovador de las empresas en categorías conceptuales es una práctica que persigue aumentar la coherencia del análisis de datos y la interpretación de los resultados en la investigación empírica de la innovación, y así aparece en una abundante la literatura (e.g. Ar y Baki, 2011; Gamero, 2014; Martinez-Roman, Gamero y Tamayo, 2011; Radas y Bozic, 2009; Varis y Littunen, 2010; Yam, Lo, Tang y Lau, 2011). En nuestro caso, la categorización se ha realizado respetando la estructura original de la encuesta utilizada y la definicion de las variables contenidas en los diferentes apartados de la misma. En el caso de la variable a explicar en esta primera etapa, el nivel de innovación en productos, se ha elaborado un constructo para medir el grado de novedad de los productos introducidos en los mercados por las empresas. El resultado de la primera etapa será una colección de modelos explicativos del nivel de innovación en productos de las empresas a nivel global, por sectores y por países en un conjunto de estados miembros de la U.E. a partir de las encuestas comunitarias de innovación CIS IV, CIS 2006 y CIS 2008. La segunda etapa analizara el impacto del nivel de innovación en productos sobre el porcentaje de ventas por nuevos productos y la expansión comercial, con el fin de dar una respuesta parcial al modo en el que la intensidad innovadora puede añadir valor económico y ganar competitividad a las empresas que innovan. Esta importante cuestión señalada por la literatura (Crossan y Apaydin, 2010) ha sido abordada en diversos trabajos en los que se relaciona los resultados innovadores con la rentabilidad (Ar y Barki, 2011; Martínez - Román, Tamayo, Gamero y Romero, 2015), la extensión del mercado (Deshpande, Farley y Webster, 1993; Gamero, 2014) y las ventas, cuotas de mercado e internacionalización (Romjin y Albaladejo, 2002; Yan, Lo, Tang y Lau, 2011), entre otros resultados. Los resultados obtenidos en este trabajo de investigación señalan la mayor importancia de las variables explicativas que se refieren a factores que impulsan la innovación desde el interior de las organizaciones empresariales, de la categoría denominada empresa, frente a las correspondientes a los bloques mercado y soporte institucional. Asimismo, los modelos obtenidos de las encuestas comunitarias de innovación CIS IV, CIS 2006 y CIS 2008 muestran la fuerte variación experimentada por algunas variables a lo largo del tiempo, unas debidas probablemente a las primeras manifestaciones de la ralentización económica anterior a la crisis (aumento de la posición en los modelos de la variable financiación publica X7, caída del posicionamiento de la variable X13 consultores como fuente de información y de la variable X20 cooperación con consultores), otras debidas a la globalización de la economía (menor importancia en la explicación del nivel de innovación de las variables X2 pertenencia a grupo empresarial y X3 localización de la sede central del grupo) y otras a un cambio de comportamiento en las organizaciones empresariales (mejora del posicionamiento de la variable X18 cooperación con clientes). Al construir los modelos explicativos del nivel de innovación para países y sectores, se observan diferencias notables que permiten agrupar a las variables explicativas según su comportamiento en los diferentes modelos por sectores y países. Así como agrupar estos según el parecido o grado de similitud entre sus modelos. Por otro lado, al analizar el impacto del nivel de innovación en resultados empresariales, se manifiesta la importancia positiva de la misma tanto en la extensión geográfica del mercado donde la empresa ejerce su actividad, como en el porcentaje de ventas por nuevos productos, quedando patente la disminución de incertidumbre en la consecución de los resultados cuando se alcanzan los mayores niveles de innovación. En relación al perfil de las empresas innovadoras, destacar la gran diferencia entre las características de las empresas que innovan y las que no lo hacen, así como de su relación con el entorno. Finalmente, los factores o variables discriminatorios entre las empresas innovadoras y no innovadoras conciernen por un lado a las orientaciones estratégicas de las empresas y a las actividades realizadas por las mismas, es decir, se corresponden con acciones impulsadas desde el interior de las organizaciones empresariales, y por otro lado con la adquisición de información, ya sea a partir de las relaciones internas en la empresa, de sus relaciones con agentes de la cadena de valor o de canales externos al desarrollo empresarial, o desde el soporte institucional a partir de intermediarios de conocimiento. En este apartado se expone brevemente el contenido de los diferentes capítulos en los cuales se ha estructurado esta investigación sobre la innovación. El capitulo 1 corresponde a la introducción y en el se desarrolla la justificación teórica del trabajo, los objetivos perseguidos en el mismo, un breve resumen de resultados, la metodología general aplicada y la estructura del trabajo. Seguidamente, el capítulo 2 recoge el marco teórico en el cual se encuadra la investigación. Se presenta una breve introducción, para analizar inmediatamente el concepto de innovación y su naturaleza, así como diferentes teorías sobre la innovación. En el marco del enfoque interactivo se encuadran el modelo teórico general y el especifico adaptado a la encuesta comunitaria de innovación que se utilizara en el desarrollo empírico del trabajo. El capítulo 3 se dedica a la base de datos y a las variables. En el se incluye información sobre las encuestas comunitarias de innovación de las cuales se extraen los datos que se usan en el desarrollo empírico del trabajo. Se definen en base a las encuestas las 25 variables explicativas del modelo, que se contrastara empíricamente, así como las tres variables a explicar: nivel de innovación, extensión del mercado, porcentaje de ventas por nuevos productos. Y se señalan las operaciones que han sido necesarias para obtener la base de datos. Se clasifican dichas variables en base a las tres categorías de variables explicativas utilizadas en el modelo teórico. En el capítulo 4 se presenta la metodología especifica, ya que la metodología general está recogida en el capítulo 1. En primer lugar, se presenta la metodología aplicada en la construcción de los diferentes modelos representativos del nivel de innovación. Seguidamente se expone el procedimiento utilizado en la modelización del impacto de la innovación en resultados empresariales, para finalizar con la metodología utilizada para distinguir los factores explicativos que posibilitan la discriminación entre empresas innovadoras y no innovadoras. El capítulo 5 esta dedicado al análisis marginal de las variables, para conocer las formas distribucionales de las mismas y sus anomalías si existiesen. Se calculan la asimetría y curtosis como medidas de forma unidimensional y las correlaciones lineales bidimensionales en el marco del análisis marginal bidimensional, todo ello para los datos de las diferentes encuestas comunitarias de innovación CIS 2008, CIS 2006 y CIS IV. En el capítulo 6 se aborda la construcción y validación, dentro de la primera etapa del modelo conceptual bietapico, de los diferentes modelos explicativos del nivel de innovación de las empresas, para las diferentes encuestas manejadas en la base de datos, los diferentes modelos sectoriales y por países para los que la muestra CIS 2008 es representativa. En el también se procede a la comparación de los modelos globales, los modelos sectoriales y los modelos por países, identificando las variables con comportamientos similares y diferentes para los distintos sectores y países. Se construye un mapa por países para los datos de la encuesta CIS 2008, en el cual se presentan las agrupaciones obtenidas cuando se valoran las similitudes entre sus modelos explicativos. El capítulo 7 se dedica a la construcción y validación dentro de la segunda etapa del modelo conceptual bietapico del modelo explicativo del impacto del nivel de innovación sobre resultados económicos empresariales. Concretamente se modeliza la extensión geográfica del mercado de las empresas en función de sus niveles de innovación y el porcentaje de ventas por nuevos productos en función igualmente del nivel de innovación para la encuesta CIS 2008. El capítulo 8 se analiza a la caracterización del perfil de la empresa innovadora. Para ello se han considerado los 25 factores explicativos utilizados a lo largo de la investigación estableciendo su capacidad discriminadora respecto al carácter innovador o no de las empresas. Estos factores explicativos discriminantes determinan el perfil de las empresas innovadoras. Por último, en el capítulo 9 se recogen las principales conclusiones que pueden obtenerse de los resultados del estudio empírico, desglosándolas a partir de los diferentes análisis desarrollados a lo largo del trabajo.

Lost circulation in the oil industry is a recurrent and costly challenge, especially in mature fields or weak fracture-gradient zones. Incidents can result in partial to total losses in a variety of formations, including highly permeable, fractured, or cavernous types. In most cases, the first treatment options include using gel or mud pills with lost circulation materials (LCMs). However, this and other solutions currently in the market might not fix severe or total losses. This paper presents a low-solids lost circulation solution that develops rapid gel strength when the shear rate decreases. The gel strength buildup is based on polymers and nanomaterials in the fluid system. In situations where the vein or cavernous zones are large, traditional solutions tend to be ineffective. In such cases, a shear-dependent fluid system can be used that develops gel strength as it enters the larger-flow-area lost circulation zone. This helps prevent the fluid from continuously flowing into the zone. Once the gel strength has developed, the system develops nominal compressive strength to adhere to the formation, helping prevent displacement during subsequent well operations. A mature production field in Santa Cruz, Bolivia presented significant challenges during drilling operations. The low fracture gradient and pressurized gas formation created a narrow operational window, increasing the probability of lost circulation because of the mud density required to avoid fluid influx during drilling. In this scenario, LCMs would not stop fluid losses and were limited to pumping through the bottomhole assembly (BHA). The low-solids lost circulation solution was pumped through the drill bit. Having low solids and low rheology under shear, it can be easily pumped through the drill bit without having to pull out of the hole (POOH). The losses were stopped by using this low-solids shear-dependent (LSSD) fluid system. Subsequently, the primary cementing was performed successfully, and effective zonal isolation was achieved. This helped eliminate non-productive time (NPT) in gas wells in Bolivia. This paper presents a successful methodology, lessons learned, and engineering design to cure lost circulation during drilling operations by pumping a novel LSSD solution through the drill bit. The fluid system contains a low amount of solids; hence, it can be pumped through the drill bit, and the fluid characteristics are such that it will plug trouble zones effectively.