Disentangling the last 1,000 years of human-environment interactions along the eastern side of the southern Andes (34-52°S lat.).

Researchers have long debated the degree to which Native American land use altered landscapes in the Americas prior to European colonization. Human-environment interactions in southern South America are inferred from new pollen and charcoal data from Laguna El Sosneado and their comparison with high-resolution paleoenvironmental records and archaeological/ethnohistorical information at other sites along the eastern Andes of southern Argentina and Chile (34-52°S). The records indicate that humans, by altering ignition frequency and the availability of fuels, variously muted or amplified the effects of climate on fire regimes. For example, fire activity at the northern and southern sites was low at times when the climate and vegetation were suitable for burning but lacked an ignition source. Conversely, abundant fires set by humans and infrequent lightning ignitions occurred during periods when warm, dry climate conditions coincided with ample vegetation (i.e., fuel) at midlatitude sites. Prior to European arrival, changes in Native American demography and land use influenced vegetation and fire regimes locally, but human influences were not widely evident until the 16th century, with the introduction of nonnative species (e.g., horses), and then in the late 19th century, as Euro-Americans targeted specific resources to support local and national economies. The complex interactions between past climate variability, human activities, and ecosystem dynamics at the local scale are overlooked by approaches that infer levels of land use simply from population size or that rely on regionally composited data to detect drivers of past environmental change.

The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.

Income or educational attainment: which is more effective in the fight against overweight? Evidence from Spain and Andalusia.

Considered the epidemic of the 21st century by the WHO, obesity is a global problem that is on the rise and will continue to increase in the coming years. Spain and Andalusia, in particular, are no exception to this pathology, which has tripled since the 1970s, representing a public health challenge. The aim of this study is to analyse the socioeconomic determinants of this pathology, with special emphasis on answering the question of what has a greater influence on overweight, education level, or income. For this purpose, we have used the European Survey of Health in Spain (ESHS-2020), a microdata base, with a total of 22,072 valid individual observations (of which 2,820 belong to the Andalusian population). Results we obtain in our estimations of qualitative response models reveal that, although both income and educational attainment could be effective in the fight against overweight, the social gradient of this health problem is greater with respect to educational attainment. Additionally, there are many other variables and other factors related to the individual's overweight (mental health, subjective state of health, oral health, among others) which are much less explored and which must be considered in health policies to combat this disease.

Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes.

BACKGROUND & AIMS: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. METHODS: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. RESULTS: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. CONCLUSIONS: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.

Parallel diversification of the African tree toad genus Nectophryne (Bufonidae).

African amphibian diversity remains underestimated with many cryptic lineages awaiting formal description. An important hotspot of amphibian diversification is the Guineo-Congolian rainforest in Central Africa, its richness attributable to present day and ancestral range fragmentation through geological barriers, habitat expansion and contraction, and the presence of steep ecological gradients. The charismatic Nectophryne tree toads present an interesting case study for diversification in this region. The two formally described species comprising this genus show nearly identical geographic distributions extending across most of the Guineo-Congolian rainforest, but show little morphological disparity. Both species harbour extensive genetic diversity warranting taxonomic revisions, and interestingly, when comparing the subclades within each, the two species show remarkably parallel diversification histories, both in terms of timing of phylogenetic splits and their geographic distributions. This indicates that common processes may have shaped the evolutionary history of these lineages.

[Etiology and antimicrobial resistance profile of urinary tract infection in children, Valdivia 2012]. / Etiología y perfil de resistencia antimicrobiana en infección del tracto urinario en niños, Valdivia 2012.

INTRODUCTION: Since initial antibiotic treatment in patients with urinary tract infection (UTI) is empiric, is very important to know the local epidemiology to make the correct therapeutical decisions. OBJECTIVE: Determinate local features of antimicrobial resistance in pediatric patients with UTI. METHOD: Retrospective review of urine culture tests of children under 15 years old, obtained in a pediatric emergency department in Valdivia, between february and december 2012. RESULTS: Escherichia coli showed high percentage of resistance to ampicillin (44,8%) and first generation cephalosporin (36%). DISCUSSION: A well understanding of local antimicrobial resistance profile is useful to a correct empiric treatment.

Amidation of arabinoglucuronoxylans to modulate their flow behavior.

Arabinoglucuronoxylans obtained from the exudate of Cercidium praecox (Brea gum) were subjected to an amidation reaction to modulate their flow behavior to obtain a product with similar behavior to gum Arabic. The amidation reaction of the uronic acids present in this exudate was studied using the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS) system with the aim of maximizing product yield and minimizing by-product. An analysis of the significant factors involved in the reaction was carried out and a response surface methodology was conducted to optimize the stoichiometry of the reagents used. It was possible to obtain models for predicting the degree of amidation (DA) of arabinoglucuronoxylans and the formation of by-products. The formation of a secondary product derived from the amino acid ß-alanine which has not been reported previously in the reaction with polysaccharides, was described. The flow behavior of an amidated product (DA = 52 %) was determined, showing a pseudoplastic behavior and a decreased Newtonian viscosity (η0 = 36.2 Pa s) at the lowest shear rate range with respect to native product solution (η0 = 115 Pa s). Amidated arabinoglucuronoxylans had a flow behavior more similar to that of gum Arabic.

Structure and rheology of the polysaccharides from Schizymenia dubyi: Isolation of an unusual glucurono-carrageenan.

The system of polysaccharides from Schizymenia dubyi (Nemastomatales) was investigated. It contains a mixture of hybrid dl galactans (SH-S) and carrageenan-like polysaccharides, which were separated by means of precipitation with KCl at high concentrations. The structural features of the carrageenan-like fraction (SH-I) were investigated by methylation analysis, desulfation, uronic acid reduction, and NMR spectroscopy. It was concluded that the structure has the typical alternance α-(1 â†’ 3), ß-(1 â†’ 4) of d-galactose units, with most of the 3-linked units sulfated in O-2 (and some in O-4), and most of the 4-linked units sulfated in O-3, and substituted in O-2 by single stubs of ß-d-glucuronic acid (partly sulfated in each of the three available positions). This substituent has been only seldom found in red seaweed galactans. Rheological studies of 5 % and 10 % w/v SH, SH-S and SH-I aqueous systems, either without ions, or in KCl or CaCl2 solution gave thickening behaviors. Their random coil conformations justify the pseudoplastic behavior observed in the viscosity versus shear rate curves. As SH-S and SH-I are both contained in SH, an interpenetrating network could form in SH between the glucurono-carrageenan and the agaran, as inferred from the mechanical spectra recorded in water, especially with potassium ion.

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

BACKGROUND: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. METHODS: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. RESULTS: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. CONCLUSIONS: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Image Patch-Matching With Graph-Based Learning in Street Scenes.

Matching landmark patches from a real-time image captured by an on-vehicle camera with landmark patches in an image database plays an important role in various computer perception tasks for autonomous driving. Current methods focus on local matching for regions of interest and do not take into account spatial neighborhood relationships among the image patches, which typically correspond to objects in the environment. In this paper, we construct a spatial graph with the graph vertices corresponding to patches and edges capturing the spatial neighborhood information. We propose a joint feature and metric learning model with graph-based learning. We provide a theoretical basis for the graph-based loss by showing that the information distance between the distributions conditioned on matched and unmatched pairs is maximized under our framework. We evaluate our model using several street-scene datasets and demonstrate that our approach achieves state-of-the-art matching results.

Social Isolation, Healthy Habits, Inequality and Mental Health in the United States.

The objective of this work is to deepen the analysis of the socioeconomic determinants of mental health, paying special attention to the impact of inequality, not only in income distribution but also in gender, racial, health and education inequality, social isolation, including new variables to measure loneliness, and healthy habits, on the mental health status. For this purpose, a cross-sectional model for a sample of 2735 counties in the United States is estimated using Ordinary Least Squares in its robust version to solve the detected heteroscedasticity problems. The results obtained show that inequality, social isolation and certain lifestyles, such as smoking or insomnia, are detrimental to mental health, while sexual activity prevents mental distress. On the other hand, poor counties suffer more cases of suicide, with food insecurity being the main problem for mental health. Finally, we found detrimental effects of pollution on mental health.

Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR).

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis due to its late diagnosis and strong chemoresistance to the current treatments. Therefore, finding new therapeutic targets is an urgent need nowadays. In this study, we report the role of the chromatin remodeler BPTF (Bromodomain PHD Finger Transcription Factor) as a therapeutic target in PDA. BPTF-silencing dramatically reduced cell proliferation and migration in vitro and in vivo in human and mouse PDA cell lines. Moreover, BPTF-silencing reduces the IC50 of gemcitabine in vitro and enhanced its therapeutic effect in vivo. Mechanistically, BPTF is required for c-MYC recruitment to the promoter of ABC-transporters and its downregulation facilitates gemcitabine accumulation in tumour cells, increases DNA damage, and a generates a strong synergistic effect in vivo. We show that BPTF is a therapeutic target in pancreatic ductal adenocarcinoma due to its strong effect on proliferation and in response to gemcitabine.

Addition of hydrochloric acid to collection bags or collection containers did not change basal endogenous losses or ileal digestibility of amino acid in corn, soybean meal, or wheat middlings fed to growing pigs.

OBJECTIVE: The hypothesis was that apparent ileal digestibility (AID), basal endogenous losses, and standardized ileal digestibility (SID) of amino acids (AA) are not affected by adding acid to collection containers or bags used to collect ileal digesta from pigs. METHODS: Twenty-four growing barrows (initial body weight: 77.8±4.5 kg) that were fitted with a T-cannula in the distal ileum were fed diets for three 7-d periods. An N-free diet and 3 diets containing corn, soybean meal, or wheat middlings as the sole source of AA were used. Within each period, each of the 4 diets were fed to 6 pigs. Among the 6 pigs, digesta from 3 pigs were collected in bags containing no HCl, whereas 40 mL of 3 N HCl was included in the bags used to collect digesta from the remaining 3 pigs. Every other bag collected from each pig was emptied into a container without adding HCl, whereas the remaining bags were added to a container along with 40 mL of 3 N HCl for each bag. All digesta were stored at -20°C immediately after collection. Data were analyzed using a model that included feed ingredient, HCl in bags, HCl in containers, and all 2-way and 3-way interactions as fixed effects. No 3-way interactions were significant, and data were, therefore, reanalyzed independently for each diet as a 2×2 factorial. RESULTS: There were no interactions between adding HCl to collection bags and to containers, and no effects of adding HCl to collection bags or containers for AID, basal endogenous losses, or SID of most AA were observed. CONCLUSION: It is not necessary to add acid to digesta collection bags or collection containers if ileal digesta are stored at -20°C immediately after collection.

Perennial halophyte Salicornia neei Lag.: Cell wall composition and functional properties of its biopolymers.

Salicornia neei halophyte extends in Argentina seashores. To envisage potential applications, cell wall sequential extraction performed on dry plant yielded 1.1, 2.4, 0.3 and 0.9% of pectin fractions respectively extracted by room temperature water, 90 °C-water, CDTA and Na2CO3. They contained 21-33% uronic acids (UA) with low degree of methylation and 0.5-1.2 M ratios of neutral sugars to UA. High arabinose level suggests that long arabinan side-chains maintain cell wall flexibility in water deficit. Fractions also contained 10-36% of proteins. The KOH-soluble fractions (4.3%) were mainly arabinoxylans. At 2.0% w/v, pectin fractions developed "weak gel"-type networks with Ca2+, while arabinoxylans generated "dilute solutions". Cellulose (28%) and lignin (45.1%) were the main biopolymers in the final residue, which showed low water swelling capacity (3.6 mL/g) due to lignin, increasing when arabinoxylans were also present. Phenolics (9.8%) were mainly water-extractable. Salicornia is a source of biopolymers and antioxidants potentially useful for food applications.

Techno-functional properties of HoPS from lactic acid bacteria of different origins as potential food additives.

Homopolysaccharides (HoPS) produced by lactic acid bacteria (LAB) are highly versatile, biocompatible and safe compounds. In this work, six HoPS from different species of Weisella and Leuconostoc were identified as thermally stable dextrans, with endothermic crystalline deformations between 214 and 239 °C. These dextrans proved to have greater solubility and capacities to retain water and oil than similar polymers in other reports. Furthermore, a surface morphology study presented cubic grumps, stratify mesh with irregular grumps, and highly compact filaments. Assays in vitro revealed moderate antioxidant, browning and foaming activities as well as technological properties, such as anti-syneresis, emulsifying and flocculating activities, even at low concentrations. Taking into account bipolymers' microstructure, functionalities and performance in both, aqueous and hydrophobic matrixes, plus their capacity to maintain themselves at elevated temperatures, we consider these HoPS beneficial and natural food additives.

The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes beta-catenin/TCF-mediated transcription.

Tumours of the Ewing family, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumours, are highly aggressive and mostly affect children and adolescents. They are characterized by chromosomal translocations leading to the generation of fusion proteins between EWS (or very rarely FUS) and members of the E-twenty-six (ETS) family of transcription factors that are capable of transforming cells. EWS/FLI1, the most frequent fusion, is thought to cause transformation through activation or repression of specific target genes. We present evidence demonstrating that the Wnt inhibitor and beta-catenin/T-cell factor (TCF)-responsive gene DICKKOPF-1 (DKK-1) is a transcriptional target of EWS/FLI1, which can inhibit both basal and beta-catenin-induced transactivation of the DKK-1 promoter. Moreover, our data indicate that EWS/FLI1 has a more general effect on beta-catenin/TCF-mediated transcription since it can block transactivation of a consensus beta-catenin/TCF reporter construct. Consistently, Ewing tumour cells expressing different EWS/ETS translocations cannot engage beta-catenin/TCF-dependent transcription, whereas silencing of EWS/FLI1 restores beta-catenin responsiveness in A673 and RD-ES Ewing tumour cells. Accordingly, gene set enrichment analysis shows that beta-catenin/TCF target genes are significantly enriched among genes downregulated by EWS/FLI1 in the Ewing cell line A673. Mechanistically, the inhibitory effect of EWS/FLI1 can be overcome by a constitutively active TCF4 protein (TCF4-VP16). Moreover, EWS/FLI1 binds lymphoid enhancer factor 1, a TCF family member, and interferes with its binding to beta-catenin, which could explain its negative effect on beta-catenin/TCF-mediated transcription. Our results show that EWS/FLI1 inhibits both DKK-1 expression as well as beta-catenin/TCF-dependent transcription, which could contribute to progression of tumours of the Ewing family.

Rheology of partially and totally oxidized red seaweed galactans.

Agarose and κ-carrageenan were oxidized using (2,2,6,6-tetramethylpiperidinyl)oxy (TEMPO) in the presence of NaOCl and NaBr. Products with several degrees of oxidation were structurally characterized. The mechanical spectra were determined: derivatives with a medium to high degree of oxidation give rise to polysaccharides that behave like dilute solutions in water, whereas those with a degree of oxidation close to 20 % keep the gelling properties with a different thermo-rheological response towards pH (6.5 or 4.0) and counterions (K+ or Ca2+) in comparison with the native polysaccharides. For instance, they showed a marked dependence on the presence of calcium ions, observed in the increase of thermal stability and dynamic elastic component (G') value, due to the known interaction of this divalent cation with the carboxylate groups. In this sense, these derivatives with low oxidation degrees have proven to be not only thermosensitive, like the native polysaccharide, but also pH- and calcium-sensitive.

Chemical structure and rheological studies of arabinoglucuronoxylans from the Cercidium praecox exudate brea gum.

The structure of the arabinoglucuronoxylans from brea gum was elucidated through an chemical and NMR spectroscopical analysis. They are composed of xylose, arabinose, glucuronic acid and 4-O-methylglucuronic acid in a molar ratio 1:0.44:0.16:0.22. The structure consists of a central chain of (1→4)-ß-d-xylopyranose of which ca.70% are susbstituted in C2 with single stubs of others sugars (ß-d-Xylp, α-d-GlcpA and 4-O-Me-α-d-GlcpA), with disaccharides (α-l-Arap-(1→2)-4-O-Me-α-d-GlcpA-(1→, α-l-Arap-(1→2)-α-d-GlcpA-(1→, ß-l-Araf-(1→3)-α-l-Araf-(1→ and α-l-Araf-(1→3)-α-l-Araf-(1→5), and possibly with trisaccharides of xylose. The determination of the location of the acetyl groups and their quantification in these arabinoglucuronoxylans has been achieved for the first time. Brea gum presents a higher thickening effect than gum arabic in 5% aqueous solution, demonstrating its potential usefulness for food and pharmaceutical applications.

ISG15 and ISGylation is required for pancreatic cancer stem cell mitophagy and metabolic plasticity.

Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.

Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells.

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7-9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.